KR20220133243A - Method of treating cancer using anti-TIGIT antagonist antibody - Google Patents

Abstract

The present invention provides methods, uses and compositions for the treatment of cancer (e.g., lung cancer; cervical cancer; breast cancer; head and neck cancer; liver cancer; stomach cancer; bladder cancer; esophageal cancer; pancreatic cancer; kidney cancer; melanoma; ovarian cancer; or colorectal cancer). it's about More specifically, the present invention relates to the treatment of patients with cancer with anti-TIGIT antagonist antibodies, including treatment with anti-TIGIT antagonist antibodies in combination therapy.

Description

Method of treating cancer using anti-TIGIT antagonist antibody

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed on January 27, 2020 in U.S. Patent Application Serial Nos. 62/966,448; US Patent Application No. 62/985,822, filed March 5, 2020; US Patent Application No. 62/994,272, filed March 24, 2020; International Application No. PCT/US2020/024526, filed March 24, 2020; U.S. Patent Application Serial No. 63/059,054, filed July 30, 2020; U.S. Patent Nos. 63/059,960, filed July 31, 2020; U.S. Patent Nos. 63/074,807, filed September 4, 2020; U.S. Patent Nos. 63/074,827, filed September 4, 2020; International Application No. PCT/US2020/049415 filed on September 4, 2020; U.S. Patent Application Serial No. 63/085,890, filed September 30, 2020; U.S. Patent Application Serial No. 63/105,198, filed October 23, 2020; U.S. Patent Application Serial No. 63/114,517, filed on November 16, 2020; U.S. Patent Application Serial No. 63/124,693, filed December 11, 2020; and U.S. Patent Application No. 63/127,109, filed on December 17, 2020, the contents of each of which are incorporated herein by reference in their entirety.

sequence list

This application contains a sequence listing submitted electronically in ASCII format, the contents of which are incorporated herein by reference in their entirety. The file name of this ASCII copy, created on January 25, 2021, is 50474-206WO2_Sequence_Listing_1_25_2021_ST25 and is 30,641 bytes in size.

The present invention relates to methods, uses, and compositions for the treatment of cancer. More specifically, the present invention relates to treatment of a patient with cancer with an anti-TIGIT antagonist antibody (eg, treatment with an anti-TIGIT antagonist antibody as monotherapy or combination therapy).

Cancer is characterized by the uncontrolled growth of subpopulations of cells. Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed each year and over 8 million cancer deaths. Therefore, cancer treatment has become a significant and continuously increasing social burden.

Accordingly, there is an unmet need in the field of development of effective immunotherapy for cancer treatment and methods of administering the same.

In one aspect, the present invention provides a method of treating a subject having cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, the PD-1 axis at a dose of about 900 mg to about 1500 mg every 3 weeks. A method is provided, comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.

In another aspect, the invention provides a method of treating a subject having cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and PD-1 axis binding at a dose of about 1400 mg to 2000 mg every 4 weeks A method is provided comprising administering to the subject a dosing regimen comprising one or more dosing cycles of the antagonist.

In another aspect, the present invention provides a method of treating a subject having cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and the PD-1 axis at a dose of about 600 mg to about 1200 mg every two weeks. A method is provided comprising administering to the subject a dosing regimen comprising one or more dosing cycles of the binding antagonist.

In another aspect, the invention provides a kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to the methods provided herein.

In another aspect, the invention provides an anti TIGIT antagonist antibody and an anti-PD-1 axis binding antagonist for use in a method of treating a subject having cancer, said method comprising an anti-TIGIT antagonist antibody and anti-PD-1 according to a method provided herein. Axial binding antagonists are provided.

In another aspect, the invention provides the use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having cancer, wherein said treatment is according to a method provided herein. .

In another aspect, the invention provides a method of treating a subject having cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and PD-1 axis binding at a dose of about 1400 mg to 2000 mg every 4 weeks A method is provided comprising administering to the subject a dosing regimen comprising one or more dosing cycles of the antagonist.

In another aspect, the present invention provides a method of treating a subject having cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and the PD-1 axis at a dose of about 600 mg to about 1200 mg every two weeks. A method is provided comprising administering to the subject a dosing regimen comprising one or more dosing cycles of the binding antagonist.

In another aspect, the present invention provides a method of treating a subject having cancer, comprising an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis at a dose of about 900 mg to about 1500 mg every 3 weeks. A method is provided, comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.

In another aspect, the present invention provides a method of treating a subject having cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and anti-PD-1 at a dose of about 100 mg to about 300 mg every 3 weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of the antagonist antibody, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

In another aspect, the invention provides a method of treating a subject having cancer comprising administering to the subject a dosing regimen comprising at least one dosing cycle of tiragolumab and pembrolizumab, wherein said pembrolizumab is administered at a dose of about 300 mg to about 500 mg every 6 weeks.

In another aspect, the invention provides a method of treating a subject having cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, the PD-1 axis at a dose of about 900 mg to about 1500 mg every 3 weeks a dosing regimen comprising one or more dosing cycles of the combination antagonist, and an antimetabolite at a dose of about 10 mg/m ² to about 10000 mg/m ² orally twice daily every 3 weeks of a 2 week dosing/1 week washout. A method is provided, comprising administering to the subject.

In another aspect, the present invention provides a method of treating a subject having cancer, comprising an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis at a dose of about 900 mg to about 1500 mg every 3 weeks. Provided is a method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a binding antagonist, gemcitabine, and nap-paclitaxel.

In another aspect, the present invention provides a method of treating a subject having cancer, comprising an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis at a dose of about 900 mg to about 1500 mg every 3 weeks. A method is provided, comprising administering to the subject a dosing regimen comprising a binding antagonist and one or more dosing cycles of a VEGF antagonist at a dose of about 1 mg/kg to about 35 mg/kg every three weeks.

In another aspect, the invention provides a method of treating a subject having cancer, comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein: (a) the induction phase is from about 500 mg to about every 3 weeks Anti-TIGIT antagonist antibody at a dose of about 700 mg, PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, platinum-based chemotherapeutic agent every 3 weeks, and non-platinum-based chemotherapeutic agent once every 3 weeks comprising more than one dosing cycle; and (b) said maintenance phase comprises one or more additional dosing cycles of said anti-TIGIT antagonist antibody every 3 weeks, said PD-1 axis binding antagonist every 3 weeks, and said non-platinum-based chemotherapeutic agent every 3 weeks, wherein said The maintenance phase does not include administration of the platinum-based chemotherapeutic agent.

In another aspect, the invention provides a method of treating a subject having cancer, comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein: (a) the induction phase is from about 500 mg to about every 3 weeks Anti-TIGIT antagonist antibody at a dose of about 700 mg, PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, platinum-based chemotherapeutic agent every 3 weeks, and non-platinum-based chemotherapeutic agent once every 3 weeks comprising more than one dosing cycle; and (b) the maintenance phase comprises one or more additional dosing cycles of the anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and the PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks. and wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent.

In another aspect, the invention provides a method of treating a subject or population of subjects having lung cancer, comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a single dose of a topoisomerase II inhibitor. administering to the subject or population of subjects a dosing regimen comprising at least one dosing cycle, wherein the treatment is a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II in the absence of the anti-TIGIT antagonist antibody. A method of prolonging progression-free survival (PFS) in the subject as compared to treatment with an inhibitor is provided.

In another aspect, the invention provides a method of treating a population of subjects having lung cancer, comprising one or more administrations of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. A method is provided, comprising administering to the subject population a dosing regimen comprising a cycle, wherein the treatment results in a median PFS in the subject population of from about 8.2 months to about 9.2 months.

In another aspect, the invention provides a method of treating a subject or population of subjects having lung cancer, comprising an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a single dose of a topoisomerase II inhibitor. administering to the subject or population of subjects a dosing regimen comprising at least one dosing cycle, wherein the treatment is a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II in the absence of the anti-TIGIT antagonist antibody. A method of prolonging OS in the subject as compared to treatment with an inhibitor is provided.

In another aspect, the invention provides a method of treating a population of subjects having lung cancer, comprising one or more administrations of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. A method is provided, comprising administering to the subject population a dosing regimen comprising a cycle, wherein the treatment results in a median OS of the subject population of from about 15.3 months to about 17.6 months.

In another aspect, the present invention provides a method of treating a subject or population of subjects having SCLC, comprising: on Day 1 of each dosing cycle an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg, on Day 1 of each dosing cycle Atezolizumab at a dose of about 900 mg to about 1500 mg, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and Day 1, 2 of each dosing cycle administering to the subject or population of subjects one or more 21-day dosing cycles of etoposide at a dose of 100 mg/m ² on each of days, and 3 days, wherein said treatment is without said anti-TIGIT antagonist antibody. Provided is a method of prolonging PFS and/or OS of a subject or population of subjects as compared to treatment with atezolizumab, carboplatin, and etoposide.

In another aspect, the invention provides a method of treating a subject or population of subjects having ES-SCLC, comprising administering to said subject or population of subjects four initial dosing cycles followed by one or more additional dosing cycles, wherein : (a) said four initial dosing cycles are tiragolumab at a dose of about 600 mg on Day 1 of each initial dosing cycle, atezolizumab at a dose of about 1200 mg on Day 1 of each initial dosing cycle, each initial dose Carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of the cycle, and a 100 mg/m ² dose on each of Days 1, 2, and 3 of each initial dosing cycle. administering etoposide of and (b) said one or more additional dosing cycles comprises about 600 mg of tiragolumab on day 1 of each additional dosing cycle and about 1200 mg of atezolizumab on day 1 of each additional dosing cycle. administering, wherein said four initial dosing cycles and said one or more additional dosing cycles are each 21-day dosing cycle, wherein said treatment is atezolizumab, carboplatin, and eto without said tiragolumab Provided is a method of prolonging PFS and/or OS of said subject or population of subjects as compared to treatment with Forside.

In another aspect, the invention provides a method of treating a subject or population of subjects having cancer, comprising an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent, and a second agent that is a non-platinum-based chemotherapeutic agent 2 is provided a method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of a chemotherapeutic agent.

In another aspect, the invention provides a method of treating a subject or population of subjects with advanced nonsquamous NSCLC comprising four 21 day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed. administering to the subject or population of subjects a dosing regimen comprising The carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min every 3 weeks, or the cisplatin is administered at a dose of 75 mg/m ² every 3 weeks, and the pemetrexed is administered in 4 doses of 21 and administered at a dose of about 500 mg/m ² every 3 weeks on each day of the dosing cycle.

In another aspect, the invention provides a method of treating a subject or population of subjects having advanced nonsquamous NSCLC, wherein said subject or population of subjects: (i) tyragolumab at a dose of about 600 mg every 3 weeks, about 1200 every 3 weeks 4 induction phase dosing cycles for atezolizumab at a mg dose, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and pemetrexed at a dose of about 500 mg/m ² every 3 weeks ; and (ii) one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m 2 every 3 weeks. wherein said at least one 21-day dosing cycle of said maintenance phase does not comprise administration of said carboplatin, wherein said subject or population of subjects has received prior systemic therapy for advanced nonsquamous NSCLC. Never before, provide a way.

In another aspect, the invention provides a method of treating a subject with resectable lung cancer, comprising an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and PD- at a dose of about 900 mg to about 1500 mg every 3 weeks. A method is provided comprising administering to the subject one or more dosing cycles of a uniaxial binding antagonist.

In another aspect, the invention provides a method of treating a subject having lung cancer, comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein during said dosing cycles administering as neoadjuvant treatment a dose of about 500 mg to about 700 mg of an anti-TIGIT antagonist antibody at least once every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks , provides a method.

In another aspect, the present invention provides a method of treating a subject with resectable lung cancer, comprising: tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and (a) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or (ii) cisplatin at a dose of about 75 mg/m ² every 3 weeks; and (b) (i) pemetrexed at a dose of about 500 mg/m ² every 3 weeks or gemcitabine at a dose of about 1000 mg/m ² or about 1250 mg/m ² on days 1 and 8 of each dosing cycle. ; or (ii) administering to the subject one or more dosing cycles of paclitaxel at a dose of about 175 mg/m ² or about 200 mg/m ² every 3 weeks.

In another aspect, the present invention provides a method of treating a subject having lung cancer, comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein (I) at least one of said dosing cycles One time is neoadjuvant treatment and the subject is given (a) tyragolumab at a dose of about 1200 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m ² on days 1 and 8 of each dosing cycle. ; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m ² or about 200 mg/m ² every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m ² every 3 weeks and gemcitabine at a dose of 1250 mg/m ² on days 1 and 8 of each dosing cycle; and (II) at least once in said dosing cycle administering to said subject as adjuvant treatment a dose of about 500 mg to about 700 mg of tiragolumab every 3 weeks and a dose of about 900 mg to about 1500 mg of atezolizumab every 3 weeks A method is provided, comprising the step of administering.

In another aspect, the invention provides a method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1, the method comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method is provided, comprising the steps of:

In another aspect, the present invention provides a method for selecting a therapy for a subject having cervical cancer, comprising (a) PD on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining. - detecting the protein expression level of L1; and (b) an anti-TIGIT antagonist antibody administered at a dose of about 500 mg to about 700 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1; selecting a regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist administered at a dose of about 900 mg to about 1500 mg every three weeks.

In another aspect, the invention provides a method of treating a subject having cervical cancer having a detectable expression level of PD-L1, wherein the tiragolumab at a dose of about 600 mg every 3 weeks and atezoli at a dose of about 1200 mg every 3 weeks Provided is a method comprising administering to the subject one or more dosing cycles of zumab.

In another aspect, the invention provides a method of treating a subject or population of subjects having breast cancer, comprising tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and dosing for 3 weeks/1 A method is provided, comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of nap-paclitaxel at a dose of about 100 mg/m ² of a weekly break.

In another aspect, the present invention provides a method of treating a subject with early stage triple negative breast cancer (eTNBC) comprising an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and about 600 mg to about 1200 mg every two weeks. A method is provided comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a dose of a PD-1 axis binding antagonist.

In another aspect, the invention provides a method of treating a subject with eTNBC, comprising: tiragolumab at a dose of about 420 mg every two weeks, atezolizumab at a dose of about 840 mg every two weeks, and: (a) (i) dosing Nap-paclitaxel at a dose of about 125 mg/m ² every week for the first 12 weeks of therapy and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and (ii) doxorubicin at a dose of about 60 mg/m ² every 2 weeks, cyclophosphamide at a dose of about 600 mg/m ² every 2 weeks, and G-CSF every 2 weeks for weeks 13 to 19 of the dosing regimen. or GM-CSF; or (b) (i) nap-paclitaxel at a dose of about 125 mg/m ² weekly for the first 12 weeks of said dosing regimen; and (ii) doxorubicin at a dose of about 60 mg/m 2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m ² every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF; wherein the method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

In another aspect, the present invention provides a method of treating a subject or population of subjects having SCCHN having a detectable protein expression level of PD-L1, the method comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method is provided, comprising the steps of:

In another aspect, the invention provides a method of selecting a therapy for a subject or population of subjects having SCCHN: (a) PD in a tumor sample from said subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining. - detecting the protein expression level of L1; and (b) a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks based on PD-L1 expression detected for said subject or population of subjects having a detectable expression level of PD-L1; A method is provided, comprising selecting a regimen comprising at least one dosing cycle of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg per week.

In another aspect, the present invention provides a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. administering to the subject one or more dosing cycles of

In another aspect, the invention provides a method of treating a subject or population of subjects having hepatocellular carcinoma (HCC) comprising administering to said subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist. wherein the subject or population of subjects has not received prior systemic therapy for HCC.

In another aspect, the invention provides a method of treating a subject or population of subjects having HCC, comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist. A method is provided, comprising the steps of:

In another aspect, the invention provides a method of treating a subject or population of subjects having HCC, comprising a dose of about 600 mg tiragolumab every 3 weeks, a dose of about 1200 mg atezolizumab every 3 weeks, and about 15 every 3 weeks Provided is a method comprising administering to the subject one or more dosing cycles of bevacizumab at a dose of mg/kg.

In another aspect, the present invention provides a method of treating a subject or population of subjects with MIBC, comprising an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and PD at a dose of about 900 mg to about 1500 mg every 3 weeks. - administering to the subject one or more dosing cycles of a -1 axis binding antagonist, wherein the subject is ineligible for treatment with a platinum-based chemotherapeutic agent.

In another aspect, the present invention provides a method of treating a subject or population of subjects with MIBC, comprising an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and PD at a dose of about 900 mg to about 1500 mg every 3 weeks. - administering to the subject one or more dosing cycles of the -1 axis binding antagonist, wherein the treatment is perioperative treatment.

In another aspect, the invention provides a method of treating a subject or population of subjects with MIBC comprising one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. administering to the subject or population of subjects, wherein the subject or subjects are cisplatin ineligible.

In another aspect, the invention provides a method of treating a subject or population of subjects with MIBC comprising one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. administering to the subject or population of subjects, wherein the treatment is perioperative treatment.

In another aspect, the present invention provides a method of treating a subject or population of subjects having mUC, wherein the anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and PD at a dose of about 900 mg to about 1500 mg every 3 weeks - administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of the -1 axis binding antagonist.

In another aspect, the invention provides a method of treating a subject or population of subjects having mUC, comprising one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. and administering to the subject or population of subjects.

In another aspect, the invention provides a method of treating a subject or population of subjects having mUC, comprising administering to said subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein: (a) said the first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; and (b) said second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks, and (i) enfortumab vedotin is administered weekly of 2 weeks on / 1 week off. is administered at a dose of 1.25 mg/kg, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg of 2 weeks of dosing/weekly off, wherein the second dosing regimen is administered to the subject or population of subjects and to the subject or population of subjects after experiencing disease progression or unacceptable toxicity during said first dosing regimen.

In another aspect, the present invention provides a method of treating a subject or population of subjects having pancreatic cancer, comprising: tyragolumab at a dose of about 420 mg on days 1 and 15 of each 28-day dosing cycle; Atezolizumab at a dose of about 840 mg on days 1 and 15, gemcitabine at a dose of about 1000 mg/m ² on days 1, 8, and 15 of each 28-day dosing cycle, and each 28 days. administering to the subject or population of subjects a dosing regimen comprising one or more 28-day dosing cycles of nap-paclitaxel at a dose of about 125 mg/m ² on days 1, 8, and 15 of the dosing cycle , provides a method.

In another aspect, the present invention provides a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, wherein on Day 1 of each dosing cycle, an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg and an agent of each dosing cycle. A method is provided comprising administering to the subject or population of subjects a dosing regimen comprising at least one 21 day dosing cycle of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg per day.

In another aspect, the present invention provides a method of treating a subject or population of subjects having esophageal cancer, wherein the anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on Day 1 of each dosing cycle and on Day 1 of each dosing cycle. administering to the subject or population of subjects a dosing regimen comprising at least one 21-day dosing cycle of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg, wherein the subject or subjects are subjected to platinum-based chemistry; previously treated with a therapeutic agent and a non-platinum-based chemotherapeutic agent are provided.

In another aspect, the invention provides a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising: tyragolumab at a dose of about 600 mg on Day 1 of each dosing cycle, about 1200 on Day 1 of each dosing cycle Atezolizumab in mg dose, cisplatin at a dose of about 80 mg/m ² on day 1 of each dosing cycle, and 5 at a dose of about 800 mg/m ² /24 hours on days 1-5 of each 21-day cycle -administering to said subject or population of subjects a dosing regimen comprising at least one 21 day dosing cycle of fluorouracil, wherein cisplatin is omitted from said dosing regimen after six doses.

In another aspect, the present invention provides a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosage regimen and a second dosage regimen, wherein: (a ) said first dosing regimen is cisplatin at a dose of about 80 mg/m ² on day 1 of each dosing cycle and 5-fluoro at a dose of 800 mg/m ² /24 hours on days 1 to 5 of each 21 day cycle. one or more 21-day dosing cycles of lauracil, wherein cisplatin is omitted from said dosing regimen after 6 doses; and (b) said second dosing regimen is one or more 21 day doses of about 600 mg of tiragolumab on Day 1 of each dosing cycle and about 1200 mg of atezolizumab on Day 1 of each dosing cycle. include cycle.

In another aspect, the invention provides a kit comprising a PD-1 axis binding antagonist and/or anti TIGIT antagonist antibody for treating a subject having cancer according to the methods provided herein.

In another aspect, the invention provides a kit comprising a PD-1 axis binding antagonist for use in combination with an anti TIGIT antagonist antibody to treat a subject having cancer according to the methods provided herein.

In another aspect, the invention provides a kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to the methods provided herein.

In another aspect, the present invention provides an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having cancer, said method comprising an anti TIGIT antagonist antibody and an anti-TIGIT antagonist antibody according to the methods provided herein. PD-1 axis binding antagonists are provided.

In another aspect, the invention provides the use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject or population of subjects having cancer, wherein the treatment is according to a method provided herein. provides

1 is a flow chart depicting Phase Ib Chemotherapy Expansion and Phase Ib Q4W Dosing Expansion.
2 is a flow chart of the phase Ib experimental design. EOCG = Eastern Cooperative Oncology Group; IHC = immunohistochemistry; PD-L1+ = programmed death-ligand 1 positive; Q4W = every 4 weeks; RECIST v1.1 = Response Criteria in Solid Tumors, version 1.1; TFI = treatment-free interval; TNBC = triple-negative breast cancer.
3 is a flow chart of the Phase Ia study design. CRC = colorectal cancer, DLT = dose limiting toxicity, GC = gastric cancer, HNSCC = head and neck squamous cell carcinoma, IV = intravenous, MAD = maximum dose administered, MSI = microsatellite instability, MSS = microsatellite instability, MTD = maximum tolerated dose , NSCLC = non-small cell lung cancer, OC = ovarian cancer, PD = disease progression, PK = pharmacokinetics, RCC = renal cell carcinoma, TNBC = triple negative breast cancer, UBC = urothelial bladder cancer.
4 is a flowchart of the study design of the Phase Ib Tiragolumab and Atezolizumab Expansion Cohort, Serial Biopsy Cohort, and Q4W Dosing Expansion Cohort. CIT = cancer immunotherapy; DLT = dose limiting toxicity; HNSCC = head and neck squamous cell carcinoma, IV = intravenous, MAD = maximal dose, MSI = microsatellite instability, MSS = microsatellite stable, MTD = maximally tolerated dose, NSCLC = non-small cell lung cancer, PD = disease progression; PD 1 = programmed cell death-1; PD-L1 = programmed apoptosis ligand 1; PK = pharmacokinetics, TIGIT = cellular immunoreceptors with Ig and ITIM domains. Remarks: Limited to patients with PD-L1 selection and/or TIGIT selection tumors. ^a Advanced, refractory, refractory tumor. Tiragolumab IV and atezolizumab 1200 mg IV every 3 weeks. Enroll only after IMC review of phase Ia safety data. 3+3 dose escalation with a DLT duration of 21 days. Other intermediate doses of tiragolumab may be studied if the MTD is not exceeded. To obtain additional safety, PK and PD data, patients may be re-enrolled if they consent to an optional continuous biopsy. Evaluation of dose levels above 1200 mg tyragolumab will require protocol modifications with supporting evidence. ^b Expansion may start at a capacity below the MTD or MAD. ^c Up to about half of the patients will consent to an optional serial biopsy. Patients with tumors (e.g., NSCLC melanoma, renal cell carcinoma) for which an anti-PD-L1/PD-1 agent has been approved by local regulatory authorities are permitted to conduct clinical trials with an investigational agent in combination with anti-PD-L1. Enrollment in an expansion cohort (indication expansion or serial biopsy) is only possible if it is considered a viable treatment option. ^d Limited to patients who have consented to an optional serial biopsy (acceptable samples include core needle, excision, incision, punch, and/or forceps biopsies). ^e In the Q4W Dosing Expansion Cohort, a safety search for approximately 3 patients will be completed. All relevant safety data from the safety search must be thoroughly reviewed by the IMC and investigators before registration continues.
5 is a flow diagram of a phase Ib chemotherapy expansion cohort study design.
6 is a flow chart of a phase Ib non-chemotherapy expansion cohort study design.
7 is a flow chart illustrating conditions for continuing study treatment beyond progression. EOCG = Eastern Cooperative Oncology Group; RECIST = Response Criteria in Solid Tumors,
8 is a flow chart illustrating the transition from phase Ia to phase Ib. AE = adverse event, DLT = dose limiting toxicity, PD = disease progression.
9 is a graph depicting the pharmacokinetics of tiragolumab.
10 is a series of graphs depicting the pharmacokinetics of tiragolumab.
11 is a graph depicting all adverse events ≥ 10% in a phase la tiragolumab dose escalation study. * Grade 5 AE was progression of malignant neoplasm (n=3) and was not related to tiragolumab.
12 is a graph depicting all adverse events ≥ 10% in a phase Ib tiragolumab and atezolizumab dose escalation study. * Grade 5 AEs were malignant neoplasia progression (n=12) and pulmonary embolism (n=2) and were not related to study drug(s).
13 is a graph depicting tumor size reduction in a phase Ia tyragolumab dose escalation study.
14 is a graph depicting tumor size reduction in a phase Ib tiragolumab and atezolizumab dose escalation study.
15 is a graph depicting CIT-naive PD-L1 positive NSCLC tumor size reduction in a phase Ib tiragolumab and atezolizumab dose escalation study.
16 is a graph depicting CIT-naive PD-L1 positive NSCLC tumor size reduction over time in a phase Ib tiragolumab and atezolizumab dose escalation study.
17 is a flowchart of a three-phase experimental design. 1L = primary; CE = carboplatin and etoposide; ECOG PS = Eastern Corporate Oncology Group Systemic Activity; ES-SCLC = diastolic small cell lung cancer; LDH = lactase dehydrogenase; RECIST = response criteria for solid tumors; ITT = intent to treat; PP = primary population.
18 is a schematic of a study design depicting parameters regarding subject selection, stratification criteria, randomization of treatment groups, and treatment endpoints.
19 is a schematic diagram of the study design of the GO42501 Phase II clinical study. Resectable stage II, IIIA or selection IIIB (T3N2) non-small cell lung cancer (NSCLC) without an activating EGFR mutation (EGFR-), without an ALK fusion oncogene (ALK-), and with ECOG systemic activity of 0 or 1 selected ) patient. Cohort A consists of patients with high PD-L1. Patients in Cohort A are treated with atezolizumab (Atezo) and tiragolumab (Tira) every 3 weeks (Q3W) for 4 cycles. Cohort B consists of patients with any PD-L1 status. Patients in Cohort B are treated with Artezo, Tyra and Platinum-based dual chemotherapy (Chemo) Q3W for 4 cycles. After cycles 2 and 4, computed tomography (CT) of the chest is performed. Two cohorts of patients undergo surgery and evaluate for major pathological response (MPR) and pathological complete response (pCR). After surgery, patients in Cohort A are treated with Artezo and Tyra Q3W for 16 cycles or Chemical Q3W for 4 cycles. Patients in Cohort B are treated with Artezo and Tyra Q3W for 16 cycles. Postoperative radiation therapy (PORT) is optional for R1/R2 ablation and/or ypN2 prior to adjuvant administration. Conduct survival follow-up.
20 is a flowchart illustrating patient enrollment in the GO42501 Phase II clinical trial. For Cohort A (patients with high PD-L1; PD-L1 Tumor Rate Score (TPS) ≥ 50%), a safety introduction is performed using 6 patients. If surgical safety criteria are not met, discontinue enrollment in Cohort A. If surgical safety criteria are met, continue enrollment in Cohort A. For Cohort B (patients with any PD-L1 status), a safety introduction is performed utilizing 6 patients with PD-L1 TPS <50%. If surgical safety criteria are not met, discontinue enrollment in Cohort B. If surgical safety criteria are met, continue enrollment in Cohort B, enrolling patients with a PD-L1 TPS of <50% and a PD-L1 TPS of >50%. Eight patients with tumors expressing PD-L1 > 50% will be enrolled in Cohort B, then continue with Cohort A enrollment of patients with PD-L1 TPS > 50%.
21 is a flow chart of the Phase II experimental design. 1L = primary; CDx = companion diagnosis; ECOG PS = Eastern Corporate Oncology Group Systemic Activity; IHC = immunohistochemistry; IRC = independent review committee; PD-L1 = programmed cell death ligand 1; Q3W = every 3 weeks; R = randomized; s/p = state after; IV = intravenous.
22 is a flow chart of the phase Ib experimental design. TNBC = triple negative breast cancer; G-CSF = granulocyte colony stimulating factor; GM-CSF = granulocyte-macrophage colony stimulating factor; Rand. = randomized, pCR = pathological complete response, QW = once weekly, Q2W = every 2 weeks, Q3W = every 3 weeks.
23 is a flowchart of the phase 2b experimental design. HPV = human papillomavirus; IHC = immunohistochemistry; IV = intravenous; Q3W = every 3 weeks; PD-L1 low = TIC 10%-49%; PD-L1 High = TIC ≥ 50%; SCCHN = squamous cell carcinoma of the head and neck; RECIST = Solid Tumor Response Criteria.
24 is a schematic diagram depicting the design of the muscle invasive bladder cancer (MIBC) cohort of the WO39613 Phase Ib/II clinical trial. At the screening stage, MIBC patients who are cisplatin ineligible and either PD-L1 positive (+) (top) or PD-L1 negative (-) (bottom) are identified. After randomization (R), patients are treated with either atezolizumab (Atezo; control) or atezolizumab and tiragolumab (Tira).
25 is a schematic diagram depicting the design of the metastatic urothelial carcinoma (mUC) cohort of WO39613 Phase Ib/II clinical trial. In the screening phase, patients with secondary locally advanced or metastatic UC who have progressed on or after platinum-containing therapy and who are not cancer immunotherapy (CIT) are identified. After randomization (R), patients were treated with atezolizumab (atezo; control); atezolizumab and enfortumab vedotin (EV); atezolizumab and niraparib (Nira); atezolizumab and Hu5F9-G4; atezolizumab and tiragolumab (Tira); atezolizumab and sacituzumab gobitecan (SG); atezolizumab and tocilizumab (TCZ); atezolizumab and RO7122290 (FAP-4-1BBL); or RO7121661 (PD1/TIM-3) during Phase 1. ^a During Phase 1, a patient who experiences loss of clinical benefit or unacceptable toxicity as determined by the investigator may be eligible to receive a different treatment combination during Phase 2 if the eligibility criteria are met. ^b There are 40 patients in the Artezonia group. ^c Patients who received enfortumab vedotin in step 1 did not receive enfortumab vedotin in step 2, and patients who received sacituzumab gobitecan in step 1 were treated with sacituzumab gobitecan in step 2 without being administered; Other patients eligible for more than one treatment group will be assigned treatment groups by the investigator. Once the Artezo SG group is open, the registration of the Artezo EV group is closed. ^d Artezo RO7122290 (FAP-4-1BBL) military is open outside the United States only.
26 is a low or high PD-L1 TPS, or CE-IVD VENTANA SP263 IHC assay (high TC > 50%) as assessed by the PalmDx 22C3 IHC assay (high TPS ≥ 50%; low TPS 1-49%). ; objective response rate (ORR) (complete response/partial response (CR/PR)) in patients from the CITYSCAPE trial with low or high PD-L1 tumor content (TC) as assessed as low TC 1-49%). Stable disease/progressive disease (SD/PD); or non-evaluative (NE)).
FIG. 27A is a bar graph depicting response rates (95% confidence intervals (CI)) for patients in the CITYSCAPE trial with a TPS greater than or equal to 1% as measured using the 22C3 IHC assay.
27B shows response rates (95% CI) for patients in the CITYSCAPE trial with TPS ≥1% (and TPS ≥1% as measured using the 22C3 IHC Assay) as determined using the SP263 IHC assay. It is a bar graph showing.
FIG. 28A shows progression-free survival (percentage) for patients in the CITYSCAPE trial treated with tiragolumab and atezolizumab (Tira + atezo) or placebo + atezo and had a TPS of 1% or greater as measured using the 22C3 IHC assay. ) is a graph showing The inset table shows the median PFS of month (month) and hazard ratio (HR).
FIG. 28B shows a TPS greater than or equal to 1% (and as measured using the 22C3 IHC assay) treated with tiragolumab and atezolizumab (Tira + atezo) or placebo + atezo and as measured using the SP263 IHC assay. A graph depicting progression-free survival (percent) for patients in the CITYSCAPE trial with a TPS equal to or greater than 1%). The inset table shows the median PFS (months) and HR.
29A is a bar graph depicting response rates (95% confidence intervals (CI)) for patients in the CITYSCAPE trial with a TPS of 50% or greater as measured using the 22C3 IHC assay.
29B is a bar graph depicting response rates (95% CI) for patients in the CITYSCAPE trial with a TC greater than or equal to 50% as determined using the SP263 IHC assay.
30A shows progression-free survival (percentage) for patients in the CITYSCAPE trial treated with tiragolumab and atezolizumab (Tira + atezo) or placebo + atezo and had a TPS greater than or equal to 50% as measured using the 22C3 IHC assay. ) is a graph showing The inset table shows the median PFS (months) and HR.
30B shows progression-free survival (percentage) for patients in the CITYSCAPE trial treated with tiragolumab and atezolizumab (Tira + atezo) or placebo + atezo and had a TC greater than or equal to 50% as measured using the SP263 IHC assay. ) is a graph showing The inset table shows the median PFS (months) and HR.

The present invention relates to cancers (eg, lung cancer (eg, early stage lung cancer (eg, resectable lung cancer)), SCLC (eg ES-SCLC), NSCLC (eg, squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, stage IIIB) NSCLC, relapsed or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., the subject has not been previously treated for stage IV NSCLC) if absent); )) or HER2 positive breast cancer); head and neck cancer (eg, SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); liver cancer (eg, HCC, such as locally advanced or metastatic HCC and/or unresectable HCC); bladder cancer (such as , MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; ovarian cancer; stomach cancer (eg, gastroesophageal junction cancer); or CRC ( (e.g., MSS or low MSI CRC)).The present invention provides an anti-TIGIT antibody (e.g., anti-TIGIT antibody) in combination with a PD-1 axis binding antagonist, a VEGF antagonist, and/or a chemotherapeutic agent. It is based at least in part on the discovery that immunotherapy comprising TIGIT antagonist antibody (such as tiragolumab) can be useful for cancer treatment.Composition, use, and kit comprising the combination and/or dosing regimen are also described herein. is provided

I. general technique

The techniques and procedures described or referenced herein will be generally well understood and commonly used by those skilled in the art using conventional methods, such as, for example, the widely used methods described below: Sambrook et al. , Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FM Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual , and Animal Cell Culture (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology , Humana Press; Cell Biology: A Laboratory Notebook (JE Cellis, ed., 1998) Academic Press; Animal Cell Culture (RI Freshney), ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JB Griffiths, and DG Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller and MP Calos, eds., 1987); PCR: The Polymerase Chain Reaction , (Mullis et al., eds., 1994); Current Protocols in Immunology (JE Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JB Lippincott Company, 1993).

II. I. Definition

Aspects and embodiments of the invention described herein are to be understood to include aspects and embodiments “comprising”, “consisting of” and “consisting essentially of”. As used herein, the singular forms “a” and “the” include plural references unless otherwise indicated.

As used herein, the term “about” refers to a common error range for an individual value readily known to one of ordinary skill in the art. Reference to “about” to a value or parameter herein includes (and describes) aspects relating to that value or parameter per se. For example, a description referring to “about X” includes a description of “X”.

In general, the terms “level of expression” or “expression level” are used interchangeably and generally refer to the amount of a biomarker in a biological sample. "Expression" generally refers to the process by which information (eg, gene-encoded and/or epigenetic information) is converted into structures present and functioning in a cell. Thus, as used herein, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide, or even modification of a polynucleotide and/or a polypeptide (eg, post-translational modification of a polypeptide). Fragments of transcribed polynucleotides, translated polypeptides or polynucleotides and/or polypeptide modifications (eg, post-translational modifications of a polypeptide) are also derived from transcripts in which they are produced by alternative splicing or digested transcripts. expression according to whether or not it is derived from post-translational processing of the polypeptide, for example by proteolysis. "Expressed genes" include genes that are transcribed into polynucleotides such as mRNA and then translated into polypeptides, and also genes that are transcribed into RNA but not translated into polypeptides (eg, transfer and ribosomal RNA). “Amount” and “level” (eg, expression level) of a biomarker are known to those of skill in the art and can also be determined by the methods disclosed herein. The amount or level of a biomarker with respect to an increased clinical benefit to an individual may be, for example, a detectable level in a biological sample. In some aspects, the expression level or amount of a biomarker is dependent on a specific therapy (eg, a therapy comprising one or more dosing cycles comprising a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody or one or more dosing cycles of an anti-TIGIT antagonist antibody. to identify/characterize a subject having cancer who may be likely to respond to, or benefit from, a therapy comprising

"Increased expression", "increased expression level", "increased level", "elevated expression", "elevated expression level" or "elevated level" refers to a control, such as a disease or disorder (eg, cancer). refers to increased expression or increased level of a biomarker in an individual or individuals not suffering from or compared to an internal control (eg, a housekeeping biomarker).

"Decreased expression", "reduced expression level", "reduced level", "decreased expression", "decreased expression level" or "decreased level" refers to a control, such as a disease or disorder (eg, cancer). Refers to reduced expression or reduced level of a biomarker in an individual compared to an individual or individuals not suffering from or an internal control (eg, a housekeeping biomarker). In some aspects, reduced expression is little or no expression.

The presence and/or expression level/amount of the various biomarkers described herein in a sample can be analyzed by a number of methodologies, including immunohistochemistry (“IHC”), Western blot analysis, immunoprecipitation, molecular binding assay, ELISA, ELIFA, Fluorescence Activated Cell Sorting (“FACS”), MassARRAY, Proteomics, Quantitative Blood Based Assays (eg, Serum ELISA), Biochemical Enzyme Activity Assay, In Situ Hybridization, Fluorescence In Situ Hybridization (FISH), Southern Assay, Northern Assay , whole genome sequencing, massively parallel DNA sequencing (e.g., next-generation sequencing), NANOSTRING ^® , polymerase chain reaction (PCR) including quantitative real-time PCR (qRT-PCR), and other amplification types detection methods , such as for example branched DNA, SISBA, TMA, etc., RNA-seq, microarray analysis, gene expression profiling and/or serial analysis of gene expression (“SAGE”) as well as protein, gene and/or tissue array analysis Many of these are known in the art and understood by one of ordinary skill in the art, including but not limited to any one of the wide variety of assays that can be performed by General protocols for assessing the status of genes and gene products are, for example, Ausubel et al., eds., 1995, Current Protocols In Molecular Biology , Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting). and 18 (PCR Analysis). Multiple immunoassays such as those available from Rules Based Medicine or Meso Scale Discovery (“MSD”) may also be used.

By “correlate” or “correlating” is meant comparing in any way the performance and/or results of a first analysis or protocol with the performance and/or results of a second analysis or protocol. For example, the results of a first analysis or protocol may be used when conducting a second protocol, and/or the results of a first analysis or protocol may be used to determine whether a second analysis or protocol should be performed. have. With respect to aspects of a polypeptide assay or protocol, the results of a polypeptide expression assay or protocol can be used to determine whether a particular treatment regimen should be administered. With respect to aspects of a polynucleotide assay or protocol, the results of a polynucleotide expression assay or protocol may be used to determine whether a particular treatment regimen should be administered.

As used herein, the phrase "substantially reduced" or "substantially different" means that there is a sufficiently high degree of between two numerical values (generally one associated with a molecule and the other associated with a reference/comparator molecule). Indicative of a difference, one of ordinary skill in the art would consider a difference between these two values to be statistically significant in the context of the biological property measured by said value (eg, K _D value). The difference between the two values is, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and/or greater than about 50% as a function of the value for the reference/comparison molecule.

As used herein, the term "substantially similar" or "substantially identical" refers to a sufficiently high degree between two numerical values (eg, one associated with an antibody of the invention and the other associated with a reference/comparison antibody). Because of the _similarity of The difference between the two values is, for example, less than about 50%, less than about 40%, less than about 30%, less than about 20%, and/or less than about 10% as a function of the reference/comparison value.

As used herein, the phrase “based on” means that information regarding one or more biomarkers is used to inform treatment decisions, information provided on a package insert, or marketing/promotional guidelines, etc.

As used herein, the term “TIGIT” or “T cell immunoreceptor having Ig and ITIM domains” refers to any, unless otherwise indicated, including mammals such as primates (eg, humans) and rodents (eg, mice and rats). refers to any native TIGIT of vertebrate origin. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V set and immunoglobulin domain containing protein 9, V set and transmembrane domain containing protein 3, VSIG9, VSTM3, and WUCAM. This term is "full-length", untreated TIGIT (eg, full-length human TIGIT having the amino acid sequence of SEQ ID NO: 30) and any form of TIGIT resulting from intracellular processing (eg, a signal having the amino acid sequence of SEQ ID NO: 31) Processed human TIGIT without sequence).This term also includes naturally occurring variant of TIGIT, such as splice variant or allelic variant.The amino acid sequence of exemplary human TIGIT is UniProt accession number Q495A1 can be found in

The terms “programmed cell death 1” and “PD-L1” refer herein to native sequence human PD-L1 polypeptides. The native sequence PD-L1 polypeptide is provided under Uniprot Accession No. Q9NZQ7 (SEQ ID NO: 32). For example, the native sequence PD-L1 may have the amino acid sequence set forth in Uniprot Accession No. Q9NZQ7-1 (isoform 1). In another example, the native sequence PD-L1 may have the amino acid sequence set forth in Uniprot Accession No. Q9NZQ7-2 (isoform 2). In another example, the native sequence PD-L1 may have the amino acid sequence set forth in Uniprot Accession No. Q9NZQ7-3 (isoform 3). The term also includes naturally occurring variants of PD-L1, such as splice variants or allelic variants. PD-L1 is also referred to in the art as “programmed cell death 1 ligand 1,” “PDCD1LG1,” “CD274,” “B7-H,” and “PDL1”.

As used herein, the term “PD-1” or “programmed cell death ligand 1” refers to, unless otherwise indicated, of any vertebrate origin, including mammals such as primates (eg humans) and rodents (eg mice and rats). Refers to any unique PD-L1. PD-1 is also known in the art as CD279, PDCD1, and programmed cell death 1 . The term also encompasses naturally occurring variants of PD-1, such as splice variants or allelic variants. The amino acid sequence of exemplary human PD-1 can be found in Uniprot Accession No. Q15116.

As used herein, the term “PD-L2” or “apoptotic death 1 ligand 2” refers to, unless otherwise indicated, from any vertebrate source, including mammals such as primates (eg humans) and rodents (eg mice and rats). refers to any unique PD-L2 of PD-L2 is also known in the art as the CD273 molecule, B7DC and PDCD1L2. The term also encompasses naturally occurring variants of PD-L2, such as splice variants or allelic variants. The amino acid sequence of an exemplary human PD-L2 can be found in Uniprot Accession No. Q9BQ51.

The term “antagonist” is used in its broadest sense and includes any molecule that partially or fully blocks, inhibits or neutralizes the biological activity of a native polypeptide disclosed herein. Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments (eg, antigen binding fragments), fragments of native polypeptides or amino acid sequence variants, peptides, antisense oligonucleotides, small organic molecules, and the like. A method for identifying an antagonist of a polypeptide may comprise contacting the polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide.

The term "PD-1 axis binding antagonist" refers to an agent that inhibits the interaction of a PD-1 axis binding partner with one or more binding partners thereof in order to eliminate T cell dysfunction due to signaling in the PD-1 signaling axis. molecule, whereby T cell function (eg, proliferation, cytokine production, and/or target cell death) is restored or enhanced. PD-1 axis binding antagonists as used herein include PD-L1 binding antagonists, PD-1 binding antagonists and PD-L2 binding antagonists. In some cases, the PD-1 axis binding antagonist comprises a PD-L1 binding antagonist or a PD-1 binding antagonist. In one embodiment, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In another embodiment, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In another embodiment, the PD-1 axis binding antagonist is a PD-L2 binding antagonist.

The term "PD-1 binding antagonist" refers to reducing, blocking, inhibiting, abrogating or abrogating signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2. interfering molecules. Pd-1 (programmed death 1) is also referred to in the art as “programmed cell death 1”, “PDCD1”, “CD279”, and “SLEB2”. An exemplary human PD-1 is shown in Uniprot KB/Swiss-Prot Accession No. Q15116. In some cases, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more binding partners thereof. In certain embodiments, the PD-1 binding antagonist inhibits PD-1 from binding to PD-L1 and/or PD-L2. For example, a PD-1 binding antagonist reduces, blocks, inhibits, eliminates or interferes with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. 1 Including antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules. In one case, the PD-1 binding antagonist reduces the dysfunction of dysfunctional T cells by reducing negative costimulatory signals mediated by or through cell surface proteins expressed in T lymphocyte mediated signaling through PD-1. less (eg, enhance effector response to antigen recognition). In some cases, the PD-1 binding antagonist binds PD-1. In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody (eg, an anti-PD-1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies are nivolumab, pembrolizumab, MEDI-0680 (AMP 514), PDR001 (spartalizumab), REGN2810 (semipliumab), BGB-108, prolgolimab, camrelizumab , scintilimab, tislelizumab, torifalimab, dostalimab, retipanrimab, sasanrimab, fenfulimab, CS1003, HLX10, SCT-I10A, gimberelimab, valstilimab, genolimzumab, BI 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21. In certain embodiments, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab, formerly known as lambrolizumab). In another specific embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, such as AMP-224. In another specific embodiment, the PD-1 binding antagonist is MEDI-0680. In another specific embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another specific embodiment, the PD-1 binding antagonist is REGN2810 (semipliumab). In another specific embodiment, the PD-1 binding antagonist is BGB-108. In another specific embodiment, the PD-1 binding antagonist is prolgolimab. In another specific embodiment, the PD-1 binding antagonist is camrelizumab. In another specific embodiment, the PD-1 binding antagonist is scintilimab. In another specific embodiment, the PD-1 binding antagonist is tislelizumab. In another specific embodiment, the PD-1 binding antagonist is torifalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

The term “anti-PD-1 antagonist antibody” refers to an antibody, or antigen-binding fragment or variant thereof, capable of binding to PD-1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-1. For example, an anti-PD-1 antagonist antibody reduces, blocks, inhibits, abrogates, signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2. or interfering molecules. It will be understood by those of skill in the art that in some cases, an anti-PD-1 antagonist antibody may antagonize one PD-1 activity without affecting the other PD-1 activity. For example, an anti-PD-1 antagonist antibody for use in a particular method or use described herein can have its binding partner (eg, PD) with no or minimal effect on any of the other PD-1 interactions. It is an anti-PD-1 antagonist antibody that antagonizes PD-1 activity in response to either -L1 or PD-L2). In one aspect, the extent of binding of the antagonist antibody of anti-PD-1 to an unrelated non-PD-1 protein is about the same as that of the binding of the antibody to PD-1 as measured by radioimmunoassay (RIA). less than 10%. In certain aspects, the anti-PD-1 antagonist antibody that binds PD-1 is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 ^- It has a dissociation constant (K _D ) of ⁸ M or less, such as 10 ^-8 M to 10 ^-13 M, such as 10 ^-9 M to 10 ^-13 M). In certain embodiments, the anti-PD-1 antagonist antibody binds to an epitope of PD-1 that is conserved between PD-1 from different species or an epitope on PD-1 that allows cross-species reactivity. In one aspect, the anti-PD-1 antagonist antibody is pembrolizumab (previously known as lambrolizumab). In one embodiment, said anti-PD-1 antagonist antibody is nivolumab.

The term “PD-L1 binding antagonist” refers to reducing, blocking, inhibiting, abrogating or interfering with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1. refers to molecules that In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In certain embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and/or B7-1. In some cases, the PD-L1 binding antagonists decrease, block, inhibit, anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoconjugates, fusion proteins, oligopeptides and other molecules that abrogate or interfere. In one case, the PD-L1 binding antagonist reduces the dysfunction of dysfunctional T cells by reducing negative costimulatory signals mediated by or through cell surface proteins expressed in T lymphocyte mediated signaling through PD-L1. less (eg, enhance effector response to antigen recognition). In some cases, the PD-L1 binding antagonist binds PD-1. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody (eg, an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies are atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX- 072, IMC-001, KL-A167, APL-502, Cosibelimab, Rhodapoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and Hs-636. In some aspects, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one particular embodiment, the PD-L1 binding antagonist is MDX-1105. In another specific embodiment, said PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific embodiment, said PD-L1 binding antagonist is MSB0010718C (avelumab). In other aspects, the PD-L1 binding antagonist may be a small molecule, such as GS-4224, INCB086550, MAX-10181, INCB090244, CA-170 or ABSK041, which in some cases may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab marketed as TECENTRIQ™. Atezolizumab is prescribed in the WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4 (published January 16, 2015, see page 485). In another specific embodiment, the anti-PD-L1 antibody is MSB0015718C.

The term “anti-PD-L1 antagonist antibody” refers to an antibody, or antigen-binding fragment or variant thereof, capable of binding to PD-L1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-L1. For example, an anti-PD-L1 antagonist antibody reduces, blocks, inhibits, abrogates, signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1. or interfering molecules. It will be understood by those of skill in the art that in some cases, an anti-PD-L1 antagonist antibody may antagonize one PD-L1 activity without affecting the other PD-L1 activity. For example, an anti-PD-L1 antagonist antibody for use in a particular method or use described herein may have its binding partner (eg, PD) with minimal or no effect on any of the other PD-L1 interactions. It is an anti-PD-L1 antagonist antibody that antagonizes PD-L1 activity in response to either -1 or B7-1). In one aspect, the extent of binding of an antagonist antibody of anti-PD-L1 to an unrelated non-PD-L1 protein is about the extent of binding of the antibody to PD-L1 as measured, eg, by radioimmunoassay (RIA). less than 10%. In certain aspects, an anti-PD-L1 antagonist antibody that binds PD-1 is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 ^- It has a dissociation constant (K _D ) of ⁸ M or less, such as 10 ^-8 M to 10 ^-13 M, such as 10 ^-9 M to 10 ^-13 M). In certain aspects, the anti-PD-L1 antagonist antibody binds to an epitope of PD-L1 that is conserved between PD-L1 from different species or an epitope on PD-L1 that allows cross-species reactivity. In one embodiment, said anti-PD-L1 antagonist antibody is atezolizumab.

The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with one or more of its binding partners, such as PD-1. PD-L2 (predetermined death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2”. An exemplary human PD-L2 is shown in Uniprot KB/Swiss-Prot Accession No. Q9BQ51. In some cases, a PD-L2 binding antagonist is a molecule that inhibits binding of PD-L2 to one or more of its binding partners. In certain embodiments, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies that reduce, block, inhibit, abrogate or interfere with signal transduction caused by PD-L2 interacting with one or more of its binding partners, such as PD-1, anti-PD-L2 antibodies thereof, antigen binding fragments, immunoconjugates, fusion proteins, oligopeptides and other molecules. In one aspect, the PD-L2 binding antagonist reduces the negative costimulatory signal mediated by or through a cell surface protein expressed in T lymphocyte mediated signal transduction through PD-L2, thereby reducing the dysfunction of dysfunctional T cells. less (eg, enhance effector response to antigen recognition). In some aspects, the PD-L2 binding antagonist binds to PD-L2. In some aspects, the PD-L2 binding antagonist is an immunoconjugate.

Additional examples of PD-1 axis binding antagonists include semiplimab, prolgolimab, camrelizumab, scintilimab, tisrelizumab, torifalimab, dostalimab, retipanrimab, spatalizumab, sasanrimab, fen fulimab, CS1003, HLX10, SCT-I10A, SHR-1316, CS1001, envafoliumab, TQB2450, ZKAB001, LP-002, gimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL- 006, BAT1306, HX008, CX-072, IMC-001, KL-A167, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, APL-502, cosibelimab , rhodafoliumab, GS-4224, INCB086550, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, MAX-10181, RC98, BION-004, AM0001, CB201 , ENUM 244C8, ENUM 388D4, AUNP-012, STI-1110, ADG104, AK-103, LBL-006, hAb21, AVA-004, PDL-GEX, INCB090244, KD036, KY1003, LYN192, MT-6035, VXM10, YBL -007, ABSK041, GB7003, JS-003, and HS-636.

For the purposes herein, "Atezolizumab" is an Fc engineered, humanized, aglycosylated IgGl kappa immunoglobulin that binds to PD-L1 and comprises the heavy chain sequence of SEQ ID NO: 28 and the light chain sequence of SEQ ID NO: 29. Atezolizumab contains a single amino acid substitution (asparagine to alanine) at position 297 of the heavy chain (N297A) using EU numbering of Fc region amino acid residues, resulting in an aglycosylated antibody with minimal binding to the Fc receptor. make it Atezolizumab is also described in the WHO Drug Information (International Common Name for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4 (published January 16, 2015, see page 485).

As used herein, “pembrolizumab” is a recombinant humanized monoclonal IgG4 antibody directed against the human cell surface receptor PD-1. Pembrolizumab is listed in the WHO Drug Information (International Common Name for Pharmaceutical Substances), Proposed INN: List 72, Vol. 28, No. 3 (published in 2014, see page 407).

"Tiragolumab," as used herein, is a fully human IgG1/kappa Mab derived from Open Monoclonal Technology (OMT) rats that binds TIGIT, SEQ ID NO:

33 and the light chain sequence of SEQ ID NO: 34. Tiragolumab contains two N-linked glycosylation sites (N306) in the Fc domain. Tiragolumab is listed in the WHO Drug Information (International Common Name for Pharmaceutical Substances), Proposed INN: List 117, Vol. 31, No. 2 (published 7 July 2017, see page 343).

As used herein, "bevacizumab" is a recombinant humanized single antibody that recognizes all isoforms of VEGF, which is described in WHO Drug Information (International Common Name for Pharmaceutical Substances), Proposed INN: List 83, Vol. 14, No. 2 (published in 2000, see p. 107). Bevacizumab comprises a heavy chain variable region sequence of SEQ ID NO: X and a light chain variable region sequence of SEQ ID NO: X.

The term “anti-TIGIT antagonist antibody” refers to an antibody or antigen-binding fragment or variant thereof capable of binding TIGIT with sufficient affinity to substantially or completely inhibit the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody may signal through PVR, PVRL2, and/or PVRL3 to restore a functional response by T cells (eg, proliferation, cytokine production, target cell death) from a dysfunctional state to antigen stimulation. can be blocked. For example, an anti-TIGIT antagonist antibody can block signaling through the PVR without affecting the PVR-CD226 interaction. It will be appreciated by those of skill in the art that in some cases, an anti-TIGIT antagonist antibody may antagonize one TIGIT activity without affecting the other TIGIT activity. For example, an anti-TIGIT antagonist antibody for use in a particular method or use described herein may contain, for example, a PVR interaction, a PVRL3 interaction, or It is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of the PVRL2 interactions. In one aspect, the extent of binding of the antagonist antibody of anti-TIGIT to an unrelated non-TIGIT protein is less than about 10% of the binding of the antibody to TIGIT as measured, eg, by radioimmunoassay (RIA). In certain embodiments, an anti-TIGIT antagonist antibody that binds TIGIT is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (eg, 10 ⁻⁸ M or It has a dissociation constant (K _D ) of less than that, such as 10 ^-8 M to 10 ^-13 M, such as 10 ^-9 M to 10 ^-13 M). In certain embodiments, an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that is conserved between TIGITs from different species or an epitope on TIGIT that permits cross-species cross-reactivity. In some aspects, the anti-TIGIT binding antibody has a prototypical Fc mediated effector function (eg, tyragolumab, bivostolimab, etigilimab, EOS084448 or TJ-T6). In some aspects, the anti-TIGIT binding antibody has enhanced Fc-mediated effector function (eg, SGN-TGT). In other aspects, the anti-TIGIT antagonist antibody lacks Fc-mediated effector function (eg, dombanalimab, BMS-986207, ASP8374, or COM902). In some aspects, the anti-TIGIT binding antibody is an IgG1 class antibody (e.g., tiragolumab, bivostolimab, dombanalimab, BMS-986207, ethigilumab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448) ), TJ-T6, or AB308). In other embodiments, the anti-TIGIT binding antibody is an IgG class antibody (eg, ASP8374 or COM902). In one embodiment, said anti-TIGIT antagonist antibody is tyragolumab.

As used herein, “administering” refers to a compound (eg, an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antibody), a VEGF antagonist, or a chemotherapeutic agent (eg, a platinum-based chemotherapeutic agent) eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an alkylating agent (eg, cyclophosphamide)), a taxane (eg, paclitaxel such as nap-paclitaxel), and/or topoiso merase II inhibitors (eg, doxorubicin)) or compositions (eg, pharmaceutical compositions such as anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists (eg anti-PD-L1 antibodies), chemotherapeutic agents (eg, platinum-based) a chemotherapeutic agent (such as carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (such as an alkylating agent (such as cyclophosphamide), a taxane (such as paclitaxel such as nap-paclitaxel), and/or a topoisomerase II inhibitor (eg, doxorubicin), an antibody-drug conjugate (ADC) (eg, enfortumab vedotin or sacituzumab gobitecan), and/or a colony stimulating factor (CSF) ( For example, pegfilgrastim, filgrastim or sagramostim) refers to the method of providing to the subject a dose of a pharmaceutical composition).The compound and/or composition used in the method described herein can For example, intravenous (eg, by intravenous infusion), subcutaneous, intramuscular, intradermal, transdermal, intraarterial, intraperitoneal, intralesional, intracranial, intraarterial, intraprostatic, intrapleural, intratracheal, intranasal , intravitreal, vaginal, rectal, topically, intratumoral, intraperitoneal, subconjunctival, intravesical, intramucosal, intrapericardial, intraumbilical, intraocular, oral, topical, topical, by inhalation, by injection, infusion It can be administered by means of continuous infusion, by localized perfusion that directly bathes the target cells, by catheter, by irrigation, by cream, or by lipid composition.The method of administration depends on a variety of factors (such as the compound or composition being administered). and the severity of the condition, disease or disorder being treated).

Therapeutic agents (eg, anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists (eg, anti-PD-L1 antibodies), VEGF antagonists, chemotherapeutic agents (eg, platinum-based chemotherapeutic agents or non-platinum-based chemotherapeutic agents), ADCs (eg, , enfortumab vedotin or sacituzumab govitecan), or a “fixed” or “constant” dose of CSF (eg, pegfilgrastim, filgrastim, or sagramostim)) depends on the patient's weight or body surface area. (BSA) refers to the dose administered to the patient. Thus, a fixed or constant dose is not provided as a mg/kg dose or a mg/m ² dose, but rather as an absolute amount of therapeutic agent (eg, absolute amount of therapeutic agent in mg).

As used herein, the term “treatment” or “treating” refers to a clinical intervention designed to alter the natural course of the individual or cell being treated during the course of a clinical pathology. Desirable effects of treatment include delaying or reducing disease progression, ameliorating or ameliorating the disease state, and improving remission or prognosis. For example, reducing the proliferation (or destruction) of cancer cells, reducing symptoms caused by the disease, increasing the quality of life of a person with the disease, reducing the dose of other drugs needed to treat the disease, delaying the progression of the disease, and/or the individual A subject is successfully "treated" when one or more symptoms associated with the cancer, including, but not limited to, prolonging survival of the cancer are alleviated or eliminated. For example, treating may include an effective amount of a therapeutic agent (eg, an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a VEGF antagonist, a chemotherapeutic agent (eg, a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent), an ADC (eg, , enfortumab vedotin or sacituzumab govitecan), and/or CSF (eg, pegfilgrastim, filgrastim or sargramostim) or combinations of therapeutic agents. Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (eg, locally advanced cancer therapy), and metastatic cancer therapy. Treatment may be primary treatment (eg, the patient may not have previously received treatment, or may not have received prior systemic therapy), or secondary or subsequent treatment.

As used herein, “in combination with” or “with” refers to administration of one treatment modality in addition to another treatment modality, e.g., a PD-1 axis binding antagonist (e.g., atezolizumab), VEGF Antagonists, chemotherapeutic agents (eg, platinum-based chemotherapeutic agents or non-platinum-based chemotherapeutic agents), ADCs (eg, enfortumab vedotin or sacituzumab govitecan), and/or CSF (eg, pegfilgrastim) , filgrastim or sagramostim), and an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab). As such, "with "Conjointly" refers to administration of one treatment modality to a patient before, during, or after administration of the other treatment modality.

A drug administered “concurrently” with one or more other drugs is administered during the same treatment cycle, on the same treatment day as the one or more other drugs, and optionally, at the same time as the one or more other drugs. For example, in the case of cancer therapy given every three weeks, the concurrently administered drugs are each administered on Day 1 of a three-week cycle.

As used herein, the term “perioperative treatment” refers to treatment administered before or after surgery. The perioperative treatment may include administration of preoperative neoadjuvant therapy (eg, cystectomy) and postoperative therapy (eg, adjuvant therapy). For example, perioperative treatment may include post-diagnosis and surgery (eg, cystectomy) and post-surgery (eg, about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, after the surgery); 8 weeks, 9 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks or more) before therapy (eg, adjuvant therapy (eg, anti-TIGIT antagonist antibody and PD-1 axis binding antagonist adjuvant therapy)) (eg, about Neoadjuvant therapy (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks or more) administered before , anti-TIGIT antagonist antibody and PD-1 axis binding antagonist neoadjuvant therapy).

A “disorder” or “disease” is any condition that would benefit from treatment, including, but not limited to, a disorder associated with some degree of abnormal cell proliferation, such as cancer.

The term “dysfunction” in the context of immune dysfunction refers to a state in which the immune response to antigenic stimulation is reduced.

As used herein, the term “dysfunction” also refers to refractory or non-responsiveness to antigen recognition, specifically, antigen recognition that is associated with downstream T-cell functions, such as proliferation, cytokine production (eg, gamma interferon) and/or targeting. including impaired ability to translate into apoptosis.

The terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Cancers include solid and non-solid tumor cancers and locally advanced or metastatic cancers (eg, locally advanced or metastatic tumors). Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancy. More specific examples of such cancers include: urothelial cancer (UC), including locally advanced and metastatic UC (mUC); bladder cancer (eg, muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC), such as BCG refractory NMIBC), MIBC urothelial bladder cancer (UBC); kidney or kidney cancer (eg, renal cell carcinoma (RCC)); urinary tract cancer; lung cancer such as small cell lung cancer (SCLC), including advanced stage SCLC (ES-SCLC); Locally advanced unresectable NSCLC (eg, stage IIIB NSCLC), or relapsed or metastatic NSCLC (eg, stage IV NSCLC), adenocarcinoma of the lung, or squamous cell carcinoma (eg, epithelial squamous cell carcinoma (eg, squamous cell carcinoma of the lung) non-small cell lung cancer (NSCLC), including squamous NSCLC or non-squamous NSCLC, pancreatic cancer (eg, pancreatic ductal adenocarcinoma (PDAC), eg, metastatic PDAC); Head and neck cancers (eg, SCCHN, eg, recurrent/metastatic PD-L1 positive SCCHN, and head and neck squamous cell carcinoma (HNSCC); ovarian cancer (OC); esophageal cancer; peritoneal cancer; hepatocellular carcinoma; gastric cancer (GC) (eg, gastric cancer) junctional junction (GEJ) cancer) or stomach cancer (including gastric and gastrointestinal stromal cancer); glioblastoma; urinary tract cancer; liver cancer; breast cancer (eg, HER2+ breast cancer and triple negative breast cancer (TNBC (eg, early TNBC (eTNBC))), estrogen receptor (ER-), progesterone receptor (PgR-) and HER2 (HER2-) negative); prostate cancer such as castration resistant prostate cancer (CRPC); Pancreatic cancer (eg, pancreatic ductal adenocarcinoma (PDAC)); glioblastoma; cervical cancer (eg, stage IVB, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer); liver cancer (eg, hepatocellular carcinoma (HCC), such as locally advanced or metastatic HCC and/or unresectable HCC); liver cancer; colorectal cancer; rectal cancer; colorectal cancer (CRC; such as microsatellite stability (MSS) and microsatellite instability) (MSI-low) CRC); endometrial or uterine cancer; salivary gland carcinoma; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal carcinoma; penile carcinoma; superficial diffuse melanoma, malignant analyte melanoma; Melanoma, including lentiginous melanoma and nodular melanoma; Multiple myeloma and B-cell lymphoma (including low-grade/follicular non-Hodgkin's lymphoma (NHL)); Small lymphocytic (SL) NHL; Intermediate/follicular NHL; Medium Grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small uncut cell NHL; large tumor NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waltenstrommacromacroglobulinemia); chronic lymphocytic leukemia (CLL) ; acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); blastic leukemia; chronic myelogenous leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndrome ( MDS), as well as abnormal vascular proliferation associated with nevus, edema (associated with brain tumors), Meigs syndrome, brain cancer, head and neck cancer and related metastases.

As used herein, the term “persistent cervical cancer” refers to cervical cancer that is undetectable or not benign after previous therapy.

As used herein, "stage IVB cervical cancer" refers to cervical cancer that is classified as such using the cervical cancer staging system (eg, the International Federation of Gynecology and Obstetrics (FIGO) staging system). In some aspects, cervical cancer is classified as stage IVB if it has metastasized to distant organs (including the spleen or liver parenchyma) or to inguinal and extra-abdominal lymph nodes.

As used herein, the term “recurrent cervical cancer” refers to cervical cancer that is discovered or relapsed after initial treatment with surgery, radiation therapy, and/or chemotherapy.

The term “TNBC” refers to breast cancer that lacks expression of ER, PR and HER2. The term “eTNBC” refers to T2-4d TNBC (eg, cT2-cT4, cN0-cN3 and cM0).

Head and neck cancers include cancers that start on the mucosal surface of the upper aerodigestive tract and affect the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx.

As used herein, "urothelial cancer" and "UC" refer to types of cancer that typically occur in the urinary system and include muscle invasive bladder cancer (MIBC) and muscle invasive urothelial cancer (UTUC). UC is also referred to in the art as transitional cell carcinoma (TCC).

"Tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer”, “cancerous”, “cell proliferative disease”, “proliferative disease” and “tumor”, as used herein, are not mutually exclusive.

As used herein, “tumor cell” refers to any tumor cell present in a tumor or sample thereof. Tumor cells can be distinguished from other cells that may be present in a tumor specimen, such as stromal cells and tumor infiltrating immune cells, using methods known in the art and/or described herein.

"Tumor immunity" refers to the process by which a tumor evades immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when this evasion is weakened and these tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor removal.

As used herein, “metastasis” refers to metastasis from the primary site of cancer to other parts of the body. Cancer cells can break away from the primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow to distant foci in normal tissue elsewhere in the body (metastasize). Metastases may be local or distant. Metastasis is a sequential process in which tumor cells break away from the primary tumor, migrate through the bloodstream, and stop at distant sites. In the new site, cells can establish a blood supply and grow to form life-threatening masses. Both stimulatory and inhibitory molecular pathways within tumor cells regulate this behavior, and interactions between tumor cells and distant host cells are also important.

As used herein, the term “cytotoxic agent” refers to any agent that is detrimental to a cell (eg, causes cell death or destruction, inhibits proliferation, or otherwise prevents cell function). Cytotoxic agents include radioisotopes (eg, At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioisotopes of Lu); Chemotherapeutic agents or drugs (eg, methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other insertion agents); growth inhibitors; enzymes and fragments thereof, such as nucleases; Antibiotic; and toxins, such as small molecule toxins, or enzymatically active toxins of bacterial, fungal, plant or animal origin, as well as fragments and/or variants thereof; and various anti-tumor or anti-cancer agents disclosed below. Exemplary cytotoxic agents include anti-microtubule agents, platinum coordination complexes, alkylating agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors , immunotherapeutic agents, pro-apoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one case, the cytotoxic agent is a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin). In one case, the cytotoxic agent is an antagonist of EGFR, such as N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (eg, erlotinib). )to be. In one case, the cytotoxic agent is a RAF inhibitor, such as a BRAF and/or CRAF inhibitor. In one case, the RAF inhibitor is vemurafenib. In one case, the cytotoxic agent is a PI3K inhibitor.

"Chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA ^® , Genentech/OSI Pharm.), bortezomib (VELCADE ^® , Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib , 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX ^® , AstraZeneca), SUTENT ^® , Pfizer/Sugen, letrozole (FEMARA) ^® , Novartis), imatinib mesylate (GLEEVEC ^® , Novartis), pinasunate (VATALANIB ^® , Novartis), oxaliplatin (ELOXATIN ^® , Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin ( Sirolimus, RAPAMUNE ^® , Wyeth), lapatinib (TYKERB ^® , GSK572016, Glaxo Smith Kline), lonapamib (SCH 66336), sorafenib (NEXAVAR ^® , Bayer Labs), gefitinib (IRESSA ^® , AstraZeneca), AG1478 , for example thiotepa and CYTOXAN ^® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, uredopa; ethyleneimine and methyllamelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethyllomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; callistatin; CC-1065 (including adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductase including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mostinostat dolastatin; aldesleukin, talc duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eluterobin; pancratistatin; sarcodictin; spongestatin; Nitrogen mustards such as chlorambucil, clomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novenvicin, phenesterine , prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, potemustine, lomustine, nimustine and ranimnustine; Antibiotics such as enedyin antibiotics (eg, calicheamicin, in particular calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183186); dynemycin A dynemycin, including; bisphosphonates such as clodronate; esperamicin; as well as neocarzinostatin chromophore and related chromoprotein endyin antibiotic chromophore), aclasinomycin, actinomycin, outramycin, azaserine , Bleomycin, Cactinomycin, Carabicin, Caminomycin, Carginophylline, Chromomycin, Dactinomycin, Daunorubicin, Detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, everolimus, sotrataurine, idarubicin , marcelomycin, mitomycin, for example mitomycin C, mycophenolic acid, nogalamicin, olibomycin, peplomycin, porphyromycin, puromycin, kelamicin, rhodorubicin, streptonigrin, strepto zocin, tubersidine, ubenimex, ginostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostan, testolactone; antiadrenal such as aminoglutethimide, mitotane, trirostan; folic acid supplements such as prolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestlabucil; bisantrene; edatraxate; depopamine; demecholcin; diagequoon; elformitin; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; Ronidinine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; fur wall; nitraerin; pentostatin; phennamet; pyrarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK ^® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); Lazoxic acid; lyzoxine; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxins, veracurin A, loridine A and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gastocin; arabinoside ("Ara-C");cyclophosphamide;thiotepa; Taxanes (taxoids) such as TAXOL ^® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ^® (creamophor-free), albumin-engineered nanoparticle formulations of paclitaxel (eg, nanoparticulate albumin engineering) paclitaxel (Nap-paclitaxel)) (American Pharmaceutical Partners, Schaumberg, Ill.), and ^TAXOTERE® (docetaxel, docetaxel; Sanofi-Aventis); chlorambucil; GEMZAR ^® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE ^® (vinorelbine); novantron; teniposide; edatrexate; daunomycin; aminopterin; Capecitabine (XELODA ^® ); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above; as well as the abbreviation CHOP for combination therapy of two or more of the above compounds, for example, cyclophosphamide, doxorubicin, vincristine, and prednisolone, and oxaliplatin (ELOXATINTM) in combination with 5-FU and leucovorin in combination with treatment regimens. including but not limited to the abbreviation FOLFOX.

Chemotherapeutic agents may also include (i), for example, tamoxifen (NOLVADEX ^® ; including tamoxifen citrate), raloxifene, droloxifene, iodoxifen, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs) that act to modulate or inhibit the action of hormones on tumors, including onapristone and FARESTON ^® (toremipine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal gland, such as, for example, 4(5)-imidazole, aminoglutethimide, ^MEGASE® (megestrol acetate), AROMASIN ^® (exemestein; Pfizer), formestani, fadrozole, RIVISOR ^® (vorozol), FEMARA ^® (retrozole; Novartis) and ARIMIDEX ^® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; Buserellin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluocimesterone, all transretinoic acids, fenretinide as well as troxacitabine (1,3-dioxolane nucleoside) cytosine analogs); (iv) protein kinase inhibitors (eg, anaplastic lymphoma kinase (Alk) inhibitors such as AF-802 (also known as CH-5424802 or alectinib)); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (eg ANGIOZYME ^® ) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines such as ALLOVECTIN ^® , LEUVECTIN ^® and VAXID ^® ; PROLEUKIN®, rIL-2; Topoisomerase 1 inhibitors such as LURTOTECAN ^® ; ABARELIX ^® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Chemotherapeutic agents also include "platinum-based" chemotherapeutic agents, also referred to herein as "platinum agents", including organic compounds containing platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Platinum-based chemotherapeutic agents are sometimes referred to in the art as "platin". Examples of platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenantriplatin, picoplatin, lipoplatin and satraplatin. Platinum-based chemotherapeutic agents (eg, cisplatin or carboplatin) may include one or more additional chemotherapeutic agents, such as nucleoside analogs (eg, gemcitabine), antimetabolites (eg, pemetrexed or gemcitabine), or in combination with a taxane (eg, paclitaxel or nap-paclitaxel).

The term “eligible for treatment with platinum-based chemotherapy” means that a subject is eligible for treatment with platinum-based chemotherapy according to the judgment of the attending clinician or according to standardized criteria for eligibility for platinum-based chemotherapy known in the art. means to be

Chemotherapeutic agents also include “non-platinum-based chemotherapeutic agents,” which as used herein refer to chemotherapeutic agents that are not “platinum-based”. As used herein, the terms "non-platinum-based chemotherapeutic agent" and "non-platinum agent" are used interchangeably. Exemplary non-platinum chemotherapeutic agents include antimetabolites (eg, pemetrexed and gemcitabine), topoisomerase II inhibitors (eg, etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsa krine, ellipticin, aurintricarboxylic acid, or HU-331), taxanes (eg, paclitaxel (eg, albumin-engineered paclitaxel, also known as nanoparticle-albumin-bound paclitaxel (nap-paclitaxel)), docetaxel, larotaxel , cabazitaxel, milataxel, tessetaxel, and/or orataxel). Exemplary non-platinum-based chemotherapeutic agents also include alkylating agents (eg, cyclophosphamide).

As used herein, "nucleoside analog" refers to nucleic acid analogs and nucleosides comprising sugars. Nucleoside analogs can act as antimetabolites. Exemplary nucleoside analogs include, but are not limited to, gemcitabine, cytarabine, fludarabine, and cladribine.

As used herein, taxanes are diterpenes that can bind tubulin to promote microtubule assembly and stabilization and/or prevent microtubule depolymerization. Taxanes included herein include the taxoid 10-deacetylbaccatin III and/or derivatives thereof. Exemplary taxanes are paclitaxel (ie, TAXOL ^® , CAS # 33069-62-4), docetaxel (ie, TAXOTERE ^® , CAS # 114977-28-5), larotaxel, cabazitaxel, mila taxel, tessetaxel and/or orataxel. In some embodiments, the taxane is an albumin coated nanoparticle (eg, nap-paclitaxel, ie, ABRAXANE ^® and/or nap-docetaxel, ABI-008). In some embodiments, the taxane is nap-paclitaxel (Abraxane ^® ). In some embodiments, the taxane is formulated with CREMAPHOR ^® (eg, TAXOL ^® ) and/or Tween, such as polysorbate 80 (eg, Taxotere ^® ). In some embodiments, the taxane is a liposomal encapsulated taxane. In some embodiments, the taxane is a prodrug form and/or a conjugated form of the taxane (eg, paclitaxel, paclitaxel polyglomex, and/or DHA covalently conjugated to linoleyl carbonate-paclitaxel). In some embodiments, the paclitaxel is formulated substantially in the absence of a surfactant (eg, in the absence of CREMAPHOR and/or Tween-such as TOCOSOL ^® paclitaxel).

As used herein, “antimetabolites” are chemotherapeutic agents that interfere (in whole or in part) and inhibit endogenous (normal) metabolic processes within cells (eg, cancer cells). Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine and pralatrexate.

Chemotherapeutic agents also include dexamethasone, interferon, colchicine, methoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, raw BCG, bevacuzi. Mab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denilukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa- 2a, interferon alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, ofrelbekin, palipermine, pamidronate, pegademase, pegaspar Gauze, pegfilgrastim, pemetrexed disodium, plimacycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin , ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide. , fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclomethasone dipropionate, betamethasone valerate , betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and flupredniden acetate; immunoselective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomer form (feG) (IMULAN BioTherapeutics, LLC); Antirheumatic drugs such as azathioprine, cyclosporine (cyclosporin A), D-penicillamine, gold salt, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers such as etaner Sept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), interleukin 1 (IL-1) blockers such as anakinra (Kineret) , T cell costimulatory blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as anti M1 prime; secreted homotrimeric LTa3 and membrane bound heterotrimeric LTa1/β2 blockers such as anti-lymphotoxin alpha (LTa); radioactive isotopes (eg, At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and radioactive isotopes of Lu); other research substances such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyltransferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, epigallocatechin gallate, theaflavin, flavanol, procyanidin, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-rapacon; Raphacol; colchicine; betulinic acid; acetylcamptothecin, scoporetin, and 9-aminocamptothecin); podophyllotoxin; Tegafur (UFTORAL®); bexarotene (TARGRETIN®); Bisphosphonates such as clodronate (eg BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX) ®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines, such as THERATOPE® vaccine; perifosine, COX-2 inhibitors (such as celecoxib or etoricoxib), proteosome inhibitors (such as PS341); CCI-779; Tipifarnib (R11577); aurafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTM); and a pharmaceutically acceptable salt, acid or derivative of any one of the above; as well as combinations of two or more of the above, such as CHOP, which is an abbreviation for combination therapeutics of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, a treatment regimen with oxaliplatin (ELOXATINTM) in combination with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs that have analgesic, antipyretic, and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, Diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, loroxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid , tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib. NSAIDs include rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylitis, psoriatic arthritis, Reita's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue damage. , for symptomatic relief of conditions such as fever, intestinal obstruction, and renal colic.

Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and "EGFR antagonists" alternatively referred to as Examples of such agents include small molecules that bind EGFR. EGFR antagonists are small molecules, such as US Pat. , 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498 as well as the following PCT publications: WO98/14451, WO98/50038, WO99/24037, compounds as described. In particular, small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6- Quinazolinyl]-, dihydrochloride, Pfizer Inc.; ZD1839, gefitinib (IRESA ^® ) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6- (3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180((6-amino-4-(3-methylphenylamino)-quinazoline, Zeneca); BIBX-1382(N8-(3-chloro-4-fluoro-phenyl)-N2-(1- Methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166((R)-4-[4-[( 1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol);(R)-6-(4-hydroxyphenyl)-4-[(1- phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butinamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2- butenamide) (Wires); AG1478 (Pfizer); AG1571 (SU 5271, Pfizer); Dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib ( ^TYKERB® , GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl] ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

Chemotherapeutic agents also include "tyrosine kinase inhibitors", including EGFR targeted drugs mentioned in the preceding paragraph; Inhibitors of insulin receptor tyrosine kinases, including anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP26113, crizotinib ( ^XALKORI® ) and ceritinib (ZYKADIA ^® ); small molecule HER2 tyrosine kinase inhibitors such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors such as EKB-569 (available from Wires) that preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells; lapatinib, an oral HER2 and EGFR tyrosine kinase inhibitor (GSK572016; available from Glaxo-SmithKline); PKI-166 (available from Novartis); Canertinib (CI-1033; pan-HER inhibitors such as Pharmacia; Raf-1 inhibitors such as the antisense agent ISIS-5132 available from ISIS Pharmaceuticals that inhibits Raf-1 signaling; Imatinib mesylate (Gleevac ( Non-HER targeted TK inhibitors such as ^GLEEVEC® , available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib ( ^SUTENT® , available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as batalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); PD 153035,4-(3-chloroanilino) quina quinazolines such as zoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2] ,3-d]pyrimidine; curcumin (diferuloyl methane, 4,5-bis(4-fluoroanilino)phthalimide); tyrphostine containing a nitrothiophene moiety; Pd-0183805 ( Warner-Lamber); Antisense molecules (e.g., molecules that bind HER encoding nucleic acids); Quinoxaline (US Pat. No. 5,804,396); Tripostin (US Pat. No. 5,804,396); ZD6474 (AstraZeneca); Novartis/Schering AG); Pan HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); Imatinib mesylate ( ^GLEEVEC® ); PKI 166 (Novatis) ); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wiers); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novatis/Schering AG); INC-1C11 ( Imclone), rapamycin (sirolimus, RAPAMUNE ^® ) or the following patent publications: US 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamide); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

The term "anthracycline" relates to a chemotherapeutic agent, preferably an anticancer agent that induces apoptosis by inhibiting DNA recombination in topoisomerase II. Examples thereof include doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, rhodomycin, pyrarubicin, valrubicin, N-trifluoro-acetyl doxorubicin-14-valerate, Aclasinomycin, (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), 5-iminodaunomycin, mitoxantrone and aclasinomycin A (aclarubicin). In some embodiments, the anthracycline is administered in combination with doxorubicin (treatment with AC) in combination with an alkylating agent such as cyclophosphamide.

As used herein, an “alkylating agent” is a chemotherapeutic agent that causes DNA damage by attaching an alkyl group to the DNA. Alkylating agents include cyclophosphamide and N,N',N''-triethylenethiophosphoramide.

An “effective amount” of the compound, e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-Ll antibody), a VEGF antagonist, a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent) agent), an effective amount of an ADC (eg, enfortumab vedotin or sacituzumab govitecan) or a CSF (eg, pegfilgrastim, filgrastim or sagramostim) may result in a desired therapeutic outcome, such as a specific disease. or at least the minimum amount necessary to achieve a measurable increase in overall survival or progression-free survival of a disorder (eg, cancer). An effective amount herein may vary depending on factors such as the disease state, age, sex and weight of the patient, and the ability of the antibody to elicit a desired response in the subject. An effective amount is also an amount in which any toxic or deleterious effect of the treatment is greater than the therapeutically beneficial effect. For prophylactic use, beneficial or desired outcomes are the elimination or reduction of risk, reduction in severity, or biochemical, histological and/or behavioral symptoms of the disease, complications during development of the disease and intermediate pathological phenotypes of the disease. including consequences such as delayed onset. For therapeutic use, beneficial or desired outcomes include, but are not limited to, reduction of one or more symptoms due to disease (e.g., cancer-related pain, reduction or delay of symptomatic skeletal-related events (SSE), European Cancer Research Treatment Organization Quality of Life Questionnaire) reduction of symptoms (EORTC QLQ-C30, e.g. fatigue, nausea, vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea or general level physical, emotional, cognitive or social functioning), e.g. , reducing pain as measured by the 10-point pain severity (measured at worst) Numerical Rating Scale (NRS), and/or increasing the quality of life of people with the disease, reducing the dose of other drugs needed to treat the disease, Improving the effectiveness of another drug, e.g., through targeting, delaying disease progression (e.g., progression-free survival or radiological progression-free survival (rPFS); delaying apparent clinical progression (e.g., cancer-related pain progression) , symptomatic skeletal-related events, deterioration of the Eastern Cooperative Oncology Society (ECOG) systemic activity (PS) (e.g., how the disease affects the patient's ability to live daily), and/or the following systemic chemotherapy initiation), and/or prolong survival.In the case of cancer or tumors, an effective amount of the drug reduces the number of cancer cells; reduces the size of the tumor; preferably arrest); inhibit (ie, slow to some extent and preferably arrest) tumor metastasis; inhibit to some extent tumor growth; and/or relieve to some extent one or more symptoms associated with the disease. An effective amount can be administered in one or more administrations.For the purposes of the present invention, an effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As will be understood, an effective amount of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition. can be Thus, an “effective amount” may be contemplated in connection with the administration of one or more therapeutic agents, and a single agent may be considered to be provided in an effective amount if a desired result can be or is achieved with one or more other agents. In some aspects, a beneficial or desirable outcome is lung cancer according to a health-related quality of life (HRQoL) questionnaire as assessed by symptoms on the lung cancer (SILC) scale (eg, time to exacerbation of cough and chest pain (TTD)). reduction of symptoms associated with, and/or delay in time to lung-specific antigen progression.

“Immunogenicity” refers to the ability of a particular substance to elicit an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of tumor cells by an immune response. Examples of enhancing tumor immunogenicity include, but are not limited to, treatment with a TIGIT and/or PD-L1 antagonist (eg, an anti-TIGIT antagonist antibody and/or an anti-PD-L1 antibody).

An “individual response” or “response” can be assessed using any endpoint that shows benefit to a subject, including but not limited to: (1) inhibition of disease progression to some extent (eg, cancer, such as, Lung cancer (e.g., progression of small cell lung cancer (SCLC), including advanced stage SCLC (ES-SCLC)); locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), lung adenocarcinoma Non-small cell lung cancer (NSCLC), including squamous NSCLC or non-squamous NSCLC, including UC, such as bladder cancer (eg, MIBC), urothelial bladder cancer (UBC), pancreatic cancer (eg, pancreatic ductal adenocarcinoma (PDAC), such as metastatic PDAC) )), kidney or kidney cancer (eg, renal cell carcinoma (RCC), melanoma, head and neck cancer (eg, head and neck squamous cell carcinoma (HNSCC)), ovarian cancer (OC), gastric cancer (GC) (eg, gastroesophageal junction) (GEJ) cancer), hepatocellular carcinoma (HCC), colorectal cancer (CRC, e.g., CRC with microsatellite stable (MSS) and microsatellite instability (MSI) (MSI-low)), or breast cancer (e.g., estrogen receptor ( HER2+ breast cancer and triple negative breast cancer (TNBC) negative for ER-), progesterone receptor (PgR-) and HER2 (HER2-) - including delayed and complete arrest; (2) reduction in tumor size; (3) adjacent peripheral organs and/or inhibiting (ie, reducing, slowing, or completely stopping) cancer cell infiltration into a tissue; (4) inhibiting metastasis (ie, reducing, slowing or completely stopping); (5) a disease or disorder (eg, cancer) relief to some extent of one or more symptoms associated with: (6) an increase or prolongation of survival, including overall survival and progression-free survival; and/or (9) a decrease in mortality at a given time point after treatment.

As used herein, “pathological complete response” (pCR) is defined as the proportion of patients free of residual invasive cancer in a completely resected specimen. In the context of breast cancer, "pathological complete response" or "pCR" refers to eradication of the tumor in both breast and lymph nodes (ypT0/ypN0).

As used herein in the context of urothelial cancer (UC), "pathological down-staging" is defined as the proportion of patients achieving ≤ pT1pN0 upon cystectomy.

As used herein, “complete remission” or “CR” refers to the disappearance of all target lesions.

As used herein, “partial remission” or “PR” refers to at least a 30% reduction in the sum of the longest diameters (SLD) of the target lesion relative to the baseline SLD.

As used herein, “objective response rate (ORR)” refers to the sum of the complete remission (CR) rate and the partial remission (PR) rate.

"Duration of objective response" (DOR), as used herein, is from the first occurrence of a documented objective response to disease progression or death from any cause within 30 days of the last dose of therapeutic agent, whichever occurs first. defined as time.

"Persistent response" refers to a lasting effect on reducing tumor growth after discontinuation of treatment. For example, the tumor size may remain the same or smaller compared to the size at the beginning of the administration phase. In some aspects, a sustained response has a duration of treatment that is at least equal to a treatment period that is at least 1.5x, 2.0x, 2.5x, or 3.0x the length of the treatment period.

"Effective response" of a subject or "response" of a subject to treatment with a medicament and similar terms refer to a clinical or therapeutic benefit conferred to a patient at risk of, or suffering from, a disease or disorder, such as cancer. do. In one aspect, such benefits include prolonging survival (including overall survival and progression-free survival); eliciting an objective response (including CR or PR); or improving any one or more of the signs or symptoms of cancer.

Subjects who “do not have an effective response” to treatment are characterized by prolongation of survival (including overall survival and progression-free survival); induction of objective responses (including CR or PR responses); or patients who do not have any improvement in signs or symptoms of cancer.

As used herein, “survival” refers to a patient who survives and includes overall survival and progression-free survival.

As used herein, "overall survival" and "OS" refer to the period from the date of diagnosis or initiation of treatment for a disease (eg, cancer) in which the patient is still alive. For example, OS may be defined as the time from randomization to death from any cause.

As used herein, “overall survival” refers to the percentage of individuals in a group that are alive after a certain duration, eg, 6 months, 1 year, or 5 years from the time of diagnosis or treatment.

As used herein, “relapse-free survival” (RFS) is defined as the time from day 1 of the first cycle after surgery to the first documented recurrence of disease or death from any cause.

As used herein, “event-free survival” (EFS) is defined as the time from randomization to the event (whichever occurs first): disease progression (e.g., progression excluding surgery as assessed by the investigator) ); local or distant disease recurrence; or death from any cause.

As used herein, “progression-free survival” (PFS) refers to the length of time during and after treatment that the disease being treated (eg, cancer) does not worsen. Progression-free survival can include the amount of time the patient has experienced CR or PR as well as the amount of time the patient has stable disease.

As used herein, "stable disease" or "SD" does not mean a sufficient increase in contractility of the target lesion suitable for CR or PR, or sufficient increase for PD, based on the minimum SLD since initiation of treatment.

As used herein, “progressive disease” or “PD” refers to the SLD of a target lesion, taken as a criterion for the smallest SLD (sum of longest diameters) recorded since treatment was initiated, or the presence of one or more new lesions. refers to an increase of at least 20% in

As used herein, a “major pathological response” (MPR) is defined as a residual viable tumor of <10% at the time of surgical resection in the primary tumor.

As used herein, “delaying progression” of a disease or disorder refers to withholding, impeding, retarding, arresting, stabilizing, and/or delaying the progression of a disease or disorder (eg, cancer). This delay may vary in length of time depending on the history of the disease and/or the subject being treated. As will be apparent to those skilled in the art, a sufficient or significant delay, in effect, may include prevention, in that the subject does not develop the disease. For example, in terminal cancer, the onset of central nervous system (CNS) metastases may be delayed.

As used herein, the term “reducing or inhibiting cancer recurrence” means reducing or inhibiting tumor or cancer recurrence or tumor or cancer progression.

“Reducing or inhibiting” means an overall reduction of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. It means ability. Reducing or inhibiting may refer to the symptoms of the disorder (eg, cancer) being treated, the presence or size of metastases, or the size of the primary tumor.

"Prolonging survival" refers to a treated patient compared to an untreated patient (eg, compared to a patient not treated with a drug) or a patient not expressing a biomarker at a designated level, and/or compared to a patient treated with an approved anticancer agent. means an increase in overall or progression-free survival in a patient. “Objective response” refers to a measurable response, including CR or PR.

The terms “detecting” and “detecting” are used herein in their broadest sense to include both qualitative and quantitative measurement of a target molecule. Detection includes not only identifying the presence of a target molecule in a sample, but also determining whether the target molecule is present in the sample at a detectable level. Detection may be direct or indirect.

As used herein, “PD-L1-positive tumor cell fraction” refers to an immunohistochemical (IHC) assay, eg, an IHC assay, for PD-L1 staining using antibodies SP142, SP263, 22C3, or 28-8. is the percentage of viable tumor cells showing partial or complete membrane staining (excluding cytoplasmic staining) at any intensities relative to all viable tumor cells present in the sample after staining the sample. Thus, the PD-L1-positive tumor cell fraction can be calculated using the PD-L1 IHC SP263 (Ventana) assay, e.g., expression PD-L1-positive tumor cell fraction = (number of PD-L1-positive tumor cells)/(PD -L1 positive and total number of PD-L1 negative tumor cells), where PD- of tumor cells and all non-tumor cells (e.g., tumor infiltrating immune cells, normal cells, necrotic cells, debris) L1 cytoplasmic staining is excluded from evaluation and scoring. It will be appreciated that any given diagnostic PD-L1 antibody may correspond to specific IHC assay protocols and/or scoring terms that may be used to derive a fraction of PD-L1-positive tumor cells. For example, a PD-L1-positive tumor cell fraction can be obtained from tumor cell samples stained with SP263, 22C3, SP142, or 28-8, respectively, with OPTIVIEW® detection at Benchmark ULTRA, AutostainerLink ) 48, OPTIVIEW® detection and amplification on benchmark ULTRA, or EnVision Flex on OcotainerLink 48. In another example, the PD-L1-positive tumor cell fraction can be calculated using the PD-L1 IHC 22C3 pharmDx assay (Dako) according to the formula above. One of ordinary skill in the art will appreciate that sensitivity may vary between different PD-L1 antibodies used in IHC assays. For example, only about 64% of samples that meet the 1% TC or 25% TC thresholds defined by staining with 28-8 or 22C3 and SP263, respectively, meet the threshold when staining with SP142. Hirsch et al., Journal of Thoracic Oncology 2016, 12(2): 208-222. As used herein, the terms PD-L1-positive tumor cell fraction and “tumor rate score” (TPS) are used interchangeably.

As used herein, "Ventana SP142 IHC assay" is performed according to the Ventana PD-L1 (SP142) assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which The entirety is incorporated herein by reference.

As used herein, "Ventana SP263 IHC Assay" is performed according to the Ventana PD-L1 (SP263) Assay Package Insert (Tucson, AZ: Ventana Medical Systems), which is incorporated herein in its entirety.

As used herein, "pharmDx 22C3 IHC assay" is performed according to the PD-L1 IHC 22C3 PharmDx assay package insert (Carpinteria, CA: Dako, Agilent Pathology) Solutions), which is incorporated herein in its entirety.

As used herein, “pharmDx 28-8 IHC assay” is performed according to the PD-L1 IHC 28-8 PharmDx assay package insert (Carpinteria, CA: Dako, Agilent Patology Solutions (Agilent). Pathology Solutions), which is incorporated herein in its entirety.

As used herein, “tumor-infiltrating immune cell” refers to any immune cell present in a tumor or sample thereof. Tumor-infiltrating immune cells include, but are not limited to, intratumoral immune cells, peritumoral immune cells, other tumor stromal cells (eg, fibroblasts), or any combination thereof. Such tumor-infiltrating immune cells include, for example, T lymphocytes (eg, CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other myeloid lineage cells including granulocytes (eg, neutrophils, eosinophils and basophils). , monocytes, macrophages, dendritic cells (eg, interdigitated dendritic cells), histocytes and natural killer cells.

As used herein, the term “biomarker” refers to an indicator that can be detected in a sample, e.g., PD-L1, ctDNA, or a cytokine (eg, a cytokine associated with T cell activation and/or lymphocyte subpopulations), such as , prediction, diagnosis and/or prognosis. A biomarker may serve as an indicator of a particular subtype of a disease or disorder (eg, cancer) characterized by a particular, molecular, pathology, tissue and/or clinical feature. In some aspects, the biomarker is a gene. Biomarkers include polypeptides, polynucleotides (eg, DNA (eg, ctDNA) and/or RNA), polynucleotide copy number alterations (eg, DNA copy number), polypeptides and polynucleotide modifications (eg, post-translational modifications), carbohydrates, and/or glycolipid-based molecular markers. In some aspects, the biomarker is PD-L1. In some aspects, the biomarker is ctDNA. In some aspects, the biomarker is one or more cytokines (eg, one or more cytokines associated with T cell activation and/or lymphocyte subpopulations). In some aspects, the biomarker is a cell (eg, an immune cell, eg, a T cell, eg, a subset of T cells, eg, an activated T cell). In some aspects, the biomarker is a direct or indirect indicator of human papillomavirus (HPV) status. In some aspects, the biomarker is p16. In some aspects, the biomarker is an HPV protein or nucleic acid.

The term “housekeeping biomarker” refers to a biomarker or group of biomarkers (eg, polynucleotides and/or polypeptides) that are typically similarly present in all cell types. In some aspects, the housekeeping biomarker is a “housekeeping gene”. “Housekeeping gene” herein refers to a gene or group of genes that encode proteins essential for activity for maintenance of cellular function, and are typically similar in all cell types.

As used herein, “circulating tumor DNA” and “ctDNA” refer to tumor-derived DNA in the circulation that is not associated with a cell. ctDNA is a type of cell-free DNA (cfDNA) that can be derived from tumor cells or circulating tumor cells (CTCs). ctDNA can be found, for example, in the bloodstream of a patient or in a biological sample obtained from the patient (eg, blood, serum, plasma or urine). In some aspects, the ctDNA may comprise aberrant mutations (eg, patient-specific variants) and/or methylation patterns.

The term “antibody” refers to monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region), polyclonal antibodies, antibody compositions having polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies), so long as they exhibit the desired biological activity. antibody fragments), duplexes, and single chain molecules as well as antigen binding fragments such as Fab, F(ab′) ₂ and Fv. The term “immunoglobulin” (Ig) is used interchangeably herein with “antibody”. In one embodiment, the antibody is a full length monoclonal antibody.

As used herein, the term IgG “isotype” or “subclass” is meant to be any subclass of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.

Depending on the amino acid sequence of the constant domain of the heavy chain, antibodies (immunoglobulins) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of these can be further subdivided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. have. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, γ, ε, γ and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known and generally described, for example, in Abbas et al. Cellular and Mol. Immunology , 4 ^th ed. (WB Saunders, Co., 2000). An antibody may be part of a larger fusion molecule, formed by covalent or non-covalent association of the antibody and one or more other proteins or peptides.

The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. IgM antibodies are made up of 5 of the basic heterotetrameric units, with an additional polypeptide called the J chain, and contain 10 antigen binding sites, while IgA antibodies are basic 4 capable of polymerizing to form a multivalent aggregate combined with the J chain. - contains 2 to 5 chain units. For IgG, a four-chain unit is generally about 150,000 daltons. Each L chain is linked to the H chain by one covalent disulfide bond, but the two H chains are linked to each other by one or more disulfide bonds, depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has, at the N-terminus, a variable domain (V _H ) followed by three constant domains ( _CH ) for each of the α and γ chains and four _CH domains for the μ and ε isoforms. do. Each L chain has, at the N-terminus, a variable domain (V _L ) followed by a constant domain at the other end. V _L is aligned with V _H and _CL is aligned with the first constant domain of the heavy chain ( _CH 1 ). Certain amino acid residues are believed to form the interface between the light and heavy chain variable domains. The pairing of V _H and V _L together forms one antigen-binding site. For the structure and properties of the different classes of antibodies, see, for example, Basic and Clinical Immunology , ^8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994 , page 71 and Chapter 6. L chains from any vertebrate species can be assigned to one of two distinctly different types called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain (CH) of their heavy chain, immunoglobulins can be assigned to different classes or isotypes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM with heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subclasses based on relatively small differences in CH sequence and function, e.g., humans express the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1 and IgA2.

As used herein, the term “hypervariable region” or “HVR” refers to each of the regions of an antibody variable domain that are hypervariable in sequence and that determine antigen binding specificity, e.g., a “complementarity determining region” (“CDR”). refers to

Generally, antibodies comprise six CDRs: three in the VH (CDR-H1, CDR-H2, CDR-H3), and three in the VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:

(a) occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) hypervariable loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

(b) occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) CDR (Kabat et al., Sequences of Proteins of Immunological Interest, ^5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and

(c) occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) antigen contact (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)).

Unless otherwise indicated, CDRs are determined according to Kabat et al., supra. Those of skill in the art will appreciate that CDR designations may also be determined according to Chothia, supra, McCallum , supra , or any other scientifically accepted system of nomenclature.

“Framework” or “FR” refers to variable domain residues other than complementarity determining regions (CDRs). The FRs of a variable domain generally consist of four FR domains: FR1, FR2, FR3, and FR4. Thus, CDR and FR sequences generally appear in the following order in VH (or VL): FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR) -L3)-FR4.

The expressions “variable domain residue-numbering as in Kabat” or “amino acid-position numbering as in Kabat” and variations thereof refer to the numbering system used for heavy chain variable domains or light chain variable domains of compilation of antibodies in Kabat et al ., supra do. Using this numbering system, an actual linear amino acid sequence may contain a few fewer amino acids, or additional amino acids to correspond to shortening or insertions of FRs or HVRs of the variable domain. For example, a heavy chain variable domain may have a single amino acid insertion after residue 52 of H2 (eg, residue 52a according to Kabat) and a residue inserted after heavy chain FR residue 82 (eg, residues 82a, 82b and 82c according to Kabat) etc.) may be included. Residue numbering of Kabat can be determined for a given antibody by aligning regions of homology of the antibody's sequence with a "standard" Kabat numbering sequence.

The Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (eg, Kabat et al. , Sequences of Immunological Interest . 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991). "EU numbering system" or "EU index" is commonly used when referring to residues in the immunoglobulin heavy chain constant region (eg, the EU index as reported in Kabat et al., supra). “EU index as in the case of Kabat” refers to the residue numbering of the human IgG1 EU antibody.

The term “variable” means that certain segments of a variable domain differ widely in sequence between antibodies. The V domain mediates antigen binding and defines the specificity of a particular antibody for a particular antigen. However, the variability is not evenly distributed over the entire range of the variable domain. Instead, it is concentrated in three segments called hypervariable regions (HVRs) in both the light and heavy chain variable domains. The more conserved portions of the variable domains are called framework regions (FR). Each variable domain of the native heavy and light chains comprises four FR regions, usually in beta-sheet configuration, joined by three HVRs, forming loop links, and in some cases becoming part of the beta-sheet structure. The HVRs in each chain are held in close proximity by the FR regions and together with the HVRs of the other chain, contributing to the formation of the antigen-binding site of the antibody (Kabat et al., Sequences of Immunological Interest , Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domains are not directly involved in antibody-antigen binding, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cytotoxicity.

A “variable region” or “variable domain” of an antibody refers to the amino-terminal domain of the heavy or light chain of an antibody. The variable domains of the heavy and light chains may be referred to as "VH" and "VL", respectively. This domain is generally the most variable part of the antibody (relative to other antibodies of the same class) and contains the antigen binding site.

“Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FRs of a variable domain generally consist of four FR domains: FR1, FR2, FR3, and FR4. Thus, HVR and FR sequences generally appear in the following order in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

As used herein, the terms “full length antibody,” “intact antibody,” and “whole antibody” refer interchangeably to an antibody in its substantially intact form, as opposed to antibody fragments. Specifically, whole antibodies include antibodies having heavy and light chains comprising an Fc region. The constant domain may be a native sequence constant domain (eg, a human native sequence constant domain) or an amino acid sequence variant thereof. In some cases, an intact antibody may have more than one effector function.

A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. The naked antibody may be present in a pharmaceutical composition.

An “antibody fragment” comprises a portion of an intact antibody, preferably the antigen binding and/or variable region of an intact antibody. examples of antibody fragments include Fab, Fab', F(ab') ₂ and Fv fragments; duplex; linear antibody (see US Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single chain antibody molecules and multispecific antibodies formed from antibody fragments. Papain cleavage of the antibodies produced two identical antigen-binding fragments, a so-called “Fab” fragment, and a residual “Fc” fragment, a name reflecting its ability to crystallize readily. The Fab fragment consists entirely of the light (L) chain and the variable region domain of the heavy (H) chain (V _H ), and the first constant domain of one heavy chain ( _CH 1 ). Each Fab fragment is monovalent with respect to antigen binding, ie, it has one antigen-binding site. Pepsin treatment of the antibody yields a single large F(ab′) ₂ fragment that largely corresponds to two disulfide linked Fab fragments with different antigen-binding activities and still cross-links the antigen. Fab' fragments differ from Fab fragments by having an additional few residues at the carboxy terminus of the C _H 1 domain, including one or more cysteines from the region of the antibody hinge. Fab'-SH denotes herein Fab' in which the cysteine residue(s) of the constant domain bear a free thiol group. F(ab') ₂ antibody fragments were initially produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

Fc fragments contain the carboxy-terminal portions of both H chains supported together by disulfides. The effector function of antibodies is determined by sequences in the Fc region, which is also recognized by the Fc receptor (FcR) found in certain types of cells.

A “functional fragment” of an antibody of the invention generally comprises a portion of an intact antibody comprising the antigen-binding or variable region of an intact antibody or the Fc region of an antibody that retains or has altered FcR-binding ability. Examples of antibody fragments include linear antibodies, single chain antibody molecules, and multispecific antibodies formed from antibody fragments.

An “Fv” is the smallest antibody fragment comprising a complete antigen recognition and binding site. This fragment consists of a dimer of one heavy and one light chain variable region domain, bound tightly, non-covalently. From the folding of these two domains arise six hypervariable loops (three loops in the H and L chains, respectively) that allow antigen binding of amino acid residues and confer antigen binding specificity to the antibody. However, a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) still has the ability to recognize and bind antigen, albeit with a lower affinity than the entire binding site.

A “single chain Fv”, also abbreviated as “sFv” or “scFv”, is an antibody fragment comprising V _H and V _L antibody domains linked to a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between said V _H and V _L domains, which linker allows said sFv to form the desired structure for antigen binding. For the content of scFv, see, eg, Pluckthun in The Pharmacology of Monoclonal Antibodies , vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

The term “Fc region” is used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region spans from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, antibodies produced by the host cell may undergo post-translational cleavage of one or more, in particular one or two amino acids, from the C terminus of the heavy chain. For this reason, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may comprise a full-length heavy chain, or it may comprise a cleaved variant of the full-length heavy chain. This may be the case when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). For this reason, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region may or may not be present. The amino acid sequence of a heavy chain comprising an Fc region herein is shown without a C-terminal lysine (Lys447), unless otherwise indicated. In one aspect, a heavy chain comprising an Fc region as specified herein, comprised within an antibody disclosed herein, comprises additional C-terminal glycine-lysine dipeptides (G446 and K447). In one aspect, a heavy chain comprising an Fc region as specified herein, comprised within an antibody disclosed herein, comprises additional C-terminal glycine residues (G446 and K447). In one aspect, a heavy chain comprising an Fc region as specified herein, comprised within an antibody disclosed herein, comprises an additional C-terminal lysine residue (K447). In one embodiment, said Fc region contains the single amino acid substitution N297A of the heavy chain. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. It follows the EU numbering system, also known as the EU index, as described in Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

ron, Annu. Rev. Immunol. 15:203-234 (1997)를 참조). FcR은 Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al., Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995)에서 검토된다. 미래에 확인될 것을 포함한 다른 FcR들이 본원의 용어 "FcR"에 포함된다."Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Moreover, preferred FcRs are FcRs comprising receptors of the FcγRI, FcγRII and FcγRIII subclasses that bind to IgG antibodies (gamma receptors) and include allelic variants and alternatively spliced forms of these receptors, FcγRII being FcγRIIA (“activating receptor”) and FcγRIIB (“inhibiting receptor”), which have similar amino acid sequences, which differ primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an immune receptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (M. Da

ron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are described in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al. , Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein.

The term "duplex" refers to the construction of an sFv fragment (see the preceding paragraph) with a short linker (about 5-10 residues) between the V _H and V _L domains, whereby interchain pairing of the V domain is achieved, rather than intrachain. It refers to small antibody fragments prepared by generating bivalent fragments, ie, fragments with two antigen binding sites. A bispecific duplex is a heterodimer of two “crossover” sFv fragments in which the V _H and V _L domains of the two antibodies are in different polypeptide chains. Duplexes are described, for example, in EP 404,097; WO 93/11161; Hollinger et al. , Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993).

Monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins), wherein the heavy and/or light chain portions are identical to or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass. On the other hand, the rest of the chain(s) are identical or homologous to the corresponding sequences in antibodies derived from other species or belonging to other antibody classes or subclasses as well as fragments of said antibodies so long as they exhibit the desired biological activity ( U.S. Patent No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA , 81 :6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED ^® antibodies, wherein the antigen binding region of the antibody is derived from an antibody produced, for example, by immunizing a macaque monkey with an antigen of interest. As used herein, “humanized antibody” is used as a subset of “chimeric antibody”.

A “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these subclasses (isotypes), such as IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ , and It can be further subdivided into IgA ₂ . The heavy chain constant domains corresponding to the different classes of immunoglobulins are called a, d, e, g, and m, respectively.

“Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen, such as TIGIT, PD-L1, or VEGF). Unless otherwise indicated, "binding affinity" as used herein refers to intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (eg, antibody and antigen). The affinity of a molecule X for its partner Y can generally be expressed by the dissociation constant (K _D ). Affinity can be measured by general methods known in the art, including those described herein. Specific illustrative and exemplary aspects for determining binding affinity are described below.

A “human antibody” is an antibody that possesses an amino acid sequence corresponding to an antibody produced by a human and/or is prepared using any technique for making human antibodies disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be generated using a variety of techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol ., 227:381 (1991); Marks et al. , J. Mol. Biol ., 222:581 (1991). For the preparation of human monoclonal antibodies, see Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); The method described in Boerner et al., J. Immunol., 147(1):86-95 (1991) is also available. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001). Human antibodies have been modified to produce such antibodies in response to antigen challenge, but transgenic animals whose endogenous loci have been inactivated, such as immunized xenomouses (e.g., US Pat. No. 6,075,181 for XENOMOUSE™ technology) and 6,150,584). See also, for example, Li et al. , Proc. Natl. Acad. Sci. USA , 103:3557-3562 (2006).

"Humanized" forms of non-human (eg, murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one aspect, the humanized antibody is derived from the HVR of a non-human species (donor antibody), such as a mouse, rat, rabbit or non-human primate, wherein residues from the recipient's HVR (defined below) have the desired specificity, affinity and/or capacity. It is a human immunoglobulin (recipient antibody) replaced by a residue. In some cases, framework (“FR”) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may contain residues that are not found in the recipient antibody or in the donor antibody. These modifications can be made to further improve antibody performance, eg, binding affinity. In general, humanized antibodies contain at least one, and typically two variable domains, wherein all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin sequences, and all or substantially all of the FR regions are those of human immunoglobulin sequences. The number of these amino acid substitutions in the FR is typically within 6 in the H chain and within 3 in the L chain. The humanized antibody will also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, eg, Jones et al. , Nature , 321:522-525 (1986); Reichmann et al. , Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol . 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech . 5:428-433 (1994); and US Pat. Nos. 6,982,321 and 7,087,409.

The term “isolated antibody” when used to describe the various antibodies disclosed herein refers to an antibody that has been identified and isolated and/or recovered from the cell or cell culture in which it is expressed. Contaminant components of the natural environment are substances that would normally interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some aspects, the antibody is determined by, e.g., electrophoresis (e.g., SDS-PAGE, isopotential focus (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC), Purified to greater than 95% or 99% purity. For a review of methods for assessing antibody purity, see, eg, Flatman et al., J. Chromatogr. B 848:79-87 (2007). In a preferred aspect, the antibody is either (1) to an extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by use of a spinning cup sequencer, or (2) Coomassie blue or, preferably, silver staining was purified to homogeneity by SDS-PAGE under non-reducing or reducing conditions. An isolated antibody includes the antibody in situ in recombinant cells, since at least one component of the polypeptide's natural environment is absent. However, ordinarily, an isolated polypeptide will be prepared by at least one purification step.

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, provided that, for example, There may be variant antibodies, which contain naturally occurring mutations, or which arise during the making of monoclonal antibody preparations, and such variants are generally present in small amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Accordingly, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies according to the present invention include, but are not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus. It can be made by a variety of technologies that are not available.

As used herein, the term "specifically binds to" or "specific Determine the presence of a target in the presence of a population. For example, an antibody that specifically binds to a target (which may be an epitope) binds to that target with greater affinity, avidity, more readily, and/or longer duration than it binds to another target. is an antibody In one aspect, the extent of binding of the antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, for example, by radioimmunoassay (RIA). In certain aspects, an antibody that specifically binds a target has a dissociation constant (K _D ) of < 1 μM, < 100 nM, < 10 nM, < 1 nM, or < 0.1 nM. In certain aspects, an antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another aspect, specific binding can include, but does not require, exclusive binding. As used herein, this term includes, for example, 10 ^-4 M or less, alternatively 10 ^-5 M or less, alternatively 10 ^-6 M or less, alternatively 10 ^-7 M or less, alternatively, for a target or less as 10 ^-8 M or less, alternatively 10 ^-9 M or less, alternatively 10 ^-10 M or less, alternatively 10 ^-11 M or less, alternatively 10 ^-12 M or less K _D or 10 ^-4 M to 10 ^-6 M or 10 ⁶ M to 10 ¹⁰ M or 10 ⁷ M to 10 ⁹ _M. As will be understood by one of ordinary skill in the art, affinity and K _D values are inversely proportional. A high affinity for an antigen is measured by a low K _D value. In one aspect, the term “specific binding” refers to binding in which the molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

"Percent (%) amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, if necessary to achieve the maximum percent sequence identity after aligning the sequences. Gaps are introduced, and any conservative substitutions are not considered as part of the identity of the sequences. Alignment to determine percent amino acid sequence identity can be implemented in a variety of ways within the skill of the art using publicly available computer software such as, for example, BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. have. One of ordinary skill in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximal alignment over the entire length of the sequences being compared. However, for purposes herein, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was produced by Genentech, Inc., the source code was submitted with user documentation to the United States Copyright Office, Washington, D.C., 20559, United States, and registered under the United States Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. of South San Francisco, CA or may be compiled from source code. The ALIGN-2 program must be compiled for use on UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and are not changed.

^{When ALIGN-2 is used for amino acid sequence comparison, the percent amino acid sequence identity of a given amino acid sequence A to, with respect to, or with respect to a given amino acid sequence B is (which can be expressed as a given amino acid sequence A having or comprising a specific % amino acid sequence identity to) is calculated as follows:}

100 x fraction X/Y

In this case, X refers to the number of amino acid residues recorded as the same match by the sequence alignment program ALIGN-2 in the program alignment of A and B, and Y is the total number of amino acid residues in B. If the length of amino acid sequence A is not equal to the length of amino acid sequence B, it is recognized that the % amino acid sequence identity of A to B is not equal to the % amino acid sequence identity of B to A. Unless otherwise specified, all amino acid sequence identity % values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

As used herein, “subject” or “individual” means a mammal, including, but not limited to, a human or non-human mammal, such as a cow, horse, dog, sheep, or cat. In some aspects, the subject is a human. A patient herein is also a subject.

The term “patient” refers to a human patient. For example, the patient is an adult.

The term “diagnosis” is used herein to refer to the identification or classification of a molecular or pathological condition, disease or condition (eg, cancer). For example, “diagnosing” may refer to the identification of a particular type of cancer. "Diagnosis" also characterizes the expression of one or a combination of, e.g., histopathological criteria or molecular characteristics (e.g., biomarkers (e.g., specific genes or proteins encoded by said genes). It can refer to the classification of a specific subtype of cancer by subtype).

As used herein, the term "sample" refers to a desired target containing cellular and/or other molecular entities that must be characterized and/or identified based, for example, on physical, biochemical, chemical and/or physiological properties. Refers to a composition obtained or derived from a subject and/or individual. For example, the phrases "tumor sample", "disease sample" and variants thereof refer to any sample obtained from a subject of interest known or expected to contain the cellular and/or molecular entity being characterized. Specimens may include tissue samples, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous humor, lymph fluid, synovial fluid, follicular fluid, semen, amniotic fluid, fluid, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates, and tissue culture media, tissue extracts such as homogenized tissue, tumor tissue, cell extracts, and combinations thereof.

"Tissue sample" or "cell sample" means a collection of similar cells obtained from the tissue of a subject or individual. Sources of tissue or cell samples include solid tissue obtained from fresh, frozen and/or preserved organs, tissue specimens, biopsies and/or aspirates; blood or any blood component such as plasma; bodily fluids such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; The cells may be obtained at any point in the subject's pregnancy or development. The tissue sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a diseased tissue/organ. For example, a “tumor sample” is a tissue sample obtained from a tumor or other cancerous tissue. A tissue sample may comprise a population of a mixture of cell types (eg, tumor cells and non-tumor cells, cancer cells and non-cancer cells). A tissue sample may contain compounds that do not naturally mix with the tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like. In some aspects, the sample is a tumor tissue sample. In some aspects, the tumor tissue sample is a UC tumor tissue sample (eg, a bladder cancer tumor tissue sample (eg, a MIBC tumor tissue sample)). In some aspects, the sample is a transurethral resection (TURBT) sample of a bladder tumor. In some aspects, the sample is a cystectomy or nephrectomy sample. In other aspects, the tumor tissue sample is a lung cancer tumor tissue sample (eg, an early lung cancer tissue sample (eg, a NSCLC tumor tissue sample (eg, a stage II, IIIA, or IIIB NSCLC tumor tissue sample)), such as a squamous or a non-squamous NSCLC tumor tissue sample, such as a resectable NSCLC tumor tissue sample)). In some aspects, the sample is a locally advanced unresectable NSCLC tumor tissue sample (eg, stage IIIB NSCLC tumor tissue sample), or a recurrent or metastatic NSCLC tumor tissue sample (eg, stage IV NSCLC tumor tissue sample), pancreatic cancer tumor tissue a sample (eg, a PDAC tumor tissue sample), eg, a metastatic PDAC tumor tissue sample), or a breast cancer tumor tissue sample (eg, a HER2+ breast cancer tumor tissue sample or a TNBC tumor tissue sample).

For purposes herein, a “section” of a tissue sample means a single portion or piece of a tissue sample, eg, a thin slice of tissue or cells cut from a tissue sample (eg, a tumor sample). The same section of a tissue sample can be analyzed at both morphological and molecular levels, or polypeptides and/or polynucleotides (e.g., by in situ hybridization) (e.g., by immunohistochemistry) It is to be understood that multiple sections of a tissue sample can be obtained and subjected to analysis, if it is understood that they can be analyzed with respect to

As used herein, “reference sample”, “reference cell”, “reference tissue”, “control sample”, “control cell”, or “control tissue” refers to a sample, cell, tissue, standard, or refers to the level. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is from a healthy and/or non-diseased portion of the body (eg, tissue or cell) of the same subject or individual. can be obtained. For example, a reference sample, reference cell, reference tissue, control sample, control cell or control tissue is a healthy and/or non-diseased cell or tissue adjacent to a diseased cell or tissue (eg, a cell or tissue adjacent to a tumor). can be In another embodiment, the reference sample is obtained from untreated tissues and/or cells of the body of the same subject or individual. In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is a healthy and/or It can be obtained from non-disease parts. In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue may be obtained from untreated tissue and/or cells of the body of an individual other than the subject or individual. have.

The term "protein," as used herein, unless otherwise indicated, refers to any native protein of any vertebrate origin, including mammals such as primates (eg, humans) and rodents (eg, mice and rats). . The term includes "full length", untreated proteins, as well as any form of protein that has been processed in a cell. The term also includes naturally occurring variants of a protein, eg, splice variants or allelic variants.

"Polynucleotide" or "nucleic acid," as used interchangeably herein, refers to a polymer of nucleotides of any length, and includes DNA and RNA. A nucleotide can be a deoxyribonucleotide, a ribonucleotide, a modified nucleotide or base and/or analogs thereof, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Thus, for example, polynucleotides as defined herein include, without limitation, single- and double-stranded DNA, DNA comprising single- and double-stranded regions, single- and double-stranded RNA, and single- and double-stranded DNA. RNA comprising a region, single-stranded or, more generally, double-stranded, or hybrid molecule comprising DNA and RNA, which may comprise single- and double-stranded regions. Also, as used herein, the term “polynucleotide” refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands of these regions may be from the same molecule or from different molecules. These regions may contain all of one or more molecules, but more generally contain only some regions of the molecules. One of the molecules of the triple-helix region is often an oligonucleotide. The terms “polynucleotide” and “nucleic acid” specifically include mRNA and cDNA.

Polynucleotides may include modified nucleotides, such as methylated nucleotides and analogs thereof. If present, modifications to the nucleotide structure may be imparted before or after polymer assembly. The sequence of nucleotides may be discontinuous by non-nucleotide components. The polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, for example, “caps”, substitution of one or more naturally-occurring nucleotides with analogs, internucleotide modifications, such as, for example, uncharged linkages (eg, methyl phosphonates, phosphotriesters). , phosphoramidates, carbamates, etc.) and charged linkages (eg, phosphorothioates, phosphorodithioates, etc.), modified with accessory moieties, such as, for example, proteins (eg, nucleas). agents, toxins, antibodies, signal peptides, poly-L-lysine, etc.), modified with intercalators (eg acridine, psoralen, etc.), chelators (eg metals, radioactive metals, boron, oxidizing metals, etc.), modifications with alkylating agents, modifications with modified linkages (eg, alpha anomeric nucleic acids), as well as unmodified forms of the polynucleotide(s). In addition, any hydroxyl groups ordinarily present in sugars can be replaced with, for example, phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to create additional linkages to additional nucleotides. may be, or may be bonded to a solid or semi-solid support. The 5' and 3' terminal OH may be phosphorylated or substituted with an amine or an organic capping group moiety of 1 to 20 carbon atoms. Other hydroxyl groups can also be derivatized with standard protecting groups. Polynucleotides can also be, for example, 2'-O-methyl-, 2'-O-allyl-, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-ano Mer sugars, epimeric sugars such as arabinose, xylose or lyxose, pyranose sugar, furanose sugar, sedoheptulose, acyclic analogs and abasic nucleoside analogs such as sugars, including methyl riboside similar forms of ribose or deoxyribose sugars generally known in the art. One or more phosphodiester linkages may be replaced by other linkages. These alternative linking groups include P(O)S (“thioate”), P(S)S (“dithioate”), (O)NR ₂ (“amidate”), P(O)R, P(O)OR′, CO or CH ₂ (“formacetal”), wherein each R or R′ is independently H, or an ether (-O-) linkage. , substituted or unsubstituted alkyl (1-20 C) optionally containing aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages of a polynucleotide need be identical. The above description applies to all polynucleotides mentioned herein, including RNA and DNA.

As used herein, "carrier" includes pharmaceutically acceptable carriers, excipients or stabilizers that are nontoxic to the cells or mammals to be exposed at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffer. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as mannitol or sorbitol; salt forming counterions such as sodium; and/or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

The phrase “pharmaceutically acceptable” indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation, and/or the mammal being treated therewith.

The term "pharmaceutical preparation" or "pharmaceutical composition" refers to a preparation that is in a form that allows the biological activity of the active ingredient contained therein to be effective, and which does not contain additional ingredients that are unacceptably toxic to the subject to which the preparation is administered. it means.

The term "package insert" refers to a therapeutic product or product, including contraindications and/or warnings regarding the indications, directions for use, dosage, administration, combination therapy, other drugs in combination with the packaged product, and/or the use of such therapeutic products or drugs. Used to refer to instructions commonly included in commercial packages of drugs.

As used herein, the term “induction phase” refers to a series of one or more dosing cycles (e.g., about 4 to 6 cycles), wherein said one or more dosing cycles are optionally followed by a maintenance phase.

As used herein, the term “maintenance phase” refers to a series of one or more dosing cycles for one or more therapeutic agents (eg, anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and/or chemotherapeutic agents) administered to a subject after an induction phase. refers to In some cases, the maintenance phase is initiated only when the subject does not experience disease progression or unacceptable toxicity during the induction phase. The induction and maintenance phases may or may not involve the use of the same therapeutic agent. For example, in some cases, the induction phase comprises the use of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, and the maintenance phase comprises an anti-TIGIT antagonist antibody and a PD -Including the use of -1 axis binding antagonists.

In the context of bladder cancer, the terms “ineligible for platinum-based chemotherapy” or “not suitable for treatment with platinum-based chemotherapy” are used at the discretion of the attending clinician or as an indication of eligibility for platinum-based chemotherapy known in the art. means ineligible or ineligible for treatment with platinum-based chemotherapy according to standardized criteria. See, for example, Galsky et al. Lancet Oncol. The criteria set forth in 12(3):211-4, 2011 can be used to determine whether a subject is eligible for cisplatin-based chemotherapy. Galsky et al. describe an agreed definition of a patient with metastatic UC (mUC) who is considered ineligible for cisplatin-based chemotherapy in which one or more of the following are met: (i) WHO (World Health Association) or ECOG 2 or Karnowski performance status 60-70% of systemic activity, (ii) creatinine clearance less than 1 mL/s (calculated or measured); (iii) National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade ≥ 2 Hearing Loss; (iv) CTCAE v.4.0 grade > 2 peripheral neuropathy; and/or New York Heart Association (NYHA) Class III heart failure. In one example, a patient is considered ineligible for cisplatin-based chemotherapy if it has one or more of the following: impaired renal function (eg, glomerular filtration rate (GFR) >30, <60 mL/min); GFR can be assessed by direct measurement (ie creatinine clearance or ethyldediaminetetraacetate), or by calculating from serum/plasma creatinine (Cockcroft-Gault formula) if not available; Hearing loss (eg, NCI CTCAE v4.0 grade > 2 audiological hearing loss, 25 decibels at two adjacent frequencies); peripheral neuropathy (eg, NCI CTCAE v4.0 grade > 2 peripheral neuropathy (ie, sensory changes or paresthesia, including tingling)); and/or ECOG systemic activity assessment (see Oken et al. Am . J. Clin. Oncol. 5:649-655, 1982, which is incorporated herein in its entirety) (eg, ECOG systemic activity 2). In some embodiments, a subject having one of the following may be eligible for carboplatin-based chemotherapy: impaired renal function (eg, GFR >30, <60 mL/min); GFR can be assessed by direct measurement (ie creatinine clearance or ethyldediaminetetraacetate), or by calculating from serum/plasma creatinine (Cockcroft-Gault formula) if not available; Hearing loss (eg, NCI CTCAE v4.0 grade > 2 audiological hearing loss, 25 decibels at two adjacent frequencies); peripheral neuropathy (eg, NCI CTCAE v4.0 grade > 2 peripheral neuropathy (ie, sensory changes or paresthesia, including tingling)); and/or ECOG systemic activity assessment (eg, ECOG systemic activity 2). For example, cisplatin disqualification can be defined by any one of the following criteria: (i) impaired renal function (GFR <60 mL/min); GFR can be assessed by direct measurement (eg creatinine clearance or ethyldediaminetetraacetate), or by calculating from serum/plasma creatinine (Cockcroft-Gault formula) if not available; (ii) a hearing loss of 25 dB (measured by audiometry) at two adjacent frequencies; (iii) Grade 2 or greater peripheral neuropathy (ie, paralysis with sensory changes or tingling); and (iv) ECOG systemic activity 2.

III. Treatment and diagnostic methods and use

A. Treatment methods and uses associated with cancer

Treatment methods and use

Cancers (e.g., solid tumors and/or locally advanced or metastatic cancers such as lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer)), small cell lung cancer (SCLC) (e.g., expanded stage (ES)-SCLC), Non-small cell lung cancer (NSCLC) (e.g., squamous or nonsquamous NSCLC, locally advanced unresectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC) NSCLC)), or stage IV NSCLC (eg, if the subject has not been previously treated for stage IV NSCLC), cervical cancer (eg, stage 4B, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or persistent) or recurrent PD-L1 positive cervical cancer), breast cancer (eg, triple negative breast cancer (TNBC) (eg, estrogen receptor negative (ER-), progesterone receptor negative (PR-), and HER2 negative (HER2-) breast cancer), such as Early TNBC (eTNBC)) or HER2-positive breast cancer); locally advanced or metastatic HCC and/or unresectable HCC); bladder cancer (such as muscle invasive bladder cancer (MIBC) or locally advanced or metastatic urothelial cancer (mUC)); esophageal cancer; pancreatic cancer (such as pancreatic ductal adenocarcinoma (PDAC), such as metastatic) PDAC); renal cancer (eg, renal cell carcinoma (RCC)); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); lumab), or a combination of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab). colorectal comprising administering a cycle to the subject Cancer (CRC; Methods and uses are provided, such as for the treatment of microsatellite-stable (MSS) or low microsatellite instability (MSI) (MSI-Low) CRC).

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or Provided are methods and uses that involve administering an anti-PD-1 antagonist antibody, such as pembrolizumab) to a subject in need thereof every 4 weeks (eg, on Day 1 of each 28-day dosing cycle). In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in a complete response (CR) or a partial response (PR). In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in progression-free survival (PFS) or duration of objective response (DOR). In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in overall survival (OS). In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in PFS in a subject as compared to, for example, treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in OS in a subject compared to, for example, treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

The present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject in need thereof every 4 weeks (eg, on Day 1 of each 28 day dosing cycle). ) methods and uses involving administration. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered every 4 weeks (eg, on Day 1 of each 28-day dosing cycle), A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as, eg, pembrolizumab) is administered every two weeks (eg, each 28-day dosing cycle). on days 1 and 15), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on Day 1 of each 28-day dosing cycle). In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in a CR or PR. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in PFS in the subject as compared to baseline PFS. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in DOR. In some instances, administration of an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) prolongs the OR in a subject.

The present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject in need thereof every two weeks (eg, on the first day of each 28-day dosing cycle, and on day 15) and methods and uses involving administration. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered every two weeks (eg, on days 1 and 15 of each 28-day dosing cycle). and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as, eg, pembrolizumab) every two weeks (eg, each 28 Dosing every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on Day 1 of each 28-day dosing cycle), on days 1 and 15 of one dosing cycle do. The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or Provided are methods and uses that involve administering an anti-PD-1 antagonist antibody, such as pembrolizumab, to a subject in need thereof every two weeks (eg, on days 1 and 15 of each 28-day dosing cycle). . In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab) results in CR or PR. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in PFS in a subject as compared to, for example, treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in OS in a subject as compared to, for example, treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

The present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject in need thereof every 3 weeks (eg, on Day 1 of each 21 day dosing cycle). ) methods and uses involving administration. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered every 3 weeks (eg, on day 1 of each 21 day dosing cycle), A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as, eg, pembrolizumab) is administered every two weeks (eg, each 28-day dosing cycle). on days 1 and 15), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on Day 1 of each 28-day dosing cycle). In certain instances, the present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject in need thereof every 3 weeks (eg, each 21 day dosing cycle). on day 1) of In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in a CR or PR. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in PFS in the subject as compared to baseline PFS. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) prolongs the OR in a subject. In some cases, the present invention provides a method of treating a subject having cancer, comprising an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, PD-1 at a dose of about 900 mg to about 1500 mg every 3 weeks a method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an axis binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks. In some cases, the method comprises a dose of 500 mg to 700 mg of anti-TIGIT antagonist antibody every 3 weeks, a dose of 900 mg to 1500 mg of PD-1 axis binding antagonist every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and administering to the subject a dosing regimen comprising at least one dosing cycle of a non-platinum-based chemotherapeutic agent every three weeks.

In certain instances, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered without a chemotherapeutic agent (eg, without any chemotherapeutic agent, eg, the total dosing regimen includes administration of the chemotherapeutic agent to the subject). none).

In some embodiments, the subject has not been previously treated with therapy for cancer (eg, cancer immunotherapy and/or chemotherapeutic agents). In some embodiments, the subject has not previously received prior treatment for cancer (eg, cancer immunotherapy and/or chemotherapeutic agents). In some cases, the subject receives prior systemic therapy (eg, prior systemic therapy for therapeutic purposes, such as chemotherapy) at least within the month prior to administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (eg, the Within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, within 5 years prior to administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody , or within 10 years). In some cases, the subject is naive to chemotherapy.

In some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered in combination with chemotherapy. For example, the once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W) dosing regimen of the PD-1 axis binding antagonist and/or the anti-TIGIT antagonist antibody comprises one or more chemical agents. It may be administered with a therapeutic agent. The one or more chemotherapeutic agents are administered at the same frequency or at a different frequency than the dosing frequency of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (Q2W, Q3W, or Q4W) (e.g., on a 3-week dosing/1 week off schedule eg, on days 1 and 15 of each 28-day cycle).For example, in some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every two weeks, The one or more chemotherapeutic agents are administered weekly, every 3 weeks dosing/1 week off, every 2 weeks, every 3 weeks, or every 4 weeks Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every 3 weeks, and said one or more chemotherapeutic agents are administered every week, every 2 weeks, every 3 weeks, or every 4 weeks Alternatively, said PD-1 axis binding antagonist and said anti-TIGIT antagonist antibody are administered every 4 weeks and the one or more chemotherapeutic agents are administered every week, every 3 weeks dosing/1 week off, every 2 weeks, every 3 weeks, or every 4 weeks In certain instances, the chemotherapeutic agent is administered several times per week (eg, weekly 2, 3, 4, 5, 6 or 7 (eg, on days 1, 2, and 3 of the dosing cycle).

In some embodiments, the dose of the chemotherapeutic agent is reduced after one or more initial doses (eg, after 1, 2, 3, 4 or more initial doses). For example, a chemotherapeutic agent (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an alkylating agent (eg, cyclophosphamide)), a taxane ( For example, subsequent doses of paclitaxel, such as nap-paclitaxel), and/or topoisomerase II inhibitors (eg, doxorubicin)) may be administered at about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%. For example, an initial dose of nap-paclitaxel of 125 mg/m ² may be reduced for subsequent doses, such as 100 mg/m ² or 75 mg/m ² ; The initial dose of nap-paclitaxel of 100 mg/m ² may be reduced for subsequent doses, eg to 75 mg/m ² ; The initial dose of paclitaxel of about 175 mg/m ² may be reduced for subsequent doses, such as 150 mg/m ² , 125 mg/m ² , 100 mg/m ² , or 75 mg/m ² ; The initial dose of paclitaxel of about 200 mg/m ² is reduced for subsequent doses, such as 175 mg/m ² , 150 mg/m ² , 125 mg/m ² , 100 mg/m ² , or 75 mg/m ² . can be; An initial dose of gemcitabine of about 1000 mg/m ² for subsequent doses, such as 900 mg/m ² , 800 mg/m ² , 750 mg/m ² , 700 mg/m ² , 600 mg/m ² , or can be reduced to 500 mg/m ² ; An initial dose of cisplatin of about 75 mg/m ² is for subsequent doses, such as 70 mg/m ² , 65 mg/m ² , 60 mg/m ² , 55 mg/m ² , 50 mg/m ² or 45 mg. can be reduced to /m ² ; An initial dose of pemetrexed of about 500 mg/m ² is for subsequent doses, such as 450 mg/m ² , 400 mg/m ² , 350 mg/m ² , 300 mg/m ² , 250 mg/m ² , or 200 mg/m ² ; and/or an initial dose of carboplatin in a dose sufficient to achieve AUC=6 mg/ml/min for subsequent doses, such as AUC=5.5 mg/ml/min, 5.0 mg/ml/min, 4.5 mg/min. ml/min or a dose sufficient to achieve 4.0 mg/ml/min. In some cases, the initial dose of nap-paclitaxel of 125 mg/m ² may be reduced for a subsequent dose, such as 100 mg/m ² or 75 mg/m ² ; The initial dose of nap-paclitaxel of 100 mg/m ² may be reduced for subsequent doses, eg to 75 mg/m ² ; The initial dose of paclitaxel at 175 mg/m ² may be reduced for subsequent doses, such as 150 mg/m ² , 125 mg/m ² , 100 mg/m ² , or 75 mg/m ² ; The initial dose of 200 mg/m ² paclitaxel may be reduced for subsequent doses, such as 175 mg/m ² , 150 mg/m ² , 125 mg/m ² , 100 mg/m ² , or 75 mg/m ² . can; The initial dose of gemcitabine of 1000 mg/m ² is for subsequent doses, such as 900 mg/m ² , 800 mg/m ² , 750 mg/m ² , 700 mg/m ² , 600 mg/m ² , or 500 can be reduced to mg/m ² ; An initial dose of cisplatin of 75 mg/m ² is for subsequent doses, such as 70 mg/m ² , 65 mg/m ² , 60 mg/m ² , 55 mg/m ² , 50 mg/m ² or 45 mg/m 2 . can be reduced to m ² ; An initial dose of pemetrexed of 500 mg/m ² is for subsequent doses, such as 450 mg/m ² , 400 mg/m ² , 350 mg/m ² , 300 mg/m ² , 250 mg/m ² , or can be reduced to 200 mg/m ² ; and/or an initial dose of carboplatin in a dose sufficient to achieve AUC=6 mg/ml/min for subsequent doses, such as AUC=5.5 mg/ml/min, 5.0 mg/ml/min, 4.5 mg/min. ml/min or a dose sufficient to achieve 4.0 mg/ml/min.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or methods and uses involving administering to a subject in need thereof an anti-PD-1 antagonist antibody, such as pembrolizumab), and a chemotherapy combination. In some embodiments, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, Yeckerdae Arte) Zolizumab) is administered every 2 weeks (eg, on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on day 1 of each 21-day dosing cycle). on Day 1 of each 28-day dosing cycle). In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered every 4 weeks (eg, on Day 1 of each 28-day dosing cycle), The PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody, such as atezolizumab) is administered every 2 weeks (eg, on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (eg, each on Day 1 of a 21-day dosing cycle), or every 4 weeks (eg, on Day 1 of each 28-day dosing cycle). In some cases, the chemotherapy combination comprises an effective amount of a first non-platinum-based chemotherapeutic agent and an effective amount of a second non-platinum-based chemotherapeutic agent. In some cases, the first non-platinum-based chemotherapeutic agent is an antimetabolite and the second non-platinum-based chemotherapeutic agent is a taxane. In some embodiments, the chemotherapy combination (eg, antimetabolites (eg, gemcitabine, pemetrexed or capecitabine) and taxanes (eg, nap-paclitaxel and paclitaxel) is administered weekly, every other week, or every 4 weeks. It is administered three times (eg, on days 1, 8 and 15 of each 28-day dosing cycle).

In certain embodiments, the method comprises an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg atezolizumab), gemcitabine, and paclitaxel to a subject in need thereof, wherein said anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and said A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab) is administered every two weeks (eg, on days 1 and 15 of each 28-day dosing cycle) and the chemotherapy combination ( For example, an antimetabolite and taxane (eg, gemcitabine and paclitaxel) are administered more frequently (eg, 3 times every 4 weeks (eg, on days 1, 8 and 15 of each 28-day dosing cycle).

In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), antimetabolites (eg gemcitabine), and taxanes (eg paclitaxel) result in CR or PR. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), antimetabolites (eg gemcitabine), and taxanes (eg paclitaxel) result in an increase in PFS in the subject. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), antimetabolites (eg gemcitabine), and taxanes (eg paclitaxel) prolong OS in the subject.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or methods and uses comprising administering to a subject in need thereof an anti-PD-1 antagonist antibody, such as pembrolizumab), and a chemotherapeutic combination, wherein the chemotherapy combination comprises an effective amount of a platinum-based chemotherapeutic agent and and an effective amount of a non-platinum-based chemotherapeutic agent. In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody, e.g. Atezoli) Zumab) every 2 weeks (eg, on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, each on Day 1 of a 28-day dosing cycle). In some cases, the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is an antimetabolite (eg, pemetrexed). In some embodiments, the chemotherapeutic combination (eg, the platinum-based chemotherapeutic agent and the antimetabolite (eg, pemetrexed)) is administered three times (eg, every week, every 2 weeks, every 4 weeks, or every 4 weeks) ( eg, on days 1, 8, and 15 of each 28-day dosing cycle).

In certain embodiments, the method comprises an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg atezolizumab), a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and an antimetabolite (eg, pemetrexed) to a subject in need thereof, wherein said anti-TIGIT antagonist An antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab) are administered every 3 weeks (eg, each on day 1 of a 21 day dosing cycle), the chemotherapy combination (eg, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and the antimetabolite (eg, pemetrexed)) are administered at the same frequency (eg, every 3 weeks, eg, on Day 1 of each 21 day dosing cycle) In some cases, the dosing is continued for 4 to 6 induction dosing cycles (eg, 4 induction dosing cycles) , 5 induction dosing cycles, or 6 induction dosing cycles).After said induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles.In certain embodiments, said one or more maintenance dosing cycles The cycle does not include the platinum-based chemotherapeutic agent.

In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg carboplatin or cisplatin), and the antimetabolites (eg pemetrexed) result in CR or PR. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the antimetabolite (eg, pemetrexed) result in an increase in PFS in the subject. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the antimetabolite (eg, pemetrexed) prolong the OS in the subject.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the antimetabolite (eg, pemetrexed) are being treated for a solid tumor or locally advanced or metastatic cancer. Additionally or alternatively, the cancer is lung cancer (eg, early stage lung cancer (eg, resectable lung cancer), SCLC (eg, ES-SCLC), NSCLC (eg, squamous or non-squamous NSCLC, locally advanced unresectable NSCLC, Stage IIIB NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously received treatment for stage IV NSCLC) cervical cancer (eg, stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer); breast cancer (eg, TNBC (eg, early TNBC) (eTNBC)) or HER2-positive breast cancer); (eg, MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; ovarian cancer; stomach cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or low MSI CRC).

The present invention also provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab; or an anti-PD-1 antagonist antibody, such as pembrolizumab), and a chemotherapy, such as a taxane (eg, paclitaxel or nap-paclitaxel), to a subject in need thereof. In instances, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, ecker vs. atezolizumab) ) every 2 weeks (eg, on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on days 1 and 15 of each 28-day dosing cycle) on day 1 of one dosing cycle) In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, , anti-PD-L1 antagonist antibody, such as atezolizumab) is administered every 4 weeks (eg, on Day 1 of each 28-day dosing cycle) In some embodiments, the chemotherapy is weekly, every 2 weeks, It is administered every 4 weeks, or 3 times every 4 weeks (eg, on days 1, 8, and 15 of each 28-day dosing cycle) In some embodiments, the chemotherapy is administered weekly.

In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) , or administration of an anti-PD-1 antagonist antibody, such as pembrolizumab), and a chemotherapy, such as a taxane (eg, paclitaxel or nap-paclitaxel), results in CR or PR. In some cases, an effective amount of anti-TIGIT an antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody; Administration of such as pembrolizumab) and chemotherapy (such as taxanes (such as paclitaxel or nap-paclitaxel) results in an increase in PFS in the subject compared to baseline PFS. In some cases, an effective amount of an anti-TIGIT antagonist an antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as Administration of pembrolizumab) and chemotherapy (eg, taxane (eg, paclitaxel or nap-paclitaxel) results in an increase in DOR. In some cases, an effective amount of an anti-TIGIT antagonist antibody (eg, as disclosed herein) An anti TIGIT antagonist antibody such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody such as atezolizumab, or an anti PD-1 antagonist antibody such as pembrolizumab), and chemotherapy ( For example, administration of a taxane (eg, paclitaxel or nap-paclitaxel) prolongs the subject's OS.

The present invention also provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab; or an anti-PD-1 antagonist antibody, such as pembrolizumab), and a chemotherapeutic combination comprising administering to a subject in need thereof, wherein the chemotherapy combination comprises an effective amount of a platinum-based chemotherapeutic agent. and an effective amount of a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is a taxane (eg, paclitaxel or nap-paclitaxel). In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, e.g. Atezoli) Zumab) every 2 weeks (eg, on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, each on Day 1 of a 28-day dosing cycle). In some cases, the chemotherapy combination (eg, the platinum-based chemotherapeutic agent and the taxane (eg, paclitaxel or nap-paclitaxel) is administered weekly, every 2 weeks, every 4 weeks, or 3 times every 4 weeks (eg, on days 1, 8, and 15 of each 28-day dosing cycle).

In certain embodiments, the method comprises an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg atezolizumab), a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and a taxane (eg, paclitaxel or nap-paclitaxel) to a subject in need thereof, wherein said anti-TIGIT antagonist An antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab) are administered every 3 weeks (eg, each on day 1 of a 21 day dosing cycle), the chemotherapy combination (eg, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and the taxane (eg, paclitaxel or nap-paclitaxel)) are administered at the same frequency (eg, every 3 weeks, eg, on Day 1 of each 21 day dosing cycle) In some cases, the dosing is continued for 4 to 6 induction dosing cycles (eg, 4 induction dosing cycles) , 5 induction dosing cycles, or 6 induction dosing cycles).After the induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles.In certain embodiments, the one or more maintenance dosing cycles The cycle does not include the platinum-based chemotherapeutic agent.

In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the taxane (eg, paclitaxel or nap-paclitaxel) result in CR or PR. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the taxane (eg, paclitaxel or nap-paclitaxel) result in an increase in PFS in the subject. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the taxane (eg, paclitaxel or nap-paclitaxel) prolong OS in the subject.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the taxane (eg, paclitaxel or nap-paclitaxel) are being treated for a solid tumor or locally advanced or metastatic cancer. Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g. ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, Stage IIIB NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously received treatment for stage IV NSCLC) cervical cancer (eg, stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (eg, TNBC (eg, early TNBC) (eTNBC)) or HER2-positive breast cancer); (eg, MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; ovarian cancer; stomach cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or low MSI CRC).

Also disclosed herein is an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or Methods and uses are provided that involve administering an anti-PD-1 antagonist antibody, such as pembrolizumab), and a chemotherapeutic combination to a subject in need thereof, wherein the chemotherapy combination comprises an effective amount of a platinum-based chemotherapeutic agent and An effective amount of a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is a topoisomerase II inhibitor (eg, etoposide). In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody, e.g. Atezoli) Zumab) every 2 weeks (eg, on days 1 and 15 of each 28-day dosing cycle), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, each on Day 1 of a 28-day dosing cycle). In some embodiments, the chemotherapy combination (eg, the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor (eg, etoposide)) is administered weekly, every 2 weeks, every 4 weeks, or every 4 weeks. It is administered three times (eg, on days 1, 8, and 15 of each 28-day dosing cycle). In some embodiments, the topoisomerase II inhibitor (eg, etoposide) is administered more frequently than the platinum-based chemotherapeutic agent (eg, 3 times per week, eg, days 1, 2 of each dosing cycle) day, and on day 3).

In certain embodiments, the method comprises an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg atezolizumab), a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and a topoisomerase II inhibitor (eg, etoposide) to a subject in need thereof, wherein said An anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab) are administered every 3 weeks ( For example, on Day 1 of each 21 day dosing cycle), the chemotherapy combination (eg, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin)) and the topoisomerase II inhibitor (eg, eto Forsyd) is administered at the same frequency (eg, every 3 weeks, eg, on Day 1 of each 21-day dosing cycle) In some cases, the dosing is continued for 4 to 6 induction dosing cycles (eg, , 4 induction dosing cycles, 5 induction dosing cycles, or 6 induction dosing cycles).After the induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, The one or more maintenance dosing cycles do not include the platinum-based chemotherapeutic agent or the topoisomerase II inhibitor (eg, etoposide).

In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg carboplatin or cisplatin), and the topoisomerase II inhibitor (eg etoposide) (a) generate CR or PR. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the topoisomerase II inhibitor (eg, etoposide) result in an increase in PFS in the subject. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the topoisomerase II inhibitor (eg, etoposide) prolong OS in the subject.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the topoisomerase II inhibitor (eg, etoposide) are treated for solid tumors or locally advanced or metastatic cancer. are receiving Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g. ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, Stage IIIB NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously received treatment for stage IV NSCLC) cervical cancer (eg, stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (eg, TNBC (eg, early TNBC) (eTNBC)) or HER2-positive breast cancer); (eg, MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; ovarian cancer; stomach cancer (eg, gastroesophageal junction cancer); or CRC (eg, MSS or low MSI CRC).

Also disclosed herein is an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or Provided are methods and uses that involve administering an anti-PD-1 antagonist antibody, such as pembrolizumab), and a VEGF antagonist (eg, an anti-VEGF antibody, such as bevacizumab) to a subject in need thereof. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered every 3 weeks (eg, on Day 1 of each 21-day dosing cycle).

In certain embodiments, the method comprises an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg atezolizumab), and the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (eg, as disclosed herein) anti-TIGIT antagonist antibodies, such as tyragolumab), the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody, such as atezolizumab), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizu) mob)) every 3 weeks (eg, on Day 1 of each 21-day dosing cycle). In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) result in an increase in OS in the subject. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) result in an increase in PFS in the subject.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), and the subject receiving the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is being treated for a solid tumor or locally advanced or metastatic cancer. Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g. ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, Stage IIIB NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously received treatment for stage IV NSCLC) cervical cancer (e.g., stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer); eTNBC) or HER2 positive breast cancer); head and neck cancer (eg SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); bladder cancer (eg, MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; or CRC (eg, MSS or low MSI CRC).

The present invention includes a method of treating cancer in a cancer patient comprising administering to the patient a combination of atezolizumab, bevacizumab and tiragolumab in an amount effective to treat the cancer.

Also disclosed herein is an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), an anti-PD-1 antagonist antibody, and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) ))) to a subject in need thereof, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), an anti-PD-1 antagonist antibody, and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevaciz) Mab)) is administered every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist antibody is pembrolizumab.

In certain embodiments, the method comprises an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), an anti-PD-L1 antagonist antibody, and a VEGF antagonist (eg, an anti-VEGF antibody). (eg, bevacizumab)) to a subject in need thereof, wherein said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), said anti-PD- The L1 antagonist antibody, and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) are administered every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist The antibody is pembrolizumab. In some cases, an effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (eg, an anti-VEGF antibody ( For example, bevacizumab)) results in an increase in OS in the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some cases, an effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (eg, an anti-VEGF antibody ( For example, bevacizumab)) results in an increase in PFS in the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is being treated for a solid tumor or locally advanced or metastatic cancer, wherein the anti-PD-1 antagonist antibody is pembrolizumab. Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g. ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, Stage IIIB NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously received treatment for stage IV NSCLC) cervical cancer (e.g., stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer); eTNBC) or HER2 positive breast cancer); head and neck cancer (eg SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); bladder cancer (eg, MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; or CRC (eg, MSS or low MSI CRC).

Also provided herein are methods and uses that involve administering to a subject in need thereof effective amounts of tiragolumab and pembrolizumab. In some cases, tiragolumab is administered every 3 weeks (eg, on days 1 and 22 of each 42-day dosing cycle) and pembrolizumab is administered every 6 weeks (eg, on day 1 of each 42-day dosing cycle) e) is administered.

In certain embodiments, the method involves administering to a subject in need thereof an effective amount of tiragolumab and pembrolizumab, wherein tiragolumab is administered every 3 weeks (eg, the first of each 42-day dosing cycle). days and 22) and pembrolizumab is administered every 6 weeks (eg, on Day 1 of each 42-day dosing cycle). In some cases, the effective amounts of tiragolumab and pembrolizumab result in an increase in OS in the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some cases, the effective amounts of tiragolumab and pembrolizumab result in an increase in PFS in the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

In some cases, the subject receiving tiragolumab and pembrolizumab is being treated for a solid tumor or locally advanced or metastatic cancer, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

Additionally or alternatively, the cancer is lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), SCLC (e.g. ES-SCLC), NSCLC (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, Stage IIIB NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously received treatment for stage IV NSCLC) cervical cancer (e.g., stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer); eTNBC) or HER2 positive breast cancer); head and neck cancer (eg SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); bladder cancer (eg, MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; or CRC (eg, MSS or low MSI CRC).

Also disclosed herein is a method of treating a subject having cancer, comprising: an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, 3 A method is provided, comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a platinum-based chemotherapeutic agent per week, and one or more dosing cycles of a non-platinum-based chemotherapeutic agent every three weeks. In some cases, the method includes an induction phase and a maintenance phase. In some cases, the induction and maintenance phases each comprise one or more dosing cycles. In some cases, the maintenance phase does not include administration of the platinum-based chemotherapeutic agent. In some cases, the maintenance phase does not include administration of the non-platinum-based chemotherapeutic agent. In some cases, the maintenance phase comprises one or more dosing cycles of the anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and the PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks. do.

Also disclosed herein is a method of treating a subject having cancer, comprising one of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and an anti-PD-1 antagonist antibody at a dose of about 100 mg to about 300 mg every 3 weeks. There is provided a method comprising administering to the subject a dosing regimen comprising at least one dosing cycle, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

Also provided herein is an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having cancer, wherein the method is according to a method provided herein.

Also provided herein is the use of an anti TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject or population of subjects having cancer, wherein said treatment is according to a method provided herein. In some embodiments, the PD-1 axis binding antagonist is provided in a separate formulation. In other embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single dosage form. In some aspects, tiragolumab and atezolizumab are combined in an IV bag prior to administration.

dosing of the formulation

Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, VEGF antagonists, and chemotherapeutic agents is described in Section III(K).

Cancer characterization and selection

In any of the methods, uses, or compositions for use described herein, the cancer may be a solid tumor or a locally advanced or metastatic cancer. In some cases, the cancer is lung cancer (eg, early stage lung cancer (eg, resectable lung cancer), SCLC (eg, ES-SCLC), NSCLC (eg, squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, IIIB) Stage NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously been treated for stage IV NSCLC) cervical cancer (e.g., stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (e.g., TNBC (e.g., early TNBC) eTNBC)) or HER2 positive breast cancer); head and neck cancer (eg SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); liver cancer (eg, HCC, such as locally advanced or metastatic HCC and/or unresectable HCC); bladder cancer ( e.g., MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; (eg, MSS or low MSI CRC) In some cases where the subject has breast cancer, the subject has not received prior systemic therapy for metastatic breast cancer.

In some cases, in a method, use, or compositions for use described herein, the subject does not have an epidermal growth factor receptor (EGFR) or an anaplastic lymphoma kinase (ALK) genomic tumor abnormality. In some cases, in a method, use, or compositions for use described herein, the subject does not have a sensitizing EGFR gene mutation or ALK gene rearrangement. In some cases, the subject has an Eastern Corporate Oncology Group (ECOG) systemic activity (PS) of 0 or 1.

Methods for detecting the mutant state EGFR and ALK are generally known in the art, and DNA from a clinical sample (e.g., a tumor biopsy or a blood sample (e.g., circulating tumor DNA in blood)) can be analyzed using next-generation sequencing methods; including, but not limited to, sequencing using, for example, targeted gene pulldown and sequencing methods described in Frampton et al. ( Nature Biotechnology . 31(11): 1023-1033, 2013), which is incorporated herein in its entirety. This next-generation sequencing method can be used in conjunction with any of the methods disclosed herein to detect a variety of mutations (e.g., insertions, deletions, base substitutions, local gene amplifications and/or homozygous gene deletions), while at the same time compact Allows the use of samples (eg, small core needle biopsy, fine needle aspiration and/or cell blocks) or fixed samples (eg, formalin-fixed and paraffin-embedded ( FFPE ) samples). and other methods for detecting the mutant status of ALK include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods.Exemplary methods for detecting the mutant status of ALK are disclosed in US Pat. No. 9,651,555, , which is incorporated herein in its entirety In some cases, the VENTANA® anti- ALK (D5F3) IHC assay is used to determine the mutation status of the ALK gene.

In some cases of any of the methods described herein, the mutation is a sensitizing EGFR mutation. Sensitizing EGFR mutations are generally known in the art and described in US Patent Publication Nos. US 2018/0235968 and in Juan et al. ( Therapeutic Advances in Medical Oncology. 9(3): 201-216, 2017), which is incorporated herein by reference in its entirety. In some cases, the sensitizing EGFR mutation is a mutation in any one of exon 18-21 (eg, a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some cases, the sensitizing EGFR mutation is a deletion in exon 19 (del19). In other examples, the sensitizing EGFR mutation is an L858R point mutation in exon 21. In some cases, the sensitizing EGFR mutation is a G719X point mutation of exon 18, wherein "X" is most commonly C, A, or S. In some cases, the sensitizing EGFR mutation is a G719S point mutation of exon 18. In some cases, the sensitizing EGFR mutation is a G719A point mutation in exon 18. In some cases, the sensitizing EGFR mutation is an S720F point mutation in exon 18. In some cases, the sensitizing EGFR mutation is an L861Q point mutation in exon 21. In some cases, the sensitizing EGFR mutation is an L861R point mutation in exon 21. In other cases, the sensitizing EGFR mutation is the T790M point mutation. In some cases, the sensitizing EGFR mutation is an E709X point mutation, wherein “X” is most commonly K, A, or H. In some cases, the sensitizing EGFR mutation is an S768I point mutation.

In some cases of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are generally known in the art and described in US Pat. Nos. 9,651,555 and in Du et al. ( Thoracic Cancer. 9: 423-430, 2018), which is incorporated herein by reference in its entirety. In some cases, ALK gene rearrangement results in the production of oncogenic ALK tyrosine kinases that activate downstream signaling pathways to increase cell proliferation and survival. In some cases, the ALK gene rearrangement is a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A , BIRC6, RANBP2, ATIC, CLTC, TMP4, and MSN . ALK rearrangement with and forms a fusion oncogene. In some cases, the ALK gene rearrangement is an EML4 rearrangement with ALK and forms the fusion oncogene EML4-ALK .

In some instances, in a method, use, or compositions for use described herein, the subject is free of the lung lymphothelioma-like carcinoma subtype of NSCLC. Methods for detecting subtypes of NSCLC are well known in the art and are based on histopathological criteria, or by molecular characteristics (e.g., biomarkers (e.g., specific genes or proteins encoded by said genes)). subtypes characterized by expression of one or a combination). In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some cases, the tissue sample is a tumor sample.

In some cases, in a method, use, or compositions for use described herein, the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection. An indicator of active or chronic active EBV infection for use in the methods described herein is EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein- bar virus particles, but are not limited thereto. Methods for detecting the presence of one or more indicators of active or chronic active EBV infection comprising EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample of a subject are well known in the art. serological diagnosis (e.g., detection of EBV DNA (e.g., by PCR analysis of a blood sample for detection of EBV virus particles) or detection of EBV antigen or anti-EBV antibody (e.g., EBNA, EBV IgM or detection of EBV IgG))). In some cases, the sample is selected from the group consisting of a whole blood sample, a serum sample, and a plasma sample. In some cases, the subject is negative for EBV IgM and/or is negative by EBV PCR. In some cases, the subject is negative for EBV IgM and/or negative by EBV PCR and positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA). In other cases, the subject is negative for EBV IgG and/or negative for EBNA.

In some cases, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1 selected tumor (eg, minimal PD-L1 positive tumor as determined by IHC using SP263 or 22C3 antibody) As determined by IHC with SP142 antibody, the fraction of cells or the proportion of tumor area occupied by tumor PD-L1-expressing or PD-L1-expressing tumor infiltrating immune cells (IC) with TPS ≥ 30% (eg ≥ 50%) 1% or more). In some cases, the PD-L1 selected tumor is a tumor that has been determined to be at least 30% (eg, at least 50%) by immunohistochemical (IHC) analysis of a PD-L1 positive tumor cell fraction or PD-L1 TPS. In some cases, the PD-L1-selected tumor is a tumor in which the proportion of tumor area occupied by PD-L1-expressing immune cells (IC) is determined by immunohistochemical (IHC) analysis to be greater than or equal to 1%. In some cases, the IHC assay uses anti-PD-L1 antibodies SP263, 22C3, SP142, or 28-8. In some cases, the IHC assay uses the anti-PD-L1 antibody SP263. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, the IHC assay uses anti-PD-L1 antibody 22C3. In some cases, the tumor sample was determined to have a TPS of 50% or greater. In some cases, the PD-L1-positive tumor cell fraction (eg, as determined by positive staining with anti-PD-L1 antibody SP263 (eg, using a Ventana assay)) is determined by using anti-PD-L1 antibody 22C3 greater than 50% as determined by positive staining used (eg, using pharmDx assay), or as determined by positive staining with anti-PD-L1 antibody 28-8. In some embodiments, the fraction of PD-L1-positive tumor cells is greater than or equal to 30% as determined by positive staining with anti-PD-L1 antibody SP142. In some cases, the IC was determined to be greater than or equal to 1% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 5% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 10% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 1% and less than 50% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 1% and less than 30% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay).

In some cases, in a method, use, or compositions for use described herein, the tumor sample obtained from the individual has a detectable protein expression level of PD-L1. In some cases, detectable protein expression levels of PD-L1 were determined by IHC assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 1% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 1% and less than 5% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 5% and less than 50% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 50% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 1% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 1% and less than 5% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 5% and less than 10% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 10% of the tumor sample.

In some cases, in a method, use, or compositions for use described herein, the tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1. In some cases, the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. became In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some cases, the tissue sample is a tumor sample. In some cases, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

response to treatment

In some embodiments of any of the methods described herein, the subject's response to therapy can be characterized by one or more measures. In some embodiments, the treatment results in CR or PR. In some embodiments, the treatment results in an increase in PFS or DOR.

In some cases, the treatment increases the subject's PFS, eg, as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. causes For example, in embodiments where no chemotherapeutic agent is administered (eg, only an anti TIGIT antagonist antibody (eg, tyragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), the Treatment results in an increase in the subject's PFS, eg, as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an alkylating agent (eg, cyclophosphamide), a taxane (eg, paclitaxel)) An anti-TIGIT antagonist antibody (eg, tyragolumab) and a PD-1 axis binding antagonist (eg, atezolizumab) in combination with (eg, nap-paclitaxel), and/or a topoisomerase II inhibitor (eg, doxorubicin)) ) is administered, the treatment is compared to (i) treatment with a PD-1 axis binding antagonist and one or more chemotherapeutic agents in the absence of an anti-TIGIT antagonist antibody; (ii) in the absence of a PD-1 axis binding antagonist of PFS in a subject compared to treatment with an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents; and/or (iii) treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody in the absence of one or more chemotherapeutic agents. causes an increase.

In some cases, the treatment prolongs the subject's OS, eg, as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. make it For example, in embodiments where no chemotherapeutic agent is administered (eg, only an anti-TIGIT antagonist antibody (eg, tyragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), the Treatment results in an increase in the subject's OS, eg, as compared to treatment with a PD-1 axis binding antagonist without an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody without a PD-1 axis binding antagonist. one or more chemotherapeutic agents (eg, platinum-based chemotherapeutic agents (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin)) and/or one or more non-platinum-based chemotherapeutic agents (eg, antimetabolites (eg, peme) Trexed, gemcitabine, or capecitabine), a taxane (e.g., paclitaxel (e.g., nap-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide)), an anti-TIGIT antagonist antibody ( In embodiments in which tiragolumab) and a PD-1 axis binding antagonist (eg, atezolizumab) are administered, the treatment comprises (i) a PD-1 axis binding antagonist and one or more chemotherapy without an anti-TIGIT antagonist antibody. (ii) treatment with an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents in the absence of a PD-1 axis binding antagonist; and/or (iii) PD- without one or more chemotherapeutic agents. results in an increase in OS in a subject compared to treatment with a uniaxial binding antagonist and an anti-TIGIT antagonist antibody.

The progression-free survival of the subject was determined by Eisenhauer et al., Eur. J. Cancer . 2009, 45:228-47, it can be measured according to the RECIST v1.1 standard. In some embodiments, PFS is measured as the period from initiation of treatment to the first occurrence of disease progression as determined by the RECIST v1.1 criteria. In some embodiments, PFS is measured as the time from initiation of treatment to death. .

In some embodiments, the treatment described herein reduces the subject's PFS by at least about 2.4 months (eg, by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0- by 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months , 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the subject's PFS by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months) by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, treatment reduces the subject's PFS by at least about 2 months (eg, by 2 to 120 months, by 3 to 100 months, by 4 to 80 months, by 6 to 60 months, by 8 to 48 months) , by 9-36 months, by 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months , 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 (by months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) make it

In some embodiments, treatment increases the subject's DOR by at least about 2.4 months (eg, by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months) , by 6.0-36 months, by 8.0-24 months, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months , 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment increases the subject's DOR by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months) by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, treatment increases the subject's DOR by at least about 2 months (eg, by 2 to 120 months, by 3 to 100 months, by 4 to 80 months, by 6 to 60 months, by 8 to 48 months) , by 9-36 months, by 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months , 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 (by months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) make it

In some embodiments, OS is measured as the period from initiation of treatment to death. In some cases, the treatment reduces the subject's OS by at least about 2 months (eg, by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months) , by 7-48 months, by 8-36 months, by 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months , 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 Months, 20 Months, 21 Months, 22 Months, 23 Months, 24 Months, 25 Months, 26 Months, 27 Months, 28 Months, 29 Months, 30 Months, 31 Months, 32 Months, 33 Months, 34 Months, 35 Months, or by 36 months). In some cases, the treatment reduces the subject's OS by at least about 3.3 months (eg, by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months) , by 8-36 months, or by 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months , 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, by 34 months, 35 months, or 36 months). In some cases, the treatment reduces the subject's OS by at least about 5.3 months (eg, by 5.3 to 120 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 to 24 months). by, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months , by 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

B. Treatment methods and uses associated with lung cancer

Lung cancer continues to be the leading cause of cancer death worldwide. In the United States, it is the most common cancer in both men and women, accounting for 12% to 14% of all new cancer cases. By 2020, approximately 228,820 new cases of lung cancer will occur and 135,720 deaths are expected in the United States (Siegel et al. CA Cancer J Clin. 70:7-30 (2020)).

non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, accounting for approximately 85% of all cases.

Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, accounting for approximately 80%-85% of all cases (Osmani et al. Semin Cancer Biol. 52 (Pt 1):103-9 (2018)). NSCLC can be divided into two main histological types: adenocarcinoma and squamous cell carcinoma (Travis et al. 2011). Adenocarcinoma histology accounts for about 40% to 50% of all NSCLCs, whereas squamous cell histology accounts for about 20% to 30% of NSCLCs (Osmani et al. Semin Cancer Biol. 52 (Pt 1):103-9 ( 2018)). The remaining cases of NSCLC are represented by large cell carcinomas, neuroendocrine tumors, and sarcoma carcinomas, with poorly differentiated histology.

In the early stages, NSCLC is treated surgically for therapeutic purposes. However, 30-70% of patients undergoing resection recur and die as a result of disease progression (Siegel et al. Cancer Statistics. CA Cancer J Clin. 70:7-30 (2020)). Therefore, there is a high unmet need for improved medical interventions for early NSCLC.

For advanced disease, the overall 5-year survival rate is 2%-4%. Poor prognostic factors for survival in patients with NSCLC include disease progression at initial diagnosis, systemic activity, and a history of unintended weight loss. More than half of NSCLC patients are diagnosed with a distant disease, which is a direct cause of poor survival prospects.

Almost all patients experience disease progression, despite improvements in first-line treatment of patients with advanced NSCLC, prolonging survival and reducing disease-related symptoms. In particular, cancer immunotherapy offers the potential for long-term disease control. In the setting of metastatic NSCLC, PD-L1/PD-1 blocking antibodies (e.g., atezolizumab, nivolumab, pembrolizumab) offer clinically meaningful benefits in patients with unselected or PD-L1-selected advanced NSCLC. provided; However, a significant proportion of patients still remain unresponsive or advanced to anti-PD-L1/PD-1 therapy, and the mechanisms of escape for these therapies are not well understood.

Thus, treatment (e.g., first line There is an unmet need in the field of developing effective immunotherapy for treatment) and methods of administering the same.

small cell lung cancer

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer cases. The majority (approximately 70%) of patients with small cell lung cancer (SCLC) are diagnosed with expanded-stage small cell lung cancer (ES-SCLC) with low survival rates (median OS of approximately 10 to 12 months). Chemotherapy alone can relieve symptoms and prolong survival in patients with expanded-stage small cell lung cancer (ES-SCLC), but long-term survival is rare. The 5-year relative survival rate for patients with stage I SCLC is approximately 31%. In stage IV, the 5-year relative survival rate decreases to about 2%.

Therefore, there is a need in the field for improved treatments for lung cancer (eg, SCLC, such as ES-SCLC).

i. Methods and uses for the treatment of lung cancer

Disclosed herein is a method of treating a population of subjects with lung cancer, comprising a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. Provided is a method comprising administering to said subject population, wherein said treatment is for at least about 6 months (eg, at least about 6 months (eg, at least about 6 months (eg, 6 months to 24 months) (eg, about 6 months to about 15 months (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months or 15 months), such as about 6 months to about 13 months ( For example, 6 months, 6.5 months, 7 months, 7.5 months, 8 months, 8.5 months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 12.5 months, 13 months)), such as , from about 8 months to about 10 months (eg, 8.1 months, 8.2 months, 8.3 months, 8.4 months, 8.5 months, 8.6 months, 8.7 months, 8.8 months, 8.9 months, 9.0 months, 9.1 months, 9.2 months, 9.3 months, 9.4 months, 9.5 months, 9.6 months, 9.7 months, 9.8 months, 9.9 months, 10.0 months), in some cases, treatment is from about 8.2 months to about 9.2 months (e.g., about 8.2 months, 8.4 months, 8.6 months, 8.8 months, 9.0 months, or 9.2 months, such as 8.2-8.4 months, 8.4-8.6 months, 8.6-8.8 months, 8.8-9.0 months, or 9.0-9.2 months) Generates the median PFS.

Also disclosed herein is a method of treating a population of subjects having lung cancer, comprising administering an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and one or more dosing cycles of a topoisomerase II inhibitor. Provided is a method comprising administering therapy to said population of subjects, wherein said treatment is for at least about 12 months (eg, at least about 12 months to about 40 months (eg, about 12 months to about 30 months (eg, 12 months)). months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, or 30 months), such as from about 12 months to about 20 months (eg, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, or 20 months)) In some cases, the treatment is about 15.3 months to about 17.6 months (e.g., about 15.5 months, 16 months, 16.5 months, 17 months, 17.5 months, or 17.6 months, such as 15.3-16 months) months, 16-17 months, or 17-17.6 months).

ii. Methods and uses for the treatment of small cell lung cancer

Disclosed herein is an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), platinum a subject or a population of subjects comprising administering to the subject or population of subjects one or more dosing cycles of a chemotherapeutic agent (eg, carboplatin or cisplatin), and a topoisomerase II inhibitor (eg, etoposide) Methods and uses are provided for treating lung cancer (eg, small cell lung cancer (SCLC), such as diastolic SCLC (ES-SCLC)) in a subject population.

Dosing regimen, administration, and response to treatment

In one aspect, the treatment methods and uses of the invention described herein are administered to a subject or population of subjects having lung cancer (eg, SCLC, such as ES-SCLC) in an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist as disclosed herein). administering an antibody such as tyragolumab), a PD-1 axis binding antagonist (such as an anti-PD-L1 antagonist antibody (such as atezolizumab)), a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor and wherein said treatment is compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody ( PFS), thereby treating said subject or population of subjects. In some cases, the treatment comprises overall survival (OS) of the subject or population of subjects compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. ) is extended.

In some embodiments, the subject's PFS is described in Eisenhauer et al., Eur. J. Cancer . 2009, 45:228-47 according to RECIST v1.1 criteria as described. In some embodiments, PFS is measured as the period from initiation of treatment to the first occurrence of disease progression as determined by the RECIST v1.1 criteria. In some embodiments, PFS is measured as the time from initiation of treatment to death. .

In some embodiments, the treatment is compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody in the subject or population of subjects. PFS by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months by, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months , 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months , by 35 months, or by 36 months). In some embodiments, the treatment is compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody in the subject or population of subjects. PFS by at least about 4 months (e.g., by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months, by 9 to 36 months, or by 10 to 24 months) by months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months. , 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 Months, 20 Months, 21 Months, 22 Months, 23 Months, 24 Months, 25 Months, 26 Months, 27 Months, 28 Months, 29 Months, 30 Months, 31 Months, 32 Months, 33 Months, 34 Months, 35 Months, or by 36 months). In some embodiments, the treatment is compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody in the subject or population of subjects. PFS by at least about 2 months (e.g., by 2 to 120 months, by 3 to 100 months, by 4 to 80 months, by 6 to 60 months, by 8 to 48 months, by 9 to 36 months, or by 10 to 24 months) by months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months. , 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months , by 33 months, 34 months, 35 months, or 36 months). In some aspects, said treatment is PFS of said subject or population of subjects compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody. to at least about 3 months to about 4 months.

In some cases, the methods and uses of treating a subject or population of subjects having lung cancer (eg, SCLC, such as ES-SCLC) include administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist as disclosed herein). TIGIT antagonist antibodies, such as tyragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies, such as atezolizumab), platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin), and topoiso and administering a merase II inhibitor (eg, etoposide), wherein said treatment is without said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase. prolongs the OS of the subject or population of subjects as compared to treatment with a II inhibitor.

In some embodiments, OS is measured as the period from initiation of treatment to death. In some instances, the treatment reduces the OS of the subject or population of subjects as compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody. by at least about 2 months (e.g., by 2 to 120 months, by 3 to 110 months, by 4 to 100 months, by 5 to 80 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months; or by 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months , 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, said treatment is an OS of said subject or population of subjects compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody. by at least about 3.3 months (e.g., by 3.3 to 120 months, by 4 to 100 months, by 5 to 80 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 to 24 months by, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months , 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, said treatment is an OS of said subject or population of subjects compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody. by at least about 5.3 months (e.g., by 5.3 to 120 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 to 24 months, such as by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months , by 34 months, 35 months, or 36 months).

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 30 mg to about 1200 mg (eg, from about 30 mg to about 1100) every 3 weeks. mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, For example, a dose (eg, a fixed dose) of 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is from about 30 mg to about 600 mg (eg, from about 50 mg to about) every 3 weeks. 600 mg, such as about 60 mg to about 600 mg, such as about 100 mg to about 600 mg, such as about 200 mg to about 600 mg, such as about 200 mg to about 550 mg, such as about 250 mg to about A dose (eg, a fixed dose) of 500 mg, such as about 300 mg to about 450 mg, such as about 350 mg to about 400 mg, such as about 375 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose (eg, a fixed dose) of about 600 mg every 3 weeks.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is 30 mg to 1200 mg (eg, 30 mg to 1100 mg, eg, 60 mg to 1000 mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as , 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) (eg, a fixed dose). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 30 mg to 600 mg (eg, 50 mg to 600 mg, such as every 3 weeks) , 60 mg to 600 mg, such as 100 mg to 600 mg, such as 200 mg to 600 mg, such as 200 mg to 550 mg, such as 250 mg to 500 mg, such as 300 mg to 450 mg, such as 350 mg to 400 mg, such as 375 mg) (eg, a fixed dose). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg (eg, a fixed dose) every 3 weeks.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg (eg, a fixed dose) every 3 weeks. In some cases, combination therapy (eg, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), a topoisomerase II inhibitor (eg, etoposide), and/or platinum A dose (e.g., a fixed dose) of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tyragolumab) administered in combination therapy with a chemotherapeutic agent (e.g., carboplatin or cisplatin) ) may be reduced compared to the standard dose of the anti-TIGIT antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 3 weeks. 1600 mg, such as about 200 mg to about 1600 mg, such as about 300 mg to about 1600 mg, such as about 400 mg to about 1600 mg, such as about 500 mg to about 1600 mg, such as about 600 mg to about 1600 mg, such as about 700 mg to about 1600 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg , eg, 1200±2.5 mg, eg, 1200±1.0 mg, eg, 1200±0.5 mg, eg, 1200 mg) (eg, a fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, a fixed dose) of about 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, a fixed dose) of about 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 100 mg to 1600 mg, such as every 3 weeks) , 200 mg to 1600 mg, such as 300 mg to 1600 mg, such as 400 mg to 1600 mg, such as 500 mg to 1600 mg, such as 600 mg to 1600 mg, such as 700 mg to 1600 mg, such as 800 mg to 1600 mg, such as 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to A dose (e.g., 1225 mg, such as 1190 mg to 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg) fixed capacity). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, a fixed dose) of 840 mg every two weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, a fixed dose) of about 1400 mg to 2000 mg every 3 weeks. . In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, a fixed dose) of 1400 mg to 2000 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, a fixed dose) of about 1680 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose (eg, a fixed dose) of 1680 mg every 4 weeks. In some cases, combination therapy (eg, an anti TIGIT antagonist antibody, such as an anti TIGIT antagonist antibody disclosed herein, such as tiragolumab), a topoisomerase II inhibitor (eg, etoposide), and/or platinum-based chemistry A dose (eg, a fixed dose) of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) administered as a therapy (eg, combination treatment with carboplatin or cisplatin) can be reduced compared to a standard dose of the PD-1 axis binding antagonist administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 50 mg/kg of the subject's body weight every 3 weeks. kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg /kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 15 mg/kg of the subject's body weight every 3 weeks. (e.g., about 0.1 mg/kg to about 15 mg/kg, such as about 0.5 mg/kg to about 15 mg/kg, such as about 1 mg/kg to about 15 mg/kg, such as about 2.5 mg/kg to about 15 mg/kg, such as about 5 mg/kg to about 15 mg/kg, such as about 7.5 mg/kg to about 15 mg/kg, such as about 10 mg/kg to about 15 mg/kg, such as , about 12.5 mg/kg to about 15 mg/kg, such as about 14 mg/kg to about 15 mg/kg, such as about 15 ± 1 mg/kg, such as about 15 ± 0.5 mg/kg, such as about 15 ± 0.2 mg/kg, such as about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 15 mg/kg administered every 3 weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 50 mg/kg of body weight of the subject every 3 weeks ( For example, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 15 mg/kg of body weight of the subject every 3 weeks ( For example, 0.1 mg/kg to 15 mg/kg, such as 0.5 mg/kg to 15 mg/kg, such as 1 mg/kg to 15 mg/kg, such as 2.5 mg/kg to 15 mg/kg, such as 5 mg/kg to 15 mg/kg, such as 7.5 mg/kg to 15 mg/kg, such as 10 mg/kg to 15 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 14 mg/kg to 15 mg/kg, for example 15 ± 1 mg/kg, such as 15 ± 0.5 mg/kg, such as 15 ± 0.2 mg/kg, such as 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 15 mg/kg administered every 3 weeks.

In some cases, combination therapy (eg, an anti TIGIT antagonist antibody, such as an anti TIGIT antagonist antibody disclosed herein, such as tiragolumab), a topoisomerase II inhibitor (eg, etoposide), and/or platinum-based chemistry The dose of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) administered as a therapy (eg, combination treatment with carboplatin or cisplatin) is administered as a monotherapy. may be reduced compared to a standard dose of the PD-1 axis binding antagonist.

In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 1-50 mg/ml/min (eg, 2-25 mg/ml/min, 3-15 mg/ml/min) min, 4-10 mg/ml/min, or 5 mg/ml/min, such as 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg /ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml /min, 45 mg/ml/min, 50 mg/ml/min). In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is a dose sufficient to achieve AUC=5 mg/ml/min.

AUC can be calculated using the Calvert formula (Calvert et al., J. Clin. Oncol . 1989, 7:1748-56):

Total dose (mg)　=(target AUC)　´(glomerular filtration rate [GFR]　+25)

In some cases, for example, 1200 mg of atezolizumab is equal to 15 m/kg of an average body weight based dose.

In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 200 mg to 1500 mg (eg, 300 mg to 1200 mg, 400 mg to 1100 mg, or 500 mg to 1000 mg, For example 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-750 mg, 750 mg-800 mg, 800 mg-900 mg, 900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg, such as about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg). In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is between about 500 mg and 1000 mg (eg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg). mg, or about 1000 mg).

In some cases, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40- 500 mg/m ² , 50-300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg /m ² , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg/m ² , about 110 mg/ m ² , about 120 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 250 mg/m ² , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , or about 1000 mg/m ² ). In some cases, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is about 100 mg/m ² .

In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 200 mg to 1500 mg (eg, 300 mg to 1200 mg, 400 mg to 1100 mg, or 500 mg to 1000 mg, For example 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-750 mg, 750 mg-800 mg, 800 mg-900 mg, 900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg, such as 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg). In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is between 500 mg and 1000 mg (eg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg). to be.

In some cases, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40- 500 mg/m ² , 50-300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as 20 mg/m ² , 30 mg/m ² , 40 mg/m ² , 50 mg/m ² , 60 mg/m ² , 70 mg/m ² , 80 mg/m ² , 90 mg/m ² , 100 mg/m ² , 110 mg/m ² , 120 mg/m ² , 130 mg/m ² , 140 mg/m ² , 150 mg/m ² , 160 mg/m ² , 170 mg/m ² , 180 mg/m ² , 190 mg/m ² , 200 mg/m ² , 250 mg/ m ² , 300 mg/m ² , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , or 1000 mg/m ² ) is. In some cases, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is 100 mg/m ² .

In any of the methods and uses of the invention, said anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody) (eg, atezolizumab)), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and a topoisomerase II inhibitor (eg, etoposide) are administered in one or more dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycle). In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab)) (with or without a platinum-based chemotherapeutic agent (eg carboplatin or cisplatin)) and/or the dosing cycle of the topoisomerase II inhibitor (eg etoposide) results in loss of clinical benefit (eg, , disease progression, drug resistance, death, or unacceptable toxicity). In some cases, the length of each dosing cycle is about 18 to 24 days (eg, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days). to be. In some cases, the length of each dosing cycle is about 21 days. In some cases, the length of each dosing cycle is about 14 days. In some cases, the length of each dosing cycle is about 28 days.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered on about day 1 (eg, day 1 ± 3 days) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) may be administered at a dose of about 600 mg (eg, on Day 1 of each dosing cycle, eg, each 21-day cycle). fixed dose) (ie, at a dose of about 600 mg every 3 weeks). In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 600 mg (eg, on Day 1 of each dosing cycle, eg, each 21 day cycle) fixed dose) (ie, at a dose of 600 mg every 3 weeks). Similarly, in some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered on about 1 day (eg, 1 day ± 3 days) of each dosing cycle. is administered For example, in some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a fixed dose of about 1200 mg on Day 1 of each 21-day cycle. It is administered intravenously (ie, at a dose of about 1200 mg every 3 weeks). In other examples, e.g., the PD-1 axis binding antagonist (e.g., an anti-PD-Ll antagonist antibody (e.g., atezolizumab)) is administered at a fixed dose of about 1200 mg (i.e., 3 administered intravenously (in a dose of about 1200 mg per week). In some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a fixed dose of 1200 mg on Day 1 of each 21-day cycle (ie, 3 weeks). at a dose of 1200 mg per day). In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab)) are both administered on about day 1 (eg, day 1±3) of each dosing cycle. In some cases, the platinum-based chemotherapeutic agent is administered on about day 1 (eg, day 1 ± 3 days) of each dosing cycle. In some cases, the topoisomerase II inhibitor is administered on about day 1 (eg, day 1 ± 3 days) of each dosing cycle. For example, in some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered intravenously at a dose of about 600 mg on Day 1 of each 21 day cycle. administered (ie, at a dose of about 600 mg every 3 weeks) and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered on Day 1 of each 21-day cycle. Administered intravenously at a dose of about 1200 mg (i.e., a dose of about 1200 mg every 3 weeks), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is used to achieve AUC=5 mg/ml/min. Sufficient doses are administered on Day 1 of each of the 4 initial dosing cycles, wherein the topoisomerase II inhibitor (eg, etoposide) is administered at 100 mg on Days 1, 2 and 3 of each of the 4 initial dosing cycles. It is administered at a dose of /m ² . In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered intravenously at a dose of 600 mg on Day 1 of each 21 day cycle (i.e., at a dose of 600 mg every 3 weeks), the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose of 1200 mg on Day 1 of each 21-day cycle ( That is, a dose of about 1200 mg every 3 weeks) is administered intravenously, and the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is administered in 4 initial doses at a dose sufficient to achieve AUC=5 mg/ml/min. Administered on each day 1 of the cycle, wherein the topoisomerase II inhibitor (eg etoposide) is administered at a dose of 100 mg/m ² on days 1, 2 and 3 of each of the 4 initial dosing cycles. do.

In some cases, the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered in each of the four initial dosing cycles. In some cases, the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg on Day 1 of each of the four initial dosing cycles. In some cases, the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 600 mg on Day 1 of each of the four initial dosing cycles. In some cases, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg on day 1 of each of the four initial dosing cycles. In some cases, the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 1600 mg on each day 1 of four initial dosing cycles (eg, about 1200 on each day 1 of four initial dosing cycles) in a dose of mg). In some cases, the anti-TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg on Day 1 of each of the 4 initial dosing cycles. In some cases, the anti TIGIT antagonist antibody is administered at a dose of 30 mg to 600 mg on Day 1 of each of the 4 initial dosing cycles. In some cases, the anti-TIGIT antagonist antibody is administered at a dose of 600 mg on day 1 of each of the four initial dosing cycles. In some cases, the PD-1 axis binding antagonist is administered at a dose of 80 mg to 1600 mg on each day 1 of 4 initial dosing cycles (eg, a dose of 1200 mg on each 1 day of 4 initial dosing cycles) by). In some cases, the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on Day 1 of each of the 4 initial dosing cycles, and/or the topoisomerase II inhibitor is administered at a dose of 100 mg/m ² on days 1, 2 and 3 of each of the 4 initial dosing cycles.

In some cases, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are further administered in one or more additional cycles after the fourth initial dosing cycle. In some cases, the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg on each day of one or more additional dosing cycles (eg, about 30 on each day of one or more additional dosing cycles). mg to about 600 mg). In some cases, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg on each day of one or more additional dosing cycles. In some cases, the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg on each day of one or more additional dosing cycles (eg, on each day of one or more additional dosing cycles) at a dose of about 840 mg, 1200 mg, or 1680 mg). In some cases, the additional dosing cycle comprises administering the PD-1 axis binding antagonist (eg, atezolizumab) at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks includes doing For example, in some cases, each of the one or more dosing cycles is about 14 days, and the PD-1 axis binding antagonist (eg, atezolizumab) is administered on Day 1 of each of the one or more additional dosing cycles. It is administered at a dose of about 840 mg. In some cases, each of said one or more dosing cycles is about 21 days, and said PD-1 axis binding antagonist (eg, atezolizumab) is administered at about 1200 mg on Day 1 of said one or more additional dosing cycles. administered in dose. In some cases, each of said one or more dosing cycles is about 28 days, and said PD-1 axis binding antagonist (eg, atezolizumab) is administered at about 1680 mg on Day 1 of said one or more additional dosing cycles. administered in dose.

In some cases, the anti TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg on each day of one or more additional dosing cycles (eg, 30 mg to 1200 mg on each day of one or more additional dosing cycles) at a dose of 600 mg). In some cases, the anti-TIGIT antagonist antibody is administered at a dose of 600 mg on each day of the one or more additional dosing cycles. In some cases, the PD-1 axis binding antagonist is administered at a dose of 80 mg to 2000 mg on each day 1 of the one or more additional dosing cycles (eg, 840 mg on each day 1 of the one or more additional dosing cycles) mg, 1200 mg, or 1680 mg). In some cases, the additional dosing cycle comprises administering the PD-1 axis binding antagonist (eg, atezolizumab) at a dose of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks do. For example, in some cases, each of the one or more dosing cycles is 14 days, and the PD-1 axis binding antagonist (eg, atezolizumab) is administered 840 on day 1 of each of the one or more additional dosing cycles. It is administered in a dose of mg. In some cases, each of said one or more dosing cycles is 21 days, and said PD-1 axis binding antagonist (eg, atezolizumab) is administered at a dose of 1200 mg on Day 1 of said one or more additional dosing cycles. is administered In some cases, each of said one or more dosing cycles is 28 days, and said PD-1 axis binding antagonist (eg, atezolizumab) is administered at a dose of 1680 mg on Day 1 of said one or more additional dosing cycles. is administered

In some cases, a subject or population of subjects with lung cancer (eg, SCLC, eg, ES-SCLC) is administered to the subject or population of subjects at a dose (eg, from about 30 mg to about 1200 mg on Day 1 of each dosing cycle) , about 30 mg to about 1100 mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tyra goluumab), about 80 mg to about 2000 mg (such as about 100 mg to about 1600 mg, such as about 200 mg to about 1600 mg, such as about 300 mg to about 1600 mg, such as about 400, on Day 1 of each dosing cycle) mg to about 1600 mg, such as about 500 mg to about 1600 mg, such as about 600 mg to about 1600 mg, such as about 700 mg to about 1600 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg , such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg) PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) )), on the first day of each dosing cycle (such as at a dose of about 30 mg to 1200 mg (such as 30 mg to 1100 mg, such as 60 mg to 1000 mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg), at a dose of 80 mg to 2000 mg ( such as 100 mg to 1600 mg, such as 200 mg to 1600 mg, such as 300 mg to 1600 mg, such as 400 mg to 1600 mg, such as 500 mg to 1600 mg, such as 600 mg to 1600 mg, such as 700 mg to 1600 mg, such as 800 mg to 1600 mg, such as 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg) PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) at 1-50 mg/ml/min (eg 2-25 mg/ml/min, 3- 15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, such as 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml /min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/ min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min , 40 mg/ml/min, 45 mg/ml/min, 50 mg/ml/min, such as 5 mg/ml/min) a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and one or ^more dosing cycles (eg, 21 one dosing cycle), wherein the treatment is a PD-1 axis binding antagonist (e.g., anti-PD- the subject as compared to treatment with an L1 antagonist antibody (eg, atezolizumab), a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and a topoisomerase II inhibitor (eg, etoposide); or prolong the PFS and/or OS of the subject population.

In some cases, a subject or population of subjects with lung cancer (eg, SCLC, eg, ES-SCLC) is administered to the subject or population of subjects at a dose (eg, 30 mg to 1200 mg on Day 1 of each dosing cycle) mg to 1100 mg, such as 60 mg to 1000 mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), 80 mg to 2000 mg (eg 100 mg to 1600 mg, such as 200 mg to 1600 mg, such as 300 mg to 1600 mg, such as 400 mg to 1600 mg, such as 500 mg to 1600 mg, such as 600 mg to 1600 mg, such as 700 mg to 1600 mg, such as 800 mg to 1600 mg, such as 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg , such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg) PD-1 axis binding antagonists (such as , anti-PD-L1 antagonist antibody (eg, atezolizumab) at 1-50 mg/ml/min (eg 2-25 mg/ml/min, 3-15 mg/ml on Day 1 of each dosing cycle) /min, 4-10 mg/ml/min, or 5 mg/ml/min, such as 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg /ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ ml/min, 45 mg/ml/min, 50 mg/ml/min, such as 5 mg/ml/min) a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) in a dose sufficient to achieve an AUC, and One or more dosing cycles (eg, a 21 day dosing cycle) of a 100 mg/m ² dose of a topoisomerase II inhibitor (eg, etoposide) on each day 1, 2, and 3 of each dosing cycle. wherein the treatment comprises administering a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, an anti-PD-L1 antagonist antibody) PFS of the subject or population of subjects as compared to treatment with a chemotherapeutic agent (eg, carboplatin or cisplatin), a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and a topoisomerase II inhibitor (eg, etoposide))) and/or extend the OS.

In some cases, said treatment is an OS of said subject or population of subjects compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody. by at least about 3.3 months (e.g., by 3.3 to 120 months, by 4 to 100 months, by 5 to 80 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 to 24 months by, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months , 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, said treatment is an OS of said subject or population of subjects compared to treatment with said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase II inhibitor without said anti-TIGIT antagonist antibody. by at least about 5.3 months (e.g., by 5.3 to 120 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 to 24 months, such as by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months , by 34 months, 35 months, or 36 months).

In some embodiments, the treatment is compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody in the subject or population of subjects. PFS by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months by, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months , 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months , by 35 months, or by 36 months). In some embodiments, the treatment is compared to treatment with the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody in the subject or population of subjects. PFS by at least about 4 months (e.g., by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months, by 9 to 36 months, or by 10 to 24 months) by months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months. , 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 Months, 20 Months, 21 Months, 22 Months, 23 Months, 24 Months, 25 Months, 26 Months, 27 Months, 28 Months, 29 Months, 30 Months, 31 Months, 32 Months, 33 Months, 34 Months, 35 Months, or by 36 months).

In some embodiments, the subject or population of subjects comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and about 80 mg to about 2000 mg on Day 1 of each additional dosing cycle. One or more additional 21-day dosing cycles of the mg dose of atezolizumab are administered, wherein carboplatin and etoposide are omitted from each of said one or more additional dosing cycles.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 60 ± 15 minutes (eg, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes , about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered in about 60 ± 15 minutes (eg, about 45 minutes, about 46 minutes, about 47 minutes, About 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, to the subject or population of subjects by intravenous infusion over about 73 minutes, about 74 minutes, or about 75 minutes).

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is combined with the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli). Zumab)) previously administered to said subject or population of subjects. In some cases, for example, after administration of the anti-TIGIT antagonist antibody and prior to administration of the PD-1 axis binding antagonist, the method comprises an intermediate first observation period. In some cases, the method further comprises a second observation period following administration of the PD-1 axis binding antagonist. In some cases, the method includes both a first observation period following administration of the anti-TIGIT antagonist antibody and a second observation period following administration of the PD-1 axis binding antagonist. In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. In cases where the first and second observation periods are each about 60 minutes in length, the method comprises about 30 ± after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist during the first and second observation periods. recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) at 10 minutes. When the first and second observation periods are each about 30 minutes in length, the method comprises about 15 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist during the first and second observation periods. and recording vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) of the subject.

In other instances, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as Tyra). gorumab) prior to said subject or population of subjects. In some cases, for example, after administration of the PD-1 axis binding antagonist and prior to administration of the anti-TIGIT antagonist antibody, the method comprises an intermediate first observation period. In some cases, the method comprises a second observation period following administration of the anti-TIGIT antagonist antibody. In some cases, the method includes both a first observation period following administration of the PD-1 axis binding antagonist and a second observation period following administration of the anti-TIGIT antagonist antibody. In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. In cases where said first and second observation periods are each about 60 minutes in length, the method comprises about 30 ± after administration of said PD-1 axis binding antagonist and said anti-TIGIT antagonist antibody during said first and second observation periods recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) at 10 minutes. When the first and second observation periods are each about 30 minutes in length, the method comprises about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody during the first and second observation periods. and recording vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) of the subject.

In other cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, anti PD-L1 (atezolizumab) antagonist antibody) ) are administered to the subject or population of subjects simultaneously. In some cases, for example, following administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody), the method comprises an observation period. In some cases, the observation period is between about 30 minutes and about 60 minutes in length. In instances where the observation period is about 60 minutes in length, the method comprises about 30 ± 10 following administration of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody during the observation period. recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) in minutes. When the observation period is about 30 minutes in length, the method comprises administering the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody at about 15 ± 10 minutes during the observation period. The method may include recording vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) of the subject.

In any of the methods, uses, or compositions for use described herein, said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti a PD-L1 antibody (eg, atezolizumab)), a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and a topoisomerase II inhibitor (eg, etoposide)), or an agent thereof, one or more additional anti-cancer therapeutic agent(s) (e.g., an immunomodulatory agent (e.g., one or more immune co-suppressive receptors (e.g., selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA) an agent that decreases or inhibits one or more immune co-suppression receptors, such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab (YERVOY®)), or one or more immune co-stimulatory receptors (eg, Agents that increase or activate one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR, such as OX-40 agonists, such as OX-40 agonist antibodies), chemistries Therapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents such as the agents mentioned herein above) (separately or together) may be administered.

In some cases, the lung cancer is small cell lung cancer (SCLC), particularly diastolic SCLC (ES-SCLC). In some cases, the subject or population of subjects is treatment naive for ES-SCLC (eg, chemotherapy naive for ES-SCLC).

In some cases, the lung cancer is not selected for PD-L1 expression. In some cases, the lung cancer is selected for PD-L1 expression. In some cases, the lung cancer is selected for PD-L1 expression by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody, such as SP263, 22C3, SP142, or 28-8. in some cases, said anti-PD-L1 antibody is SP263 and said IHC assay is a Ventana SP263 IHC assay; the anti-PD-L1 antibody is 22C3 and the IHC assay is a pharmDx 22C3 IHC assay; wherein the anti-PD-L1 antibody is SP142 and the IHC assay is a Ventana SP142 IHC assay, or the anti-PD-L1 antibody is 28-8 and the IHC assay is a PalmDx 28-8 IHC assay.

In some embodiments, in a method, use, or compositions for use described herein, a tumor sample obtained from an individual has a detectable nucleic acid expression level of PD-L1. In some instances, the detectable nucleic acid expression level of PD-L1 was determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. . In some examples, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some examples, the tissue sample is a tumor sample. In some examples, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the small cell lung cancer (SCLC) is advanced stage small cell lung cancer (ES-SCLC), also referred to as stage 4 (IV) small cell lung cancer (SCLC). In some embodiments, the small cell lung cancer (SCLC) is on the Veterans Administration Lung Study Group (VALG) staging system (see, eg, Micke et al. Lung Cancer 2002, 37:271-6). thus or as defined histologically or cytologically. In some embodiments, small cell lung cancer (SCLC) is an expanded stage small cell lung cancer when the subject is inoperable and cannot be classified as having limited or limited stage small cell lung cancer (L-SCLC or LS-SCLC). (ES-SCLC). In some embodiments, the advanced stage small cell lung cancer (ES-SCLC) is detectable and/or has spread outside of the lung where the cancer first developed. In some embodiments, the advanced stage small cell lung cancer (ES-ESSCLC) is detectable and/or directed to other (eg, distant) organs such as, but not limited to, liver, adrenal glands, lymph nodes and/or brain. further spread out. In some embodiments, the expanded stage small cell lung cancer (ES-ESSCLC) is difficult to treat.

In some embodiments, the subject or population of subjects has a poor prognosis. In some embodiments, the subject or population of subjects is a treatment naive subject or population of subjects (eg, a chemotherapy naive subject or population of subjects). In some embodiments, a treatment naive subject is a subject who has not received prior treatment, eg, for cancer, small cell lung cancer (SCLC) or expanded stage small cell lung cancer (ES-SCLC). In some embodiments, the treatment naive subject has not received prior treatment for expanded stage small cell lung cancer (ES-SCLC). In some embodiments, the treatment naive subject has not received prior chemotherapy for the treatment of chemotherapy naive, e.g., cancer, small cell lung cancer (SCLC) and/or expanded stage small cell lung cancer (ES-SCLC). object that is not In some embodiments, the subject or population of subjects has not received treatment for expanded stage small cell lung cancer (ES-SCLC). In some embodiments, the subject or population of subjects has not received prior systemic treatment for expanded stage small cell lung cancer (ES-SCLC). In some embodiments, the subject or population of subjects has received prior chemoradiation therapy for limited-stage small cell lung cancer (LS-SCLC) for therapeutic purposes, and last

After a cycle of chemotherapy, radiation therapy, or chemoradiation, a treatment-free cycle of at least 6 months was experienced. In some embodiments, the subject or population of subjects has asymptomatic upper or cerebellar central nervous system (CNS) metastases. In some embodiments, the subject or population of subjects does not have metastasis to the midbrain, pons, medulla or spinal cord. In some embodiments, the subject or population of subjects has a central nervous system (CNS) disease and does not require corticosteroid treatment for the central nervous system (CNS) disease. In some embodiments, the subject or population of subjects has new asymptomatic metastases and has undergone radiation therapy and/or surgery for central nervous system (CNS) metastases. In some embodiments, the subject or population of subjects has a measurable disease according to/as defined by RECIST v1.1 criteria (eg, Eisenhauer et al., Eur. J. Cancer 2009, 45: 228). -247). In some embodiments, the subject or population of subjects has not received prior treatment with a CD137 agonist or immune checkpoint blockade therapy.

In some embodiments, the treatment results in CR or PR. In some cases, progression-free survival (PFS) of the subject or population of subjects is increased as compared to a baseline PFS time. In some cases, the baseline PFS time is in the absence of an anti-TIGIT antagonist antibody (eg, tyragolumab) (eg, an anti-PD-L1 antibody (eg, atezolizumab)), a platinum-based chemotherapeutic agent (eg, carboplatin) or cisplatin), and the median PFS time of a population of subjects treated with a topoisomerase II inhibitor (eg, etoposide).

In some cases, the methods further comprise an additional therapy. The additional therapy may include radiation therapy, surgery (eg, tumor resection and mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination thereof. It can be a combination. The additional therapy may be in the form of adjuvant or neoadjuvant therapy. In some embodiments, the additional therapy is administration of a small molecule enzyme inhibitor or an anti-metastatic agent. In some embodiments, the additional therapy is the administration of a side-effect limiting agent (eg, an agent intended to reduce the occurrence and/or severity of side effects of treatment, such as an anti-nausea agent, etc.). In some embodiments, the additional therapy is radiation therapy. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is a combination of radiation therapy and surgery. In some embodiments, the additional therapy is gamma irradiation.

Other additional therapeutic antibodies contemplated for use herein include alemtuzumab (Campath), bevacizumab ( ^AVASTIN® , Genentech); cetuximab (ERBITUX ^® , Imclone); Panitumumab (VECTIBIX ^® , Amgen), Rituximab (RITUXAN ^® , Genentech/Biogen IDec), Pertuzumab (OMNITARG ^® , 2C4, Genentech), Trastuzumab ( Heceptin (HERCEPTIN ^® , Genentech), tositumomab (bexa, corixia), antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG ^® , Wyeth), apolizumab, celizumab, ah tlizumab, bafinuzumab, vibatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, sidfucituzumab, sidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab Zumab, erlizumab, felbizumab, pontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, rabetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, moto vizumab, natalizumab, nimotuzumab, nolovizumab, numivizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pekfucituzumab, pectuzumab, pexelizumab, ralivizumab, rani vizumab, reslibizumab, reslizumab, resivizumab, lobelizumab, luflizumab, cibrotuzumab, ciflizumab, sontuzumab, takatuzumab tetraxetane, tadozumab, talizumab, tefiva Zumab, tocilizumab, toralizumab, tucotuzumab celmorleukin, tucusituzumab, umavizumab, urtoxazumab, eustekinumab, vicilizumab, and anti-interleukin-12 (ABT-874/J695) , Wires Research and Abbott Laboratories).

In some embodiments, the additional therapy is a therapy targeting the PI3K/AKT/mTOR pathway, an HSP90 inhibitor, a tubulin inhibitor, an apoptosis inhibitor, and/or a chemopreventive agent. In some embodiments, the additional therapy is CTLA-4 (also known as CD152), such as a blocking antibody, ipilimumab (also known as MDX-010, MDX-101, or ^Yervoy® ), Tre Melimumab (also known as ticilimumab or CP-675,206), antagonists directed against B7-H3 (also known as CD276), such as blocking antibodies, MGA271, antagonists directed against TGF beta, such as meth Rimumab (also known as CAT-192), presolimumab (also known as GC1008), or LY2157299, including adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR). treatment, treatment including adoptive transfer of T cells comprising a dominant-negative TGF beta receptor, such as a dominant-negative TGF beta type II receptor, treatment including the HERCREEM protocol (see, e.g., ClinicalTrials.gov Identifier NCT00889954), to CD137 Agents directed against (also known as TNFRSF9, 4-1BB, or ILA), such as an active antibody, urelumab (also known as BMS-663513), an agent directed against CD40, such as an active antibody, CP-870893 , an agonist directed against OX40 (also known as CD134), such as an active antibody administered in combination with a different anti OX40 antibody (eg, AgonOX), an agonist directed against CD27, such as an active antibody, CDX-1127, indole Amine-2,3-dioxygenase (IDO), 1-methyl-D-tryptophan (also known as 1-D-MT), anti-drug conjugate (in some embodiments, mertansine or monomethyl auristatin E) (MMAE)), anti-NaPi2b antibody-MMAE conjugate (also known as DNIB0600A or RG7599), trastuzumab emtansine (TDM1, ado-trastuzumab emtansine, or KADCYLA ^® , also known as Genentech) ), DMUC5754A, anti-drug conjugates targeting the endothelin B receptor (EDNBR), e.g. For example, an antibody directed against EDNBR conjugated with MMAE, an angiogenesis inhibitor, an antibody directed against VEGF such as VEGF-A, bevacizumab (Avastin ^® , also known as Genentech), angiopoietin 2 ( Antibodies directed against Ang2), MEDI3617 anti-tumor agents, agents targeting CSF-1R (also known as M-CSFR or CD115), anti-CSF-1R (also known as IMCCS4), interferons, e.g. , interferon alpha or interferon gamma, Roferon-A, GM-CSF (also known as recombinant human granulocyte macrophage colony-stimulating factor, rhu GM-CSF, sagramostim, or Leukine ^® ), IL -2 (also known as ^aldesleukin or Proleukin®), IL-12, an antibody targeting CD20 (in some embodiments, the antibody targeting CD20 is obinutuzumab (GA101 or Ga (also known as ^Gazyva® ) or rituximab), an antibody that targets GITR (in some embodiments, the antibody that targets GITR is TRX518), in combination with a cancer vaccine (in some embodiments, The cancer vaccine is a peptide cancer vaccine, and in some embodiments, a customized peptide vaccine; In some embodiments, the peptide cancer vaccine is a multivalent long peptide, multi-peptide, mixed peptide, hybrid peptide, or dendritic cell sensitized to a peptide (eg, Yamada et al., Cancer Sci, 104:14-21, 2013). )), in combination with adjuvant TLR agonists, such as poly-ICLC (also known as ^Hiltonol® ), LPS, MPL, or CpG ODN, tumor necrosis factor (TNF) alpha, IL-1, HMGB1 , IL-10 antagonist, IL-4 antagonist, IL-13 antagonist, HVEM antagonist, ICOS agonist, such as ICOS-L, or agonistic antibody directed against ICOS, CX3CL1 targeted therapy, CXCL10 targeted therapy, CCL5 targeted therapy , LFA-1 or ICAM1 agonists, Selectin agonists, targeted therapy, inhibitors of B-Raf, vemurafenib (also known as Zelboraf ^® ), dabrafenib (also known as Tafinlar ^® ) erlotinib (also known as Tarceva ^® ), an inhibitor of MEKs such as MEK1 (also known as MAP2K1) or MEK2 (also known as MAP2K2), cobimetinib (GDC-0973 or XL-518) ), trametinib (also known as Mekinist ^® ), inhibitor of K-Ras, inhibitor of c-Met, onatuzumab (also known as MetMAb), of Alk inhibitor, AF802 (also known as CH5424802 or alectinib), inhibitor of phosphatidylinositol 3-kinase (PI3K), BKM120, idelarisib (also known as GS-1101 or CAL-101), perifosine (also known as KRX-0401) known), Akt, MK2206, GSK690693, GDC-0941, inhibitor of mTOR, sirolimus (also known as rapamycin), temsirolimus (also known as CCI-779 or Torisel ^® ), ebe Lolimus (also known as RAD001), ridaforolis (also known as AP-23573, MK-8669 or deforolimus), OSI-027, AZD8055, INK128, dual PI3K/mTOR inhibitors, XL765, GDC-0980, BEZ235 (also known as NVP-BEZ235), BGT226, GSK2126458, PF-04691502, PF-05212384 (also known as PKI-587) . The additional therapy may be one or more of the chemotherapeutic agents described herein.

iii. Methods and uses for treating locally advanced unresectable or metastatic lung cancer

Provided herein are lung cancer (eg, expanded stage SCLC (ES-SCLC) and locally advanced unresectable NSCLC including lung adenocarcinoma (eg, stage IIIB NSCLC), or recurrent or metastatic NSCLC (eg, stage IV NSCLC) in a subject or population . an antibody such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody such as atezolizumab), and a first and a second chemotherapeutic agent (eg, a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent) Methods and uses are provided comprising administering to the subject or population of subjects one or more dosing cycles of a chemotherapeutic agent).

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), and methods and uses involving administering a chemotherapy combination to a subject or population of subjects in need thereof. In some embodiments, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as artezoli) Zumab) is administered every 3 weeks (eg, on Day 1 of each 21-day dosing cycle). In some aspects, the present invention provides an effective amount of an anti-TIGIT antagonist antibody based on body weight (BW) or body surface area (BSA) of a subject or population of subjects every three weeks (e.g., on Day 1 of each 21-day dosing cycle) Provided are methods and uses, e.g., involving administering an anti-TIGIT antagonist antibody, such as tyragolumab, and a PD-1 axis binding antagonist, such as an anti-PD-L1 antagonist antibody, such as atezolizumab, as disclosed herein. do.

In some aspects, the present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), and methods and uses involving administering to a subject or population of subjects in need thereof, a chemotherapeutic combination, wherein the chemotherapy combination comprises an effective amount of a platinum-based chemotherapeutic agent and an effective amount of a non-platinum-based chemotherapeutic agent. including remedies. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) are administered every 3 weeks (eg, on Day 1 of each 21-day dosing cycle). In some cases, the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is an antimetabolite (eg, pemetrexed).

In certain embodiments, the method comprises an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, eg atezolizumab), a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and an antimetabolite (eg, pemetrexed) to a subject or population in need thereof, wherein said An anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab) are administered every 3 weeks ( For example, on Day 1 of each 21 day dosing cycle), the chemotherapy combination (eg, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and the antimetabolite (eg, pemetrexed)) is administered at the same frequency (eg, every 3 weeks, eg, on Day 1 of each 21-day dosing cycle) In some cases, the dosing is continued for 4 to 6 induction dosing cycles (eg, 4 doses). Induction dosing cycle, 5 induction dosing cycle, or 6 induction dosing cycle).After said induction dosing cycle, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycle.In certain embodiments, said one The above maintenance dosing cycle does not include the platinum-based chemotherapeutic agent.

In some cases, the invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) to a subject or population in need thereof every 4 weeks (eg, on Day 1 of each 28-day dosing cycle).

In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab) results in CR or PR. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) causes an increase in PFS or DOR. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) causes an increase in OS. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) increases progression-free survival in a subject or population of subjects as compared to, for example, treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. causes In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) prolongs the Os of a subject or population of subjects as compared to, for example, treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), and a chemotherapeutic combination (eg, a combination of platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and an antimetabolite (eg, pemetrexed)) to a subject or population of subjects in need thereof of the subject or population of subjects compared to treatment with pembrolizumab and the chemotherapy combination (eg, an antimetabolite (eg, pemetrexed) and the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin)). This results in an increase in the median PFS. In some cases, the treatment reduces the PFS of the subject or population of subjects by at least about 3.5 months or about 4.7 months (eg, at least about 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, or 4.7 months, such as at least about 3.5-3.7 months, 3.7-3.9 months, 3.9-4.1 months, 4.1-4.3 months, 4.3-4.5 months, or 4.5- 4.7 months).

In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) Zumab), and a chemotherapy combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) in lung cancer (eg, , NSCLC) for greater than 8.8 months (e.g., at least 8.9 months, at least 9.0 months, at least 9.2 months, at least 9.5 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months , at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, or longer, such as about 8.9 months, about 9.0 months, about 9.2 months, about 9.5 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months or more). In some cases, the treatment lasts for at least about 8 months (eg, 8 to 36 months, such as 8 to 24 months (eg, 8 months, 9 months, 10 months, 12 months, 13 months, 14 months, 15 months). , 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months). to about 14.7 months (eg, 12.5 months, 12.7 months, 12.9 months, 13.1 months, 13.3 months, 13.5 months, 13.7 months, 13.9 months, 14.1 months, 14.3 months, 14.5 months, or 14.7 months, such as about 12.5-13 months , 13 to 13.5 months, 13.5 to 14 months, or 14 to 14.7 months of the subject population.In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist as disclosed herein) An antibody, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) ) and an antimetabolite (eg, pembrolizumab) in accordance with any of the methods described herein to a subject or population of subjects with lung cancer (eg, NSCLC) results in a median PFS of at least 10 months. In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) Zumab), and a chemotherapy combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) in lung cancer (eg, , NSCLC) results in a median PFS of at least 12 months.

In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), and a chemotherapy combination (eg, a combination of platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and an antimetabolite (eg, pemetrexed)) to a subject or population of subjects with lung cancer OS of the subject or population of subjects compared to treatment with rolizumab and the chemotherapy combination (eg, an antimetabolite (eg, pemetrexed) and the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin)) causes an increase in the median value. In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 4 months (eg, 4-12 months (eg, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months). , 11 months or 12 months))). In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 5.5 months to about 8.0 months (eg, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, or 8.0 months, such as 5.5-6.5 months). months, 6.5 to 7.5 months, or 7.5 to 8.0 months).

In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) Zumab), and a chemotherapy combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) in lung cancer (eg, , NSCLC) for greater than 22 months (e.g., at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, at least 28 months, at least 29 months, at least 30 months) , at least 31 months, at least 32 months, at least 33 months, at least 34 months, at least 35 months, at least 36 months, at least 42 months, at least 48 months, at least 54 months, at least 60 months, at least 70 months, at least 80 months, at least 90 months, at least 100 months, at least 110 months, at least 120 months, at least 130 months, at least 140 months, at least 150 months, at least 160 months, at least 170 months, at least 180 months, at least 190 months, or at least 200 months, such as about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months , about 36 months, about 40 months, about 42 months, about 48 months, about 54 months, about 60 months, about 70 months, about 80 months, about 90 months, about 100 months, about 110 months, about 120 months, about 130 months, about 140 months, about 150 months, about 160 months, about 170 months, about 180 months, about 190 months, about 200 months). In some embodiments, the treatment lasts for at least about 24 months (eg, 24-42 months (eg, 24-36 months (eg, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months) months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months of the subject population.In some embodiments, the treatment is from about 27.5 months to about 32.0 months (e.g., 27.5 months, 28.0 months, 28.5 months, 29.0 months, 29.5 months, 30.0 months, 30.5 months, 31.0 months, 31.5 months, or 32.0 months (eg, 27.5 to 28.5 months, 28.5 to 29.5 months, 29.5 to 30.5 months, 30.5 to 31.5 months, or 31.5-32 months) of the subject population.In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolites (eg, pembrolizumab) in accordance with any of the methods described herein, to a subject or population of subjects with lung cancer (such as NSCLC) results in a median OS of at least 24 months. An anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination ( For example, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab) is administered to a subject or subject having lung cancer (eg, NSCLC) according to any of the methods described herein. Dosing to a population results in a median OS of at least 36 months.

In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) Zumab), and a chemotherapy combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) to a subject or population in need thereof. compared to treatment with pembrolizumab and the chemotherapy combination (eg, an antimetabolite (eg, pemetrexed) and a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin)) in the subject or population of subjects. an increase in overall response rate (ORR), such as treatment with pembrolizumab and the chemotherapy combination (eg, an antimetabolite (eg, pemetrexed) and a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin)) and compared to an ORR increase of at least 10% (eg, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%).

In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) Zumab), and a chemotherapy combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) in lung cancer (eg, , NSCLC) is greater than 47.5% (eg, at least 48%, at least 49%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%). , at least 80%, at least 85%, at least 90%, at least 95%, or 100%, such as about 48%, about 49%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) Zumab), and a chemotherapy combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) in lung cancer (eg, , NSCLC) results in an ORR of at least 50%. In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) Zumab), and a chemotherapy combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) in lung cancer (eg, , NSCLC) results in an ORR of at least 60%. In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezoli) zumab), and a chemotherapeutic combination (eg, a combination of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and an antimetabolite (eg, pembrolizumab)) in accordance with any of the methods described herein. , NSCLC) results in an ORR of at least 70%.

The present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject or population of subjects in need thereof every 4 weeks (eg, the first of each 28-day dosing cycle). per day) and methods and uses involving administration. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in a CR or PR. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in progression-free survival in a subject or population of subjects as compared to baseline PFS. make it In some cases, administration of an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in DOR. In some cases, administration of an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) prolongs the OR in a subject or population of subjects.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab). Methods and uses are provided that involve administering to a subject or population in need thereof every two weeks (eg, on days 1 and 15 of each 28-day dosing cycle). In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab) results in CR or PR. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) increases progression-free survival in a subject or population of subjects as compared to, for example, treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. causes In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) prolongs Os in a subject or population of subjects, e.g., as compared to treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. .

In certain instances, the present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject or population of subjects in need thereof every two weeks (eg, each 28 on days 1 and 15 of a dosing cycle). In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in a CR or PR. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in progression-free survival in a subject or population of subjects as compared to baseline PFS. make it In some cases, administration of an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) prolongs the OR in a subject or population of subjects.

In some cases, the subject or population of subjects receives prior systemic therapy (eg, prior systemic therapy for therapeutic purposes, such as chemotherapy) within the month prior to administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (eg, , Within 2 months, within 3 months, within 4 months, within 6 months, within 1 year, within 2 years, within 3 years, within 4 years, 5 before administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody within one year, or within 10 years). In some cases, the subject or population of subjects is naive to chemotherapy.

In some embodiments, the PD-1 axis binding antagonist and the anti TIGIT antagonist antibody are administered in combination with chemotherapy. For example, the once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W) dosing regimen of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody may include one or more chemotherapeutic agents. can be administered together with The one or more chemotherapeutic agents are administered at the same frequency or different from the dosing frequency of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (Q2W, Q3W, or Q4W) (eg, a 3-week dosing/1 week washout schedule). can be administered. For example, in some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every two weeks, and the one or more chemotherapeutic agents are administered every week, 3 weeks on/off, every 2 weeks , every 3 weeks, or every 4 weeks. Alternatively, said PD-1 axis binding antagonist and said anti TIGIT antagonist antibody are administered every 3 weeks and said one or more chemotherapeutic agents are administered every week, every 2 weeks, every 3 weeks, or every 4 weeks. Alternatively, said PD-1 axis binding antagonist and said anti-TIGIT antagonist antibody are administered every 4 weeks, and said one or more chemotherapeutic agents are administered weekly, 3 weeks dosing/weekly off, every 2 weeks, every 3 weeks, or It is administered every 4 weeks. In certain instances, the chemotherapeutic agent is administered several times per week (eg, 2, 3, 4, 5, 6, or 7 times per week (eg, on days 1, 2, and 3 of a dosing cycle)).

In some embodiments, the dose of the chemotherapeutic agent is reduced after one or more initial doses (eg, after 1, 2, 3, 4 or more initial doses). For example, a chemotherapeutic agent (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an antimetabolite (eg, pemetrexed or gemcitabine)) Subsequent doses of approximately 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25% of the initial dose %, 20%, 15%, 10% or 5% For example, an initial dose of cisplatin of 75 mg/m ² for subsequent doses, such as 70 mg/m ² , 65 mg/m ² , 60 mg/m ² , 55 mg/m ² , 50 mg/m ² , or 45 mg/m ² ; an initial dose of 500 mg/m ² pemetrexed for subsequent doses, may be reduced to eg 75 mg/m 2 ; an initial dose of about 175 mg/m 2 paclitaxel for subsequent doses, eg 450 mg/m ² , 400 mg/m ² , 350 mg/m ² , 300 mg/m ² , 250 mg/m ² , or 200 mg/m ² ; and/or an initial dose of carboplatin sufficient to achieve AUC=5 mg/ml/min for subsequent doses, For example, AUC = 4.5 mg/ml/min, 4.0 mg/ml/min, 3.5 mg/ml/min or 3.0 mg/ml/min.

In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg carboplatin or cisplatin), and the antimetabolites (eg pemetrexed) result in CR or PR. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the antimetabolite (eg, pemetrexed) result in an increase in progression-free survival in the subject or population of subjects. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab), the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin), and the antimetabolite (eg, pemetrexed) prolong OS in the subject or population of subjects.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g. pemetrexed) , are being treated for locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC).

dosing of the formulation

Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and chemotherapeutic agents is described in Section III(K).

Characterization of Cancer

In any of the methods, uses, or compositions for use described herein, the lung cancer can be NSCLC (e.g., nonsquamous NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)). In some embodiments, the subject or population of subjects has not received prior systemic therapy for lung cancer.

In some cases, in a method, use, or compositions for use described herein, the subject does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormality. In some cases, in a method, use, or compositions for use described herein, the subject does not have an EGFR gene mutation (eg, a sensitizing EGFR gene mutation) or an ALK gene rearrangement. In some cases, the subject has an Eastern Corporate Oncology Group (ECOG) systemic activity (PS) of 0 or 1.

Methods for detecting the mutant states EGFR and ALK are generally known in the art, and DNA from a clinical sample (e.g., a tumor biopsy or a blood sample (e.g., circulating tumor DNA in blood)) can be analyzed using next-generation sequencing methods; including, but not limited to, sequencing using, for example, targeted gene pull-down and sequencing methods described in Frampton et al. ( Nature Biotechnology . 31(11): 1023-1033, 2013), which is incorporated herein in its entirety. This next-generation sequencing method can be used in conjunction with any of the methods disclosed herein to detect a variety of mutations (e.g., insertions, deletions, base substitutions, local gene amplifications and/or homozygous gene deletions), while at the same time compact Allows the use of samples (eg, small core needle biopsy, fine needle aspiration and/or cell blocks) or fixed samples (eg, formalin-fixed and paraffin-embedded ( FFPE ) samples). and other methods for detecting the mutant state of ALK include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods.Exemplary methods for detecting the mutant state of ALK are disclosed in US Pat. No. 9,651,555 , which is incorporated herein in its entirety In some cases, the VENTANA® anti- ALK (D5F3) IHC assay is used to determine the mutation status of the ALK gene.

In some cases of any of the methods described herein, the mutation is a sensitizing EGFR mutation. Sensitizing EGFR mutations are generally known in the art and described in US Patent Publication Nos. US 2018/0235968 and in Juan et al. ( Therapeutic Advances in Medical Oncology. 9(3): 201-216, 2017), which is incorporated herein by reference in its entirety. In some cases, the sensitizing EGFR mutation is a mutation in any of exon 18-21 (eg, a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some cases, the sensitizing EGFR mutation is a deletion in exon 19 (del19). In other examples, the sensitizing EGFR mutation is an L858R point mutation in exon 21. In some cases, the sensitizing EGFR mutation is a G719X point mutation of exon 18, wherein "X" is most commonly C, A, or S. In some cases, the sensitizing EGFR mutation is a G719S point mutation of exon 18. In some cases, the sensitizing EGFR mutation is a G719A point mutation in exon 18. In some cases, the sensitizing EGFR mutation is an S720F point mutation in exon 18. In some cases, the sensitizing EGFR mutation is an L861Q point mutation in exon 21. In some cases, the sensitizing EGFR mutation is an L861R point mutation in exon 21. In other cases, the sensitizing EGFR mutation is the T790M point mutation. In some cases, the sensitizing EGFR mutation is an E709X point mutation, wherein “X” is most commonly K, A, or H. In some cases, the sensitizing EGFR mutation is an S768I point mutation.

In some cases of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are generally known in the art and described in US Pat. Nos. 9,651,555 and in Du et al. ( Thoracic Cancer. 9: 423-430, 2018), which is incorporated herein by reference in its entirety. In some cases, ALK gene rearrangement results in the production of oncogenic ALK tyrosine kinases that activate downstream signaling pathways to increase cell proliferation and survival. In some cases, the ALK gene rearrangement is a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A , BIRC6, RANBP2, ATIC, CLTC, TMP4, and MSN . ALK rearrangement with and forms a fusion oncogene. In some cases, the ALK gene rearrangement is an EML4 rearrangement with ALK and the fusion oncogene EML4

ALK is formed.

In some cases, in a method, use, or compositions for use described herein, the subject is free of the lung lymphothelioma-like carcinoma subtype of NSCLC. Methods for detecting subtypes of NSCLC are well known in the art and are based on histopathological criteria, or by molecular characteristics (e.g., biomarkers (e.g., specific genes or proteins encoded by said genes)). subtypes characterized by expression of one or a combination). In some examples, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some examples, the tissue sample is a tumor sample.

In some cases, in a method, use, or compositions for use described herein, the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection. An indicator of active or chronic active EBV infection for use in the methods described herein is EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein- bar virus particles, but are not limited thereto. Methods for detecting the presence of one or more indicators of active or chronic active EBV infection comprising EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr virus particles in a sample of a subject are well known in the art. serological diagnosis (e.g., detection of EBV DNA (e.g., by PCR analysis of a blood sample for detection of EBV virus particles) or detection of EBV antigen or anti-EBV antibody (e.g., heterologous antibody detection of EBNA, EBV IgM or EBV IgG used)). In some cases, the sample is selected from the group consisting of a whole blood sample, a serum sample, and a plasma sample. In some cases, the subject is negative for EBV IgM and/or is negative by EBV PCR. In some cases, the subject is negative for EBV IgM and/or negative for EBV PCR and positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA). In other cases, the subject is negative for EBV IgG and/or negative for EBNA. In some cases, the subject has a PD-L1 selected tumor (eg, minimal PD-L1 positive tumor cell fraction or TPS as determined by IHC using SP263 or 22C3 antibody > 30% (eg > 50%) If the proportion of tumor area occupied by tumor PD-L1-expressing or PD-L1-expressing tumor infiltrating immune cells (IC) is greater than or equal to 1% as determined by IHC using SP142 antibody). In some cases, the PD-L1 selected tumor is a tumor that has been determined to be at least 30% (eg, at least 50%) by immunohistochemical (IHC) analysis of a PD-L1 positive tumor cell fraction or PD-L1 TPS. In some cases, the PD-L1-selected tumor is a tumor in which the proportion of tumor area occupied by PD-L1-expressing immune cells (IC) is determined by immunohistochemical (IHC) analysis to be greater than or equal to 1%. In some cases, the IHC assay uses anti-PD-L1 antibodies SP263, 22C3, SP142, or 28-8. In some cases, the IHC assay uses the anti-PD-L1 antibody SP263. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, the IHC assay uses anti-PD-L1 antibody 22C3. In some cases, the tumor sample was determined to have a TPS of 50% or greater. In some cases, the PD-L1-positive tumor cell fraction (eg, as determined by positive staining with anti-PD-L1 antibody SP263 (eg, using a Ventana assay)) is determined by using anti-PD-L1 antibody 22C3 greater than 50% as determined by positive staining used (eg, using pharmDx assay), or as determined by positive staining with anti-PD-L1 antibody 28-8. In some embodiments, the fraction of PD-L1-positive tumor cells is greater than or equal to 30% as determined by positive staining with anti-PD-L1 antibody SP142. In some cases, the IC was determined to be greater than or equal to 1% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 5% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 10% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 1% and less than 50% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 1% and less than 30% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay).

In some cases, in a method, use, or compositions for use described herein, the tumor sample obtained from the individual has a detectable protein expression level of PD-L1. In some cases, detectable protein expression levels of PD-L1 were determined by IHC assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 1% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 1% and less than 5% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 5% and less than 50% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 50% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 1% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 1% and less than 5% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 5% and less than 10% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 10% of the tumor sample.

In some cases, the subject has lung cancer that has not been assessed from PD-L1 expression (eg, NSCLC (eg, nonsquamous NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC))). For example, in some cases, the subject with lung cancer has not been determined to have a PD-L1 positive tumor cell fraction greater than or equal to 50% (eg, the subject has a PD-L1 positive tumor cell fraction of 45%, 40% , 35%, or 30%).For example, in some cases, the subject is assessed using any IHC method, such as described herein or known in the art, The TPS was not determined to be at least 50% PD-L1 positive (eg, the subject has a TPS of at least 45% PD-L1 positive, at least 40% PD-L1 positive, at least 35% PD-L1 positive, or at least 30% PD not determined to be -L1 positive).

In some cases, a subject with lung cancer (eg, NSCLC (eg, nonsquamous NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)) has a PD-L1-positive tumor cell fraction was determined to be less than 50% (eg, 1% to 50%, 1% to 49%, 5% to 45%, 10% to 40%, 15% to 35%, or 20% to 30%, such as 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45% , or from 45% to 49%, such as less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, 8 %, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0%).For example, in certain cases, subjects with lung cancer was determined to have a fraction of PD-L1 positive tumor cells between 1% and less than 49% (eg, between 1% and 5%, between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%). , 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 49%) In other cases, the subject with lung cancer has a PD-L1 positive tumor cell fraction was determined to be less than 1% (eg, 0%, or undetectable PD-L1 expression).

For example, in some cases, a subject with lung cancer (eg, NSCLC (eg, nonsquamous NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)) has a TPS of 50% was determined to be less than PD-L1 positive (eg, between 1% and 50%, between 1% and 49%, between 5% and 45%, between 10% and 40%, between 15% and 35%, or between 20% and 30% PD-L1). positive, such as 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40% , 40% to 45%, or 45% to 49% PD-L1 positive, such as less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15% , less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0% PD-L1 positive) For example, in certain instances, a subject with lung cancer has been determined to have a TPS of 1% to 49% PD-L1 positive (eg, 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 49% PD-L1 positive). In these cases, subjects with lung cancer were determined to have a TPS of less than 1% PD-L1 positive (eg, about 0%, or undetectable PD-L1 expression).

In certain embodiments, the subject has NSCLC that has not been assessed from PD-L1 expression (eg, nonsquamous NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)). For example, in some cases, the subject with NSCLC has not been determined to have a fraction of PD-L1 positive tumor cells greater than or equal to 50% (eg, the subject has a fraction of PD-L1 positive tumor cells of 45%, 40%, 35% , or 30% or higher).For example, in some cases, the subject has a TPS of 50, eg, as assessed using any IHC method described herein or known in the art. not determined to be at least % PD-L1 positive (e.g., the subject has a TPS of at least 45% PD-L1 positive, at least 40% PD-L1 positive, at least 35% PD-L1 positive, or at least 30% PD-L1 positive has not been determined).

In some cases, a subject with NSCLC (e.g., nonsquamous NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)) has a fraction of PD-L1 positive tumor cells of less than 50%. has been determined (eg, between 1% and 50%, between 1% and 49%, between 5% and 45%, between 10% and 40%, between 15% and 35%, or between 20% and 30%, such as between 1% and 5%, 5 % to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 49%, such as less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 9%, less than 8%, 7 %, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0%).For example, in certain cases, a subject with NSCLC has PD-L1 It was determined that the fraction of benign tumor cells was between 1% and less than 49% (eg, between 1% and 5%, between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 49%) In other cases, the subject with NSCLC has a PD-L1 positive tumor cell fraction of less than 1% (eg, 0%, or undetectable PD-L1 expression).

For example, in some cases, a subject with NSCLC (eg, nonsquamous NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)) has a TPS of less than 50% PD-L1 determined to be positive (eg, 1%-50%, 1%-49%, 5%-45%, 10%-40%, 15%-35%, or 20%-30% PD-L1 positive, such as 1 % to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 49% PD-L1 positive, such as less than 49%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10% , less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or about 0% PD-L1 positive). , in certain instances, subjects with NSCLC have been determined to have a TPS of 1% to 49% PD-L1 positive (eg, 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20 %, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 49% PD-L1 positive). subjects with TPS were determined to be less than 1% PD-L1 positive (eg, about 0%, or undetectable PD-L1 expression).

In some cases, a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1. In some cases, the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. became In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some cases, the tissue sample is a tumor sample. In some cases, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

In some cases, a tumor sample obtained from a subject with lung cancer (eg, NSCLC (eg, nonsquamous NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)) is PD-L1 The nucleic acid expression level of PD-L1 is low or undetectable.In some cases, the nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique. , ISH or combination thereof.In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample.In some cases, the tissue sample is a tumor sample In some cases, the tumor sample comprises tumor infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

In some cases for any of the methods described herein, the subject has lung cancer (eg, NSCLC (eg, squamous NSCLC (eg, locally advanced unresectable or metastatic squamous NSCLC (eg, stage IV nonsquamous NSCLC))) No prior systemic treatment for said lung cancer (e.g., no prior systemic treatment for therapeutic purposes) In certain embodiments, said subject has locally advanced lung cancer and prior systemic treatment for said locally advanced lung cancer In some embodiments, the subject has NSCLC (eg, nonsquamous NSCLC, such as locally advanced unresectable or metastatic nonsquamous NSCLC), and the NSCLC (eg, nonsquamous NSCLC, such as locally advanced unresectable NSCLC). or metastatic nonsquamous NSCLC).

In other cases, a subject with lung cancer (e.g., NSCLC (e.g., nonsquamous NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)) receives prior systemic treatment for the lung cancer and have experienced a treatment-free period of at least 12 months prior to treatment according to any of the methods of the present invention.

iv. Methods and uses for treating unresectable lung cancer

Disclosed herein are methods and uses for treating lung cancer (eg, early stage lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)) in a subject, comprising an effective amount of an anti-TIGIT antagonist antibody (eg, disclosed herein) 1 of an anti-TIGIT antagonist antibody, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab), or an anti-PD-1 antagonist antibody, such as pembrolizumab) Provided are methods and uses comprising administering to the subject more than one dosing cycle.In some cases, at least one dosing cycle is administered as prior adjuvant treatment.In some cases, the treatment is neoadjuvant treatment. In some cases, at least one dosing cycle is administered as adjuvant treatment.In some cases, the treatment is adjuvant treatment.In some cases, the treatment comprises neoadjuvant treatment and adjuvant treatment. In some cases, the lung cancer is resectable lung cancer.In some cases, the lung cancer is early lung cancer (such as stage II, IIIA, or IIIB lung cancer).In some cases, the lung cancer is NSCLC (such as squamous or non-squamous NSCLC).In some cases, the lung cancer is PD-L1 positive (eg, PD-L1 high).In some cases, the lung cancer is epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) does not have a genomic tumor abnormality.In some embodiments, the subject has not previously received lung cancer treatment (eg, prior surgery, prior immunotherapy, prior chemotherapy, or prior radiotherapy). In , said subject is eligible for platinum-based chemotherapy.In some cases, said subject is eligible for R0 resection for therapeutic purposes.The subject is preferably human.

The present invention provides methods and uses for treating a subject having resectable lung cancer (eg, resectable squamous or non-squamous NSCLC), wherein the method is administered every 3 weeks (eg, of each 21-day dosing cycle). on day 1) at a dose of about 30 mg to about 1200 mg (eg, a fixed dose) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), and every 3 weeks (eg, on Day 1 of each 21-day dosing cycle) at a dose (eg, a fixed dose) of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or anti-PD) -1 comprising administering to the subject one or more dosing cycles of an antagonist antibody, such as pembrolizumab). In some aspects, the method comprises administering a 30 mg to 1200 mg dose (eg, a fixed dose) of an anti TIGIT antagonist antibody (eg, as disclosed herein) every 3 weeks (eg, on Day 1 of each 21 day dosing cycle). anti-TIGIT antagonist antibody, such as tyragolumab), and every 3 weeks (eg, on Day 1 of each 21-day dosing cycle) at a dose of 80 mg to 1600 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, , administering to the subject one or more dosing cycles of an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab).

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or methods and uses that involve administering an anti-PD-1 antagonist antibody, such as pembrolizumab) to a subject in need thereof every three weeks (eg, on Day 1 of each 21 day dosing cycle). In some cases, at least one of the dosing cycles is a dose of about 30 mg to about 1200 mg (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks (eg, a dose of 600 mg every 3 weeks), and 3 weeks administering to the subject as neoadjuvant treatment a dose of about 80 mg to about 1600 mg per dose (eg, a dose of about 1200 mg every 3 weeks) (eg, a fixed dose) of a PD-1 axis binding antagonist. In some cases, at least one of the dosing cycles is a dose of about 30 mg to about 1200 mg (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks (eg, a dose of 600 mg every 3 weeks), and 3 weeks administering to the subject a dose of about 80 mg to about 1600 mg every (eg, a dose of about 1200 mg every 3 weeks) (eg, a fixed dose) of a PD-1 axis binding antagonist as adjuvant treatment. In some cases, at least one of the dosing cycles is a 30 mg to 1200 mg dose every 3 weeks (eg, a 600 mg dose every 3 weeks) (eg, a fixed dose) anti TIGIT antagonist antibody, and 80 every 3 weeks administering to the subject a dose of a mg to 1600 mg (eg, a dose of 1200 mg every 3 weeks) (eg, a fixed dose) of a PD-1 axis binding antagonist as neoadjuvant treatment to the subject. In some cases, at least one of the dosing cycles is a 30 mg to 1200 mg dose every 3 weeks (eg, a 600 mg dose every 3 weeks) (eg, a fixed dose) anti TIGIT antagonist antibody, and 80 every 3 weeks administering to the subject a dose of between mg and 1600 mg (eg, a dose of 1200 mg every 3 weeks) (eg, a fixed dose) of a PD-1 axis binding antagonist as adjuvant treatment.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) A subject being administered is being treated for lung cancer (eg, early stage lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)).

The PD-1 axis binding antagonist and anti-TIGIT antagonist antibodies may be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody may be administered sequentially (on different days) or simultaneously (on the same day or during the same treatment cycle). In some cases, the anti-TIGIT antagonist antibody and/or the PD-1 axis binding antagonist is administered on about 1 day (eg, -3 days, -2 days, -1 days, 1 day, 2 days, or 3 days) of a dosing cycle. day) is administered. In some cases, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody may be administered on the same day. In some cases, the PD-1 axis binding antagonist is administered prior to the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered after the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered concurrently with the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist may be administered prior to the anti-TIGIT antagonist antibody administered on the same day. In some cases, the PD-1 axis binding antagonist may be administered after the anti-TIGIT antagonist antibody administered on the same day. In still other instances, the PD-1 axis binding antagonist is administered at the same time as the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered in a separate composition from the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered in the same composition as the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered via a separate intravenous line from any other therapeutic agent administered to the patient on the same day. The PD-1 axis binding antagonist and anti-TIGIT antagonist antibody may be administered by the same route of administration or by different routes of administration. In some cases, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, implanted, inhaled, intrathecally, intraventricularly, or intranasally. In some cases, the PD-1 axis binding antagonist is administered intravenously. In some cases, the anti TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, implanted, inhaled, intrathecally, intraventricularly or intranasally. In some cases, the anti-TIGIT antagonist antibody is administered intravenously. In some cases, there is a first observation period after administration of the PD-1 axis binding antagonist. In some cases, there is a second observation period following administration of the PD-1 axis binding antagonist. In some cases, there is a first observation period following administration of the anti-TIGIT antagonist antibody. In some cases, there is a second observation period following administration of the anti-TIGIT antagonist antibody. In some cases, the observation period is between about 30 minutes and about 60 minutes in length. In some cases, the anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist is administered intravenously or subcutaneously. In some cases, the intravenous infusion is administered over 30 ± 10 minutes and/or 60 ± 15 minutes. In one example, atezolizumab may be administered intravenously over 60 minutes; If the first infusion is allowed, all subsequent infusions may be delivered over 30 minutes. In some embodiments, the PD-1 axis binding antagonist is not administered as an intravenous push or bolus. In one example, tiragolumab may be administered intravenously over 60 minutes; If the first infusion is allowed, all subsequent infusions may be delivered over 30 minutes. In some embodiments, the anti-TIGIT antagonist antibody is not administered as an intravenous push or bolus.

In any of the preceding examples, each dosing cycle is of any suitable length, such as about 7 days (about 5 days, 6 days, 7 days, 8 days, or 9 days), about 14 days (eg, about 12 days). , 13 days, 14 days, 15 days, 16 days), about 21 days (eg, about 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days), about 28 days (about 25 days) days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days), or more. In some cases, each dosing cycle is about 21 days.

In some cases, the PD-L1 expression level of a sample obtained from the subject (eg, a tumor sample, a blood sample (eg, a plasma sample), or a lymph sample) is determined. In some cases, the sample has been determined to have a detectable expression level of PD-L1 (eg, a detectable protein and/or nucleic acid expression level of PD-L1). In some cases, the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1. In some cases, the detectable expression level of PD-L1 is a fraction of PD-L1 positive tumor cells (eg, at least 50% of the fraction of PD-L1 positive tumor cells). In some cases, the detectable protein expression level of PD-L1 is determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody suitable for staining (eg, anti-PD-L1 antibody SP263). It was decided. In some cases, the IHC assay is a Ventana SP263 IHC assay. In some cases, the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1. In some cases, the mutation status of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) is determined. In some cases, the method further comprises obtaining a sample from the subject. In some cases, the method further comprises determining the expression level of PD-L1.

In some cases, the first dosing cycle is initiated prior to surgery (eg, lobectomy, lobectomy, bilobectomy, or pneumonectomy). In some cases, one or more dosing cycles are completed prior to surgery. In some cases, at least 1, 2, 3, or 4 dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, or more dosing cycles) dosing cycle) is completed prior to surgery. In some cases, 4 dosing cycles are completed prior to surgery. In some cases, one or more dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13) , 14, 15, 16, 17, 18, 19, 20 or more dosing cycles) are initiated post-operatively. In some cases, 16 dosing cycles are completed post surgery. In some cases, the treatment comprises surgery. In some cases, the surgery is lobectomy, lobectomy, bilobectomy, or pneumonectomy. In some cases, the treatment includes radiation therapy (eg, post-surgical radiation therapy).

In some cases, the treatment results in an increase in the major pathological response rate (MPR) as compared to the baseline MPR rate. In some cases, the treatment results in a pathological complete response (pCR) and/or an increase in the pCR ratio compared to a baseline pCR ratio. In some cases, the treatment results in an increase in event-free survival (EFS) compared to baseline EFS time. In some cases, the treatment results in an increase in OS compared to baseline OS time. In some cases, the baseline MPR ratio, baseline pCR ratio, and/or baseline EFS time is determined by: (a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or (b) the MPR rate, pCR rate, and/or EFS time of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) causes an increase in the MPR rate. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab) results in pCR. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) causes an increase in EFS. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) causes an increase in OS.

In some cases, the treatment comprises one or more chemotherapeutic agents (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, antimetabolites (eg, peme)). Trexid or gemcitabine), and/or taxanes (such as paclitaxel, such as nap-paclitaxel) In some cases, the neoadjuvant and/or adjuvant treatment is one or more chemotherapeutic agents (such as platinum a chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an antimetabolite (eg, pemetrexed or gemcitabine), and/or a taxane (eg, paclitaxel, such as nap-paclitaxel).In some cases, the at least one chemotherapeutic agent is at least one platinum-based chemotherapeutic agent and/or at least one non-platinum-based chemotherapeutic agent.In some cases, the platinum-based chemotherapeutic agent The therapeutic agent is carboplatin or cisplatin In some cases, the non-platinum-based chemotherapeutic agent is an antimetabolite (such as pemetrexed or gemcitabine) and/or a taxane (such as paclitaxel, such as nap-paclitaxel) In some cases, the one or more chemotherapeutic agents are platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and non-platinum-based chemotherapeutic agents (eg, antimetabolites (eg, pemetrexed or gemcitabine); and/or a taxane (such as paclitaxel, such as nap-paclitaxel) In some cases, at least one chemotherapeutic agent is: (a) carboplatin and pemetrexed; (b) carboplatin and paclitaxel (c) cisplatin and pemetrexed; (d) carboplatin and gemcitabine; or (e) cisplatin and gemcitabine.In some cases, one or more chemotherapeutic agents used to treat nonsquamous NSCLC are ( a) carboplatin and pemetrexed, (b) carboplatin and paclitaxel, or (c) cisplatin and pemetrexed.In some cases, one or more chemotherapeutic agents used to treat squamous NSCLC are (a) ) carboplatin and gemcitabine, (b) carbo platin and paclitaxel, or (c) cisplatin and gemcitabine. In some cases, the treatment comprises one or more chemotherapeutic agents (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, antimetabolites (eg, peme)). Trexed or gemcitabine), and/or taxane (such as paclitaxel, such as nap-paclitaxel) In some embodiments, the one or more chemotherapeutic agents are administered every three weeks. In instances, the one or more chemotherapeutic agents are administered on about day 1 (eg, day -3, day -2, day -1, day 1, day 2, or day 3) of one or more dosing cycles. In cases, the one or more chemotherapeutic agents are about 1 (eg, -3 days, -2 days, -1 days, 1 day, 2 days, or 3 days) and about 8 days (eg, -3 days, -2 days, or 3 days) of one or more dosing cycles. For example, on day 5, 6, 7, 8, 9, 10, or 11. In some cases, the dosing cycle is, for example, on about 7 days (about 5, 6, 7 days, 8 days, or 9 days), about 14 days (eg, about 12 days, 13 days, 14 days, 15 days, 16 days), about 21 days (eg, about 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days), about 28 days (about 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days), or more. In, each dosing cycle is about 21 days In some cases, the one or more chemotherapeutic agents are intravenous, intramuscular, subcutaneous, topical, oral, transdermal, intraperitoneal, intraorbital, implantation, inhalation, intrathecal. , intraventricularly or intranasally.In some cases, said one or more chemotherapeutic agents are said PD-1 axis binding antagonist (eg, atezolizumab) and/or anti-TIGIT antagonist antibody (eg, as disclosed herein) Anti-TIGIT antagonist antibody, such as tiragolumab) is then administered.In some cases, the non-platinum-based chemotherapeutic agent (eg, antimetabolites (eg, pemetrexed or gemcitabine) and/or taxanes (eg, paclitaxel) , such as nap-paclitaxel)) is the platinum-based Administered prior to a chemotherapeutic agent (eg, carboplatin or cisplatin).

The present invention provides methods and uses for treating a subject having resectable lung cancer (eg, early resectable lung cancer (eg, resectable NSCLC (eg, resectable squamous or non-squamous NSCLC)), the method comprising: about 30 every 3 weeks. mg to about 600 mg (eg, a fixed dose) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), and a dose of about 80 mg to about 1600 mg every 3 weeks ( eg, fixed dose) a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab), a platinum-based chemotherapeutic agent (eg, cisplatin or administering to the subject one or more dosing cycles of a carboplatin), and a non-platinum-based chemotherapeutic agent (eg, an antimetabolite (eg, pemetrexed or gemcitabine) or a taxane (eg, paclitaxel or nap-paclitaxel); In some cases, the method comprises a 30 mg to 600 mg dose (eg, a fixed dose) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist as disclosed herein) every 3 weeks. antibody, such as tyragolumab), and a dose of 80 mg to 1600 mg every 3 weeks (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD- 1 Antagonist antibodies such as pembrolizumab), platinum-based chemotherapeutic agents (such as cisplatin or carboplatin), and non-platinum-based chemotherapeutic agents (such as antimetabolites (such as pemetrexed or gemcitabine) or taxanes (such as eg, administering to the subject one or more dosing cycles of paclitaxel or nap-paclitaxel.

The present invention provides methods and uses for treating a subject having lung cancer (eg, early stage lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)), the method comprising an anti-TIGIT antagonist antibody (eg, An anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody such as atezolizumab, or an anti PD-1 antagonist antibody such as pembrolizumab) , platinum-based chemotherapeutic agents (such as cisplatin or carboplatin), and non-platinum-based chemotherapeutic agents (such as antimetabolites (such as pemetrexed or gemcitabine) or taxanes (such as paclitaxel or nap-paclitaxel)) methods and uses, comprising administering to the subject one or more dosing cycles of ) anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks (eg, a fixed dose), a platinum-based chemotherapeutic agent (eg, cisplatin or carboplatin), and a non-platinum-based chemistry administering to the subject a therapy (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nap-paclitaxel)) as neoadjuvant treatment. At least once of the dosing cycle is a dose of 30 mg to 600 mg (fixed dose) of the anti-TIGIT antagonist antibody every 3 weeks, a dose of 80 mg to 1600 mg every 3 weeks (eg, a fixed dose) of the PD-1 axis binding Antagonists, platinum-based chemotherapeutic agents (such as cisplatin or carboplatin), and non-platinum-based chemotherapeutic agents (such as antimetabolites (such as pemetrexed or gemcitabine) or taxanes (such as paclitaxel or nap-paclitaxel) ) as neoadjuvant treatment to the subject.

The present invention provides methods and uses for treating a subject with resectable lung cancer (eg, early resectable lung cancer (eg, resectable NSCLC (eg, resectable squamous or non-squamous NSCLC)), the method comprising: about 30 every 3 weeks. mg to about 600 mg dose (eg, a fixed dose) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), and a dose of about 80 mg to about 1600 mg every 3 weeks ( eg, a fixed dose) a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab), and: (a) (i) 3 weeks Platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min, or (ii) about 75 mg every 3 weeks a platinum-based chemotherapeutic agent (eg, cisplatin or carboplatin) at a /m ² dose, and (b) (i) about 500 mg/m ² every 3 weeks or about 1000 on days 1 and 8 of each dosing cycle. an antimetabolite at a dose of mg/m ² or about 1250 mg/m ² ; or (ii) 1 of the taxane at a dose of about 100 mg/m ² , about 175 mg/m ² , or about 200 mg/m ² every 3 weeks Methods and uses, comprising the step of administering to the subject at least one dosing cycle, in some embodiments, the method comprises a 30 mg to 600 mg dose (eg, a fixed dose) of anti-TIGIT antagonist antibody every 3 weeks (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), and a 80 mg to 1600 mg dose (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist every 3 weeks) an antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab), and: (a) (i) an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks target to achieve platinum-based chemotherapeutic agents (eg, cisplatin or carboplatin); or (ii) a platinum-based chemotherapeutic agent (eg, cisplatin or carboplatin) at a dose of 75 mg/m ² every 3 weeks; and (b) (i) an antimetabolite at a dose of 500 mg/m ² every 3 weeks or 1000 mg/m ² or 1250 mg/m ² on days 1 and 8 of each dosing cycle; or (ii) administering to the subject one or more dosing cycles of the taxane at a dose of 100 mg/m ² , 175 mg/m ² , or 200 mg/m ² every 3 weeks.

The present invention provides methods and uses for treating a subject having lung cancer (eg, early stage lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)), the method comprising an anti-TIGIT antagonist antibody (eg, An anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody such as atezolizumab, or an anti PD-1 antagonist antibody such as pembrolizumab) , platinum-based chemotherapeutic agents (such as cisplatin or carboplatin), and non-platinum-based chemotherapeutic agents (such as antimetabolites (such as pemetrexed or gemcitabine) or taxanes (such as paclitaxel or nap-paclitaxel)) methods and uses, comprising administering to the subject one or more dosing cycles of a dose (eg, a fixed dose) of an anti TIGIT antagonist antibody; (b) a dose of from about 80 mg to about 1600 mg every 3 weeks (eg, a fixed dose) of the PD-1 axis binding antagonist; at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m ² every 3 weeks; and (d) administering a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) about 500 mg/m ² every 3 weeks or about 1000 mg/m 2 on days 1 and 8 of each dosing cycle an antimetabolite at a dose of m ² or about 1250 mg/m ² ; or (ii) a taxane at a dose of about 100 mg/m ² , about 175 mg/m ² , or about 200 mg/m ² every 3 weeks; The treatment is neoadjuvant treatment.In some embodiments, at least one dosing cycle is administered to the subject: (a) every 3 weeks at a dose of 30 mg to 600 mg (eg, a fixed dose) of an anti-TIGIT antagonist antibody; (b) every 3 weeks 8 a dose of 0 mg to 1600 mg (eg, a fixed dose) of a PD-1 axis binding antagonist; (c) at (i) a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or (ii) a platinum-based chemotherapeutic agent at a dose of 75 mg/m ² every 3 weeks; and (d) administering a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) 500 mg/m ² every 3 weeks or 1000 on days 1 and 8 of each dosing cycle an antimetabolites at a dose of mg/m ² or 1250 mg/m ² ; or (ii) a taxane at a dose of 100 mg/m ² , 175 mg/m ² , or 200 mg/m ² every 3 weeks; wherein the treatment is neoadjuvant treatment.

The present invention includes methods and uses for treating a subject having lung cancer (eg, early stage lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)), the method comprising an anti-TIGIT antagonist antibody and administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist, wherein: (a) at least one of said dosing cycles is from about 30 mg to about 1200 mg doses (e.g., every 3 weeks) , a fixed dose) of an anti-TIGIT antagonist antibody and a dose (eg, a fixed dose) of about 80 mg to about 1600 mg every 3 weeks (eg, a fixed dose) of a PD-1 axis binding antagonist to the subject as neoadjuvant therapy; (b ) at least once in said dosing cycle, at a dose of about 30 mg to about 1200 mg (eg, a fixed dose) anti-TIGIT antagonist antibody every 3 weeks, and a dose of about 80 mg to about 1600 mg every 3 weeks (eg, a fixed dose) ) administering to the subject a PD-1 axis binding antagonist as adjuvant treatment In some aspects, the method administers to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist. administering: (a) a dose of 30 mg to 1200 mg (eg, a fixed dose) anti-TIGIT antagonist antibody every 3 weeks and a dose of 80 mg to 1600 mg every 3 weeks at least once in said dosing cycle (e.g., a fixed dose) of a PD-1 axis binding antagonist as neoadjuvant treatment to said subject; eg, a fixed dose) of an anti-TIGIT antagonist antibody, and an 80 mg to 1600 mg dose (eg, a fixed dose) of a PD-1 axis binding antagonist every 3 weeks as adjuvant treatment to the subject.

The present invention includes methods and uses for treating a subject having lung cancer (eg, early stage lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)), the method comprising an anti-TIGIT antagonist antibody and administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist, wherein: (I) at least one of said dosing cycles is neoadjuvant treatment and to the subject: (a) 3 weeks (e.g., a fixed dose) of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg per day (e.g., a fixed dose) (b) a dose of about 80 mg to about 1600 mg every 3 weeks as neoadjuvant treatment (e.g., a fixed dose) of the PD-1 axis (c) (i) at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks, or (ii) about 75 mg/m ² every 3 weeks administering a dose of a platinum ^- based chemotherapeutic agent; on days 1 and 8 of about 1000 mg/m ² or about 1250 mg/m ² of the antimetabolite; or (ii) about 100 mg/m ² , about 175 mg/m ² , or about every 3 weeks a taxane at a dose of 200 mg/m ² ; (II) at least one of said dosing cycles at a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody, and about 80 every 3 weeks Adjuvant treatment comprises the step of administering as adjuvant treatment a dose of from about 1600 mg to about 1600 mg of a PD-1 axis binding antagonist, (a) 30 mg every 3 weeks. (e.g., a fixed dose) of anti-TIGIT antagonist antibody at a dose of (e.g., a fixed dose) of from 80 mg to 1600 mg (e.g., a fixed dose) of the PD-1 axis binding antagonist every 3 weeks as neoadjuvant treatment; i) 5 mg/m every 3 weeks at a dose targeted to achieve an AUC of L/min or an AUC of 6 mg/mL/min; or (ii) a platinum-based chemotherapeutic agent at a dose of 75 mg/m ² every 3 weeks; and (d) administering a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) 500 mg/m ² every 3 weeks or 1000 on days 1 and 8 of each dosing cycle an antimetabolites at a dose of mg/m ² or 1250 mg/m ² ; or (ii) a taxane at a dose of 100 mg/m ² , 175 mg/m ² , or 200 mg/m ² every 3 weeks; (II) at least one of said dosing cycles every 3 weeks at a dose of 30 mg to 1200 mg (eg, a fixed dose) anti-TIGIT antagonist antibody, and every 3 weeks at a dose of 80 mg to 1600 mg (eg, a fixed dose) PD - administering the -1 axis binding antagonist as adjuvant treatment.

In some cases, the treatment may further comprise an additional therapy. Any suitable additional therapy known in the art or described herein may be used. The additional therapy may include radiation therapy (eg, postoperative radiation therapy), surgery, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, gamma irradiation, or any of the foregoing. It can be a combination.

In some cases, the additional therapy is a side-effect limiting agent (eg, an agent intended to reduce the incidence and/or severity of side effects of treatment, such as an anti-nausea agent, a corticosteroid (eg, prednisone or equivalent, such as 1-2 mg/ kg/day), and hormone replacement drug(s), etc.).

Also disclosed herein is a method of treating lung cancer in a subject, comprising one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, antimetabolites) (eg, pemetrexed or gemcitabine) and/or taxanes (eg, paclitaxel, such as nap-paclitaxel) and/or an effective amount of PD-1 axis binding in combination with cancer therapy (eg, surgery and/or radiation therapy) Methods are provided comprising administering to the subject a treatment regimen comprising an antagonist (eg, atezolizumab) and/or an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) For example, a PD-1 axis binding antagonist may include additional chemotherapeutic or chemotherapeutic agents (see definition above); targeted therapy or targeted therapeutic agents; immunotherapeutic or immunotherapeutic agents, such as monoclonal antibodies; agent (see above definition); or a combination thereof.

dosing of the formulation

Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and chemotherapeutic agents is described in Section III(K).

Cancer characterization and selection

In some cases, in any method, use, or composition for use described herein, lung cancer (eg, early lung cancer (eg, resectable lung cancer (eg, NSCLC (eg, squamous or non-squamous NSCLC)) is resectable (e.g., eligible for R0 resection for therapeutic purposes.) In some cases, the lung cancer is NSCLC. In some cases, the NSCLC is squamous or non-squamous NSCLC. In some cases, the lung cancer is PD- L1 positive.In some cases, the lung cancer is PD-L1 high.In some cases, the lung cancer does not have epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) genomic tumor abnormality.Some cases In these cases, the lung cancer is stage II, IIIA, or IIIB lung cancer.

In some embodiments, in a method, use, or compositions for use described herein, the subject is eligible for platinum-based chemotherapy. In some cases, the subject has an Eastern Corporate Oncology Group (ECOG) systemic activity (PS) of 0 or 1. In some cases, the subject has not received prior therapy (eg, immunotherapy, chemotherapy, or radiotherapy) for lung cancer.

In some cases, in any method, use, or composition for use described herein, the presence or level of circulating tumor DNA (ctDNA) can be assessed. In some cases, ctDNA is evaluated in a sample of the subject (eg, a blood sample (eg, a plasma sample)). In some cases, ctDNA is assessed in a sample of the subject 1 day prior to a first dosing cycle (eg, a first dosing cycle of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist). In some cases, ctDNA is evaluated in a sample of the subject prior to surgery. In some cases, ctDNA is evaluated in a sample of the subject after surgery.

In some cases, in any of the methods, uses, or compositions for use described herein, the presence or level of immune cells (eg, T cells) can be assessed. In some cases, the presence or level of immune cells is assessed in a sample from the subject (eg, a blood sample, tumor tissue sample, or lymph node sample). In some cases, the presence or level of immune cells is assessed in a sample of the subject prior to surgery. In some cases, the presence or level of immune cells is assessed in a sample of the subject after surgery.

Assessment of PD-L1 expression

Expression of PD-L1 can be assessed as described in section III(L).

Assessment of EGFR and ALK or higher

Methods for detecting the mutant state EGFR and ALK are described in Section III(N) herein.

response to treatment

In some embodiments of any of the methods described herein, the subject's response to therapy can be characterized by one or more measures. In some embodiments, the treatment results in an increase in the major pathological response rate (MPR). In some embodiments, the treatment results in pCR. In some embodiments, the treatment results in an increase in event-free survival (EFS). In some embodiments, the treatment improves patient-reported outcomes. In some embodiments, the treatment improves patient-reported bodily function, role function, or GHS/QoL as measured by EORTC-QLQ-C30. In some embodiments, the treatment improves lung cancer symptoms reported by the patient for cough, dyspnea, and chest pain as measured through use of EORTC-QLQ-LC13.

In some cases, the treatment increases the MPR rate of the subject, e.g., as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. causes an increase. In some cases, the treatment includes, for example, chemotherapy (eg, platinum-based double chemotherapy (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (eg, antimetabolites ( e.g., pemetrexed or gemcitabine) or taxane (e.g., paclitaxel or nap-paclitaxel) resulting in an increase in the subject's MPR rate as compared to treatment with the anti-PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody make it

In some cases, the treatment increases the pCR of the subject, eg, as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. causes In some cases, the treatment includes, for example, chemotherapy (eg, platinum-based double chemotherapy (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (eg, antimetabolites ( e.g., pemetrexed or gemcitabine) or taxane (e.g., paclitaxel or nap-paclitaxel) results in an increase in pCR in a subject as compared to treatment with the anti-PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody .

In some cases, the treatment prolongs the subject's OS, eg, as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. make it In some cases, the treatment includes, for example, chemotherapy (eg, platinum-based double chemotherapy (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (eg, antimetabolites ( Prolongs OS in a subject as compared to treatment with the anti-PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody without (eg, pemetrexed or gemcitabine) or a taxane (eg, paclitaxel or nap-paclitaxel).

In some cases, the treatment prolongs the subject's EFS, e.g., as compared to treatment with a PD-1 axis binding antagonist without an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody without a PD-1 axis binding antagonist. make it In some cases, the treatment includes, for example, chemotherapy (eg, platinum-based double chemotherapy (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin)) and non-platinum-based chemotherapeutic agents (eg, antimetabolites ( Prolongs EFS in a subject compared to treatment with the anti-PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody without (eg, pemetrexed or gemcitabine) or a taxane (eg, paclitaxel or nap-paclitaxel).

In some embodiments, the described treatment increases the MPR rate by at least 1% (eg, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%).

In some embodiments, the treatment described herein lowers the subject's pCR by at least about 2 months (eg, by 2 to 120 months, by 2.5 to 100 months, by 3.0 to 80 months, by 4.0 to 60 months, by 5.0 to by 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months , 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, by 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment lowers the subject's pCR by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months) by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, the treatment described herein reduces the subject's EFS by at least about 2 months (eg, by 2 to 120 months, by 2.5 to 100 months, by 3.0 to 80 months, by 4.0 to 60 months, by 5.0 to by 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months , 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, by 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the subject's EFS by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months). by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, OS is measured as the period from initiation of treatment to death. In some cases, the treatment reduces the subject's OS by at least about 2 months (eg, by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months) , by 7-48 months, by 8-36 months, by 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months , 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, the treatment reduces the subject's OS by at least about 3.3 months (eg, by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months) , by 8-36 months, or by 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 5.1 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months , 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, the treatment reduces the subject's OS by at least about 5.3 months (eg, by 5.3 to 120 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 to 24 months). by, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months , by 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

A. Methods and uses for treatment and diagnosis related to cervical cancer

cervical cancer

Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer-related deaths. Each year, more than 500,000 women worldwide are diagnosed with cervical cancer and more than 300,000 die. Nearly 90% of cervical cancer deaths occur in developing countries. In the United States, there are 13,000 new cases of invasive cervical cancer each year and approximately 4000 cancer-related deaths.

Treatment of early and locally advanced cervical cancer consists of surgery and definitive chemoradiation therapy, respectively, and can be very effective in eliciting remission. However, if the cancer does not recur or disappear with first-line treatment, the 5-year survival rate is about 15%, and the prognosis is very poor, similar to that of patients with new metastatic disease. With a few exceptions, the standard of care for recurrent, persistent, or new metastatic disease is chemotherapy, including bevacizumab, based on a Gynecology Oncology Group 240 trial, and bevacizumab added to chemotherapy. showed improvement in median OS compared to chemotherapy alone (17 months vs. 13.3 months, respectively).

Currently, there is no globally accepted standard of care following relapse or progression for chemotherapy, including bevacizumab. Thus, treatment options for these patients largely include a variety of cytotoxic chemotherapeutic agents administered either as single agents or in combination. However, given historically low response rates of around 10% to 15%, it is increasingly questioned whether cytotoxic chemotherapy represents an acceptable standard of care rather than the best supportive care given the burden and impact on the patient's quality of life. focus has been

Because conventional therapies have historically low efficacy rates, coupled with the intervention of the immune response resulting from HPV infection of cervical epithelial cells, cervical cancer appears as a particularly attractive opportunity to try new immunotherapy-based approaches.

Thus, effective immunotherapy for the treatment of cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer, and methods of administering the same) There are unmet needs in the field.

i. Methods and uses for the treatment of cervical cancer

Provided herein are cancers having a detectable expression level of PD-L1 in a subject or population of subjects (eg, cervical cancer, such as stage 4B, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) ), comprising administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist). Methods and uses are provided comprising administering one or more dosing cycles of an antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)).

Dosage regimen and administration

In one aspect, the treatment methods and uses of the invention described herein can be used for cancers having a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or To a subject or population of subjects with recurrent PD-L1 positive cervical cancer) an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and an effective amount of a PD-1 axis binding antagonist ( For example, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) ) by administering one or more dosing cycles of said subject or population of subjects.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 30 mg to about 1200 mg (eg, from about 30 mg to about 1100) every 3 weeks. mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, For example, a dose (eg, a fixed dose) of 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is from about 30 mg to about 600 mg (eg, from about 50 mg to 600 mg every 3 weeks). mg, such as about 60 mg to about 600 mg, such as about 100 mg to about 600 mg, such as about 200 mg to about 600 mg, such as about 200 mg to about 550 mg, such as about 250 mg to about 500 mg, such as from about 300 mg to about 450 mg, such as from about 350 mg to about 400 mg, such as about 375 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose (eg, a fixed dose) of about 600 mg every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is 30 mg to 1200 mg (eg, 30 mg to 1100 mg, eg, 60 mg to 1000 mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as , 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) (eg, a fixed dose). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 30 mg to 600 mg (eg, 50 mg to 600 mg, such as every 3 weeks) , 60 mg to 600 mg, such as 100 mg to 600 mg, such as 200 mg to 600 mg, such as 200 mg to 550 mg, such as 250 mg to 500 mg, such as 300 mg to 450 mg, such as 350 mg to 400 mg, such as 375 mg) (eg, a fixed dose). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg (eg, a fixed dose) every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg (eg, a fixed dose) every 3 weeks. In some cases, combination therapy (eg, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or Dose of said anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) administered in combination therapy with MK-3475 (pembrolizumab, formerly known as lambrolizumab) may be reduced compared to a standard dose of the anti-TIGIT antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 80 mg to about) every two weeks. 1950 mg, such as about 80 mg to about 1900 mg, such as about 80 mg to about 1800 mg, such as about 100 mg to about 1700 mg, such as about 200 mg to about 1600 mg, such as about 300 mg to about 1400 mg, such as about 400 mg to about 1300 mg, such as about 500 mg to about 1200 mg, such as about 600 mg to about 1100 mg, such as about 700 mg to about 1000 mg, such as about 740 mg to about 940 mg, such as about 790 mg to about 890 mg, such as about 815 mg to about 865 mg, such as about 830 mg to about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as, a dose (eg, a fixed dose) of 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 3 weeks. 2000 mg, such as about 200 mg to about 1900 mg, such as about 300 mg to about 1700 mg, such as about 400 mg to about 1600 mg, such as about 500 mg to about 1600 mg, such as about 600 mg to about 1600 mg, such as about 700 mg to about 1600 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg , such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about 2000) every 3 weeks. mg, such as about 200 mg to about 2000 mg, such as about 300 mg to about 2000 mg, such as about 400 mg to about 2000 mg, such as about 500 mg to about 2000 mg, such as about 600 mg to about 1900 mg, such as about 700 mg to about 1800 mg, such as about 800 mg to about 1800 mg, such as about 900 mg to about 1800 mg, such as about 1000 mg to about 1800 mg, such as about 1100 mg to about 1800 mg, such as about 1200 mg to about 1800 mg , such as about 1300 mg to about 1800 mg, such as about 1400 mg to about 1800 mg, such as about 1500 mg to about 1800 mg, such as about 1580 mg to about 1780 mg, such as about 1630 mg to about 1730 mg, such as about 1655 mg to about 1705 mg, such as about 1670 mg to about 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 80 mg to 1950 mg, such as every two weeks) , 80 mg to 1900 mg, such as 80 mg to 1800 mg, such as 100 mg to 1700 mg, such as 200 mg to 1600 mg, such as 300 mg to 1400 mg, such as 400 mg to 1300 mg, such as 500 mg to 1200 mg, such as 600 mg to 1100 mg, such as 700 mg to 1000 mg, such as 740 mg to 940 mg, such as 790 mg to 890 mg, such as 815 mg to 865 mg, such as 830 mg to a dose (eg, a fixed dose) of 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 100 mg to 2000 mg, such as every 3 weeks) , 200 mg to 1900 mg, such as 300 mg to 1700 mg, such as 400 mg to 1600 mg, such as 500 mg to 1600 mg, such as 600 mg to 1600 mg, such as 700 mg to 1600 mg, such as 800 mg to 1600 mg, such as 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 100 mg to 2000 mg, such as every 3 weeks) , 200 mg to 2000 mg, such as 300 mg to 2000 mg, such as 400 mg to 2000 mg, such as 500 mg to 2000 mg, such as 600 mg to 1900 mg, such as 700 mg to 1800 mg, such as 800 mg to 1800 mg, such as 900 mg to 1800 mg, such as 1000 mg to 1800 mg, such as 1100 mg to 1800 mg, such as 1200 mg to 1800 mg, such as 1300 mg to 1800 mg, such as 1400 mg to 1800 mg, such as 1500 mg to 1800 mg, such as 1580 mg to 1780 mg, such as 1630 mg to 1730 mg, such as 1655 mg to 1705 mg, such as 1670 mg to 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some cases, a PD-1 axis binding antagonist (eg, anti-PD-) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of an L1 antagonist antibody (eg, atezolizumab) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 50 mg/kg of the subject's body weight every 3 weeks. kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg /kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 15 mg/kg of the subject's body weight every 3 weeks. (e.g., about 0.1 mg/kg to about 15 mg/kg, such as about 0.5 mg/kg to about 15 mg/kg, such as about 1 mg/kg to about 15 mg/kg, such as about 2.5 mg/kg to about 15 mg/kg, such as about 5 mg/kg to about 15 mg/kg, such as about 7.5 mg/kg to about 15 mg/kg, such as about 10 mg/kg to about 15 mg/kg, such as , about 12.5 mg/kg to about 15 mg/kg, such as about 14 mg/kg to about 15 mg/kg, such as about 15 ± 1 mg/kg, such as about 15 ± 0.5 mg/kg, such as about 15 ± 0.2 mg/kg, such as about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, an effective amount of an anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of about 15 mg/kg administered every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 50 mg/kg of body weight of the subject every 3 weeks ( For example, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 15 mg/kg of body weight of the subject every 3 weeks ( For example, 0.1 mg/kg to 15 mg/kg, such as 0.5 mg/kg to 15 mg/kg, such as 1 mg/kg to 15 mg/kg, such as 2.5 mg/kg to 15 mg/kg, such as 5 mg/kg to 15 mg/kg, such as 7.5 mg/kg to 15 mg/kg, such as 10 mg/kg to 15 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 14 mg/kg to 15 mg/kg, for example 15 ± 1 mg/kg, such as 15 ± 0.5 mg/kg, such as 15 ± 0.2 mg/kg, such as 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, the effective amount of an anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of 15 mg/kg administered every 3 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of the antibody (eg, atezolizumab) is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX) administered as a monotherapy. -1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)).

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, pamprolizumab)) is from about 20 mg to about 1000 mg (eg, from about 40 mg to about) every 3 weeks. 900 mg, such as about 60 mg to about 800 mg, such as about 80 mg to about 700 mg, such as about 80 mg to about 600 mg, such as about 100 mg to about 500 mg, such as about 120 mg to about 400 mg, such as about 140 mg to about 300 mg, such as about 160 mg to about 350 mg, such as about 180 mg to about 300 mg, such as about 180 mg to about 250 mg, such as about 180 mg to about A dose of 220 mg, such as about 190 mg to about 210 mg, such as 200 mg ± 5 mg, such as 200 ± 2.5 mg, such as 200 ± 1.0 mg, such as 200 ± 0.5 mg, such as 200 mg) For example, fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pamprolizumab)) is 20 mg to 1000 mg (eg 40 mg to 900 mg, such as 60) every 3 weeks. mg to 800 mg, such as 80 mg to 700 mg, such as 80 mg to 600 mg, such as 100 mg to 500 mg, such as 120 mg to 400 mg, such as 140 mg to 300 mg, such as 160 mg to 350 mg, such as 180 mg to 300 mg, such as 180 mg to 250 mg, such as 180 mg to 220 mg, such as 190 mg to 210 mg, such as 200 mg ± 5 mg, such as 200 ± 2.5 mg, such as 200 ± 1.0 mg, such as 200 ± 0.5 mg , eg 200 mg) (eg, a fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, pamprolizumab)) is a dose (eg, a fixed dose) of 200 mg every 3 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, such as an anti TIGIT antagonist antibody disclosed herein, such as tiragolumab). The dose of the antibody (eg, pembrolizumab)) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is from about 20 mg to about 1000 mg (eg, from about 40 mg to about 900) every two weeks. mg, such as about 60 mg to about 800 mg, such as about 80 mg to about 700 mg, such as about 80 mg to about 600 mg, such as about 100 mg to about 500 mg, such as about 120 mg to about 400 mg, such as about 140 mg to about 300 mg, such as about 160 mg to about 350 mg, such as about 180 mg to about 300 mg, such as about 200 mg to about 280 mg, such as about 220 mg to about 260 mg, such as from about 230 mg to about 250 mg, such as 240 mg ± 5 mg, such as 240 ± 2.5 mg, such as 240 ± 1.0 mg, such as 240 ± 0.5 mg, such as 240 mg). , fixed capacity). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is from about 100 mg to about 1000 mg (eg, from about 200 mg to about 900) every 4 weeks. mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 400 mg to about 600 mg, such as about 400 mg to about 550 mg, such as about 420 mg to about 540 mg , such as from about 440 mg to about 520 mg, such as from about 460 mg to about 500 mg, such as from about 470 mg to about 490 mg, such as 480 mg ± 5 mg, such as 480 ± 2.5 mg, such as 480 ± 1.0 mg, such as 480 ± 0.5 mg, such as 480 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is 20 mg to 1000 mg (eg 40 mg to 900 mg, such as 60 mg) every two weeks. to 800 mg, such as 80 mg to 700 mg, such as 80 mg to 600 mg, such as 100 mg to 500 mg, such as 120 mg to 400 mg, such as 140 mg to 300 mg, such as 160 mg to 350 mg, such as 180 mg. to 300 mg, such as 200 mg to 280 mg, such as 220 mg to 260 mg, such as 230 mg to 250 mg, such as 240 mg ± 5 mg, such as 240 ± 2.5 mg, such as 240 ± 1.0 mg, such as 240 ± 0.5 mg, eg 240 mg) (eg, a fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is 100 mg to 1000 mg (eg 200 mg to 900 mg, such as 300 mg) every 4 weeks. to 800 mg, such as 400 mg to 700 mg, such as 400 mg to 600 mg, such as 400 mg to 550 mg, such as 420 mg to 540 mg, such as 440 mg to 520 mg, such as 460 mg to 500 mg, such as 470 mg to 490 mg, such as 480 mg ± 5 mg, such as 480 ± 2.5 mg, such as 480 ± 1.0 mg, such as 480 ± 0.5 mg, such as 480 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 480 mg every 4 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, such as an anti TIGIT antagonist antibody disclosed herein, such as tiragolumab). The dose of the antibody (eg, nivolumab)) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

In any of the methods and uses of the invention, said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody) (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is administered in one or more dosing cycles ( For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles. For example, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) )) continue until clinical benefit is lost (e.g., disease progression, drug resistance, death, or unacceptable toxicity is identified) In some cases, the length of each dosing cycle is about 14 days to 28 days (eg, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days) days) In some cases, the length of each dosing cycle is about 21 days. In some cases, the length of each dosing cycle is about 14 days. In some cases, the length of each dosing cycle is about 28 days. In some cases, the anti-TIGIT antagonist antibody (eg, anti-TIGIT as disclosed herein) The antagonist antibody, such as tyragolumab) is administered on about day 1 (eg, day 1±3) of each dosing cycle. For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of about 600 mg (eg, a fixed dose) on Day 1 of each 21 day cycle (eg, a fixed dose) ( i.e., at a dose of about 600 mg every 3 weeks). In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 600 mg (eg, a fixed dose) on Day 1 of each 21-day cycle (eg, a fixed dose) i.e., at a dose of 600 mg every 3 weeks). Similarly, in some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK) - 3475 (pembrolizumab, formerly known as lambrolizumab) is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle.For example, the PD-1 axis binding antagonist ( For example, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered intravenously at a dose of about 1200 mg (ie, at a dose of about 1200 mg every 3 weeks) on Day 1 of each 21 day cycle. For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered at a dose of about 200 mg on Day 1 of each 21-day cycle (ie, every 3 weeks). In a dose of about 200 mg), for example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is administered on the first day of each 14-day cycle. Administer intravenously at a dose of 240 mg (i.e., at a dose of about 240 mg every 2 weeks), For example, the PD-1 axis binding antagonist (e.g., anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 480 mg (ie, at a dose of about 480 mg every 4 weeks) on Day 1 of each 28-day cycle In some cases, the PD-1 axis binding antagonist (eg, anti- PD-L1 antagonist antibody (eg, atezolizumab)) is administered intravenously at a dose of about 1200 mg (ie, at a dose of about 1200 mg every 3 weeks) on Day 1 of each 21 day cycle. , wherein the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered at a dose of about 200 mg on Day 1 of each 21 day cycle (ie, about 200 mg every 3 weeks). For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is administered on day 1 of each 14-day cycle. It is administered intravenously at a dose of about 240 mg (ie, at a dose of about 240 mg every two weeks). For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is administered at a dose of about 480 mg on Day 1 of each 28-day cycle (ie, about every 4 weeks). 480 mg) intravenously.

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) are all administered on about 1 day of each dosing cycle (e.g., Day 1 ± 3 days).For example, the anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at about 600 mg on day 1 of each 21-day cycle. administered intravenously at a dose of (e.g., a fixed dose) (i.e., at a dose of about 600 mg every 3 weeks) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) ) is administered intravenously at a dose of about 1200 mg (fixed dose) (i.e., at a dose of about 1200 mg every 3 weeks) on Day 1 of each 21 day cycle.For example, the anti-TIGIT antagonist antibody (such as , an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered intravenously at a dose of about 600 mg (i.e., at a dose of about 600 mg every 3 weeks) on Day 1 of each 21 day cycle, The PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, pembrolizumab)) is administered at a dose of about 200 mg on Day 1 of each 21-day cycle (ie, about 200 mg every 3 weeks). In some embodiments, the anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of 600 mg on day 1 of each 21-day cycle. administered intravenously (eg, a fixed dose) (ie, at a dose of 600 mg every 3 weeks), the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) each 21 At a dose of 1200 mg on day 1 of the cycle It is administered intravenously (fixed dose) (ie, at a dose of 1200 mg every 3 weeks). For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of 600 mg on Day 1 of each 21 day cycle (ie, 600 mg every 3 weeks). and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, pembrolizumab)) is administered at a dose of 200 mg on Day 1 of each 21-day cycle (i.e., , at a dose of 200 mg every 3 weeks).

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) are all administered on about day 1 of the first dosing cycle (e.g. , day 1 ± 3 days).For example, the anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered on day 1 of each 21-day cycle of about 600 Administered intravenously at a dose of mg (eg, a fixed dose) (ie, at a dose of about 600 mg every 3 weeks), the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, nivolumab)) ) is administered intravenously at a dose of about 240 mg (fixed dose) (ie, at a dose of about 240 mg every 2 weeks) on Day 1 of each 14-day cycle.For example, the anti-TIGIT antagonist antibody (such as , an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered intravenously at a dose of about 600 mg (i.e., at a dose of about 600 mg every 3 weeks) on Day 1 of each 21 day cycle, The PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, nivolumab)) is administered at a dose of about 480 mg on Day 1 of each 28-day cycle (ie, a dose of about 480 mg every 4 weeks). In some embodiments, the anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of 600 mg on Day 1 of each 21-day cycle ( For example, a fixed dose) (ie, at a dose of 600 mg every 3 weeks) is administered intravenously, and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, nivolumab)) is administered on each 14-day cycle. at a dose of 240 mg (fixed dose) on day 1 of ( i.e., at a dose of 240 mg every 2 weeks). For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of 600 mg on Day 1 of each 21 day cycle (ie, 600 mg every 3 weeks). is administered intravenously), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, nivolumab)) is administered at a dose of 480 mg on Day 1 of each 28-day cycle (i.e., at a dose of 480 mg every 4 weeks).

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 60 ± 15 minutes (eg, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes , about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab, formerly known as lambrolizumab) in about 60 ± 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes) , about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes). administered to said subject or population of subjects by intravenous infusion.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 30 ± 10 minutes (eg, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes , about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab, formerly known as lambrolizumab) in about 30 ± 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes) , about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) by intravenous infusion to the subject or population of subjects.

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is combined with the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli). Zumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) to the subject or population of subjects prior to administration. In cases, e.g., after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, Prior to administration of MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab), the method comprises an interim first observation period. In some cases, the method comprises: The PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly) and further comprises a second observation period after administration of)))) In some cases, the method includes a first observation period after administration of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) )) after the second observation period.In some cases, the first and second observation period are each about 30 minutes to about 60 minutes in length.The first and second observation period are each about In cases that are 60 minutes in length, the method comprises the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab), respectively, during the first and second observation periods). or anti-PD- 1 Vital signs (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) of the subject or population of subjects at about 30 ± 10 minutes after administration for example, pulse rate, respiration rate, blood pressure and temperature). In cases where the first and second observation periods are each about 30 minutes in length, the method comprises the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD- After administration of an L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) recording vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) of the subject or population of subjects at 15±10 minutes.

In other cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab, formerly known as lambrolizumab) is administered to said subject or population of subjects prior to said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab). In cases, for example, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK- After administration of 3475 (pembrolizumab, formerly known as lambrolizumab) and before administration of said anti-TIGIT antagonist antibody, said method comprises an interim first observation period. In some cases, said method comprises said and a second observation period following administration of anti-TIGIT antagonist antibody.In some cases, the method comprises said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 A first observation period following administration of an antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and a second observation following administration of said anti TIGIT antagonist antibody In some cases, the first and second observation period are each about 30 minutes to about 60 minutes in length.In cases where the first and second observation period are each about 60 minutes in length , the method comprises a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (eg, MDX-1106) nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) and the vital signs of the subject or population of subjects (e.g., pulse rate, respiration rate, blood pressure and temperature). In cases where the first and second observation periods are each about 30 minutes in length, the method comprises each of the first and second observation periods with a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (such as MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and drug after administration of the anti-TIGIT antagonist antibody recording vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) of the subject or population of subjects at 15±10 minutes.

In other instances, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is administered to the subject or population of subjects simultaneously. In instances, for example, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106) After administration of (nivolumab) or MK-3475 (pembrolizumab, previously known as lambrolizumab), the method comprises an observation period.In some cases, the observation period is from about 30 minutes to about 60 minutes in length.In cases where the observation period is about 60 minutes in length, the method comprises administering a PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or about 30±10 minutes after administration of an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and the anti-TIGIT antagonist antibody and recording vital signs (e.g., pulse rate, respiration rate, blood pressure and temperature) of the subject or population of subjects, In cases where the observation period is about 30 minutes in length, the method comprises the observation period either a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly (known as lambrolizumab)) and at about 15 ± 10 minutes after administration of the anti-TIGIT antagonist antibody, the vital signs (e.g., pulse rate, respiration rate, blood pressure and temperature) of the subject or population of subjects are recorded. may include steps.

In another embodiment, the present invention provides one or more dosing cycles of a 600 mg dose (eg, a fixed dose) of an anti TIGIT antagonist antibody every 3 weeks and a 1200 mg dose (eg, a fixed dose) of atezolizumab every 3 weeks to the subject or There is provided a method of treating said subject or a population of subjects having stage 4B, metastatic, relapsed or persistent cervical cancer by administering to said subject population, wherein said anti-TIGIT antagonist antibody comprises SEQ ID NO: 17 or It has a VH domain having the amino acid sequence of 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another embodiment, the present invention provides a subject or subject with one or more dosing cycles of a 600 mg dose (eg, a fixed dose) tiragolumab every 3 weeks and a 1200 mg dose (eg, a fixed dose) atezolizumab every 3 weeks. Provided is a method of treating said subject or population of subjects having stage 4B, metastatic, relapsed or persistent cervical cancer by administering to the population.

In another aspect, the present invention provides a subject or subject with one or more dosing cycles of a 600 mg dose (eg, a fixed dose) tiragolumab every 3 weeks and a 200 mg dose (eg, a fixed dose) pembrolizumab every 3 weeks. Provided is a method of treating said subject or population of subjects having stage 4B, metastatic, relapsed or persistent cervical cancer by administering to the population.

In another embodiment, the present invention provides one or more dosing cycles of a 600 mg dose (eg, a fixed dose) tiragolumab every 3 weeks and a 240 mg dose (eg, a fixed dose) nivolumab every 2 weeks to a subject or population of subjects. Provided is a method of treating said subject or population of subjects having stage 4B, metastatic, relapsed or persistent cervical cancer by administering to

In another embodiment, the present invention provides one or more dosing cycles of a 600 mg dose (eg, a fixed dose) tiragolumab every 3 weeks and a 480 mg dose (eg, a fixed dose) nivolumab every 4 weeks to a subject or population of subjects. Provided is a method of treating said subject or population of subjects having stage 4B, metastatic, relapsed or persistent cervical cancer by administering to

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-L1) for use in a method of treating a subject or population of subjects having cervical cancer) An antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is provided, wherein The method comprises an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) ) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) to the subject or population of subjects.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 30 mg to about 1200 mg (eg, from about 30 mg to about 1100) every 3 weeks. mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, For example, a dose (eg, a fixed dose) of 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is from about 30 mg to about 600 mg (eg, from about 50 mg to 600 mg every 3 weeks). mg, such as about 60 mg to about 600 mg, such as about 100 mg to about 600 mg, such as about 200 mg to about 600 mg, such as about 200 mg to about 550 mg, such as about 250 mg to about 500 mg, such as from about 300 mg to about 450 mg, such as from about 350 mg to about 400 mg, such as about 375 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is 30 mg to 1200 mg (eg, 30 mg to 1100 mg, eg, 60 mg to 1000 mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as , 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) (eg, a fixed dose). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 30 mg to 600 mg (eg, 50 mg to 600 mg, such as every 3 weeks) , 60 mg to 600 mg, such as 100 mg to 600 mg, such as 200 mg to 600 mg, such as 200 mg to 550 mg, such as 250 mg to 500 mg, such as 300 mg to 450 mg, such as 350 mg to 400 mg, such as 375 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 600 mg every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg every 3 weeks. In some cases, combination therapy (eg, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or Dose of said anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to be administered in combination therapy with MK-3475 (pembrolizumab, formerly known as lambrolizumab) may be reduced compared to a standard dose of the anti-TIGIT antagonist antibody to be administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 80 mg to about) every two weeks. 1950 mg, such as about 80 mg to about 1900 mg, such as about 80 mg to about 1800 mg, such as about 100 mg to about 1700 mg, such as about 200 mg to about 1600 mg, such as about 300 mg to about 1400 mg, such as about 400 mg to about 1300 mg, such as about 500 mg to about 1200 mg, such as about 600 mg to about 1100 mg, such as about 700 mg to about 1000 mg, such as about 740 mg to about 940 mg, such as about 790 mg to about 890 mg, such as about 815 mg to about 865 mg, such as about 830 mg to about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as, a dose (eg, a fixed dose) of 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 3 weeks. 2000 mg, such as about 200 mg to about 1900 mg, such as about 300 mg to about 1700 mg, such as about 400 mg to about 1600 mg, such as about 500 mg to about 1600 mg, such as about 600 mg to about 1600 mg, such as about 700 mg to about 1600 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg , such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 4 weeks. 2000 mg, such as about 200 mg to about 2000 mg, such as about 300 mg to about 2000 mg, such as about 400 mg to about 2000 mg, such as about 500 mg to about 2000 mg, such as about 600 mg to about 1900 mg, such as about 700 mg to about 1800 mg, such as about 800 mg to about 1800 mg, such as about 900 mg to about 1800 mg, such as about 1000 mg to about 1800 mg, such as about 1100 mg to about 1800 mg, such as about 1200 mg to about 1800 mg, such as about 1300 mg to about 1800 mg, such as about 1400 mg to about 1800 mg, such as about 1500 mg to about 1800 mg, such as about 1580 mg to about 1780 mg, such as about 1630 mg to about 1730 mg, such as about 1655 mg to about 1705 mg, such as about 1670 mg to about 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as, 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 80 mg to 1950 mg, such as every two weeks) , 80 mg to 1900 mg, such as 80 mg to 1800 mg, such as 100 mg to 1700 mg, such as 200 mg to 1600 mg, such as 300 mg to 1400 mg, such as 400 mg to 1300 mg, such as 500 mg to 1200 mg, such as 600 mg to 1100 mg, such as 700 mg to 1000 mg, such as 740 mg to 940 mg, such as 790 mg to 890 mg, such as 815 mg to 865 mg, such as 830 mg to a dose (eg, a fixed dose) of 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 100 mg to 2000 mg, such as every 3 weeks) , 200 mg to 1900 mg, such as 300 mg to 1700 mg, such as 400 mg to 1600 mg, such as 500 mg to 1600 mg, such as 600 mg to 1600 mg, such as 700 mg to 1600 mg, such as 800 mg to 1600 mg, such as 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 100 mg to 2000 mg, such as every 4 weeks) , 200 mg to 2000 mg, such as 300 mg to 2000 mg, such as 400 mg to 2000 mg, such as 500 mg to 2000 mg, such as 600 mg to 1900 mg, such as 700 mg to 1800 mg, such as 800 mg to 1800 mg, such as 900 mg to 1800 mg, such as 1000 mg to 1800 mg, such as 1100 mg to 1800 mg, such as 1200 mg to 1800 mg, such as 1300 mg to 1800 mg, such as 1400 mg to 1800 mg, such as 1500 mg to 1800 mg, such as 1580 mg to 1780 mg, such as 1630 mg to 1730 mg, such as 1655 mg to 1705 mg, such as 1670 mg to 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some cases, a PD-1 axis binding antagonist (eg, anti-PD-) to be administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of an L1 antagonist antibody (eg, atezolizumab) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody to be administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, pamprolizumab)) is from about 20 mg to about 1000 mg (eg, from about 40 mg to about) every 3 weeks. 900 mg, such as about 60 mg to about 800 mg, such as about 80 mg to about 700 mg, such as about 80 mg to about 600 mg, such as about 100 mg to about 500 mg, such as about 120 mg to about 400 mg, such as about 140 mg to about 300 mg, such as about 160 mg to about 350 mg, such as about 180 mg to about 300 mg, such as about 180 mg to about 250 mg, such as about 180 mg to about A dose of 220 mg, such as about 190 mg to about 210 mg, such as 200 mg ± 5 mg, such as 200 ± 2.5 mg, such as 200 ± 1.0 mg, such as 200 ± 0.5 mg, such as 200 mg) For example, fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pamprolizumab)) is 20 mg to 1000 mg (eg, 40 mg to 900 mg, such as every 3 weeks) , 60 mg to 800 mg, such as 80 mg to 700 mg, such as 80 mg to 600 mg, such as 100 mg to 500 mg, such as 120 mg to 400 mg, such as 140 mg to 300 mg, such as 160 mg to 350 mg, such as 180 mg to 300 mg, such as 180 mg to 250 mg, such as 180 mg to 220 mg, such as 190 mg to 210 mg, such as 200 mg ± 5 mg, such as 200 ± 2.5 mg, eg, 200±1.0 mg, eg, 200±0.5 mg, eg, 200 mg) (eg, a fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, pamprolizumab)) is a dose of about 200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pamprolizumab)) is a dose of 200 mg every 3 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of the antibody (eg, pembrolizumab)) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is from about 20 mg to about 1000 mg (eg, from about 40 mg to about 900) every two weeks. mg, such as about 60 mg to about 800 mg, such as about 80 mg to about 700 mg, such as about 80 mg to about 600 mg, such as about 100 mg to about 500 mg, such as about 120 mg to about 400 mg, such as about 140 mg to about 300 mg, such as about 160 mg to about 350 mg, such as about 180 mg to about 300 mg, such as about 200 mg to about 280 mg, such as about 220 mg to about 260 mg, such as from about 230 mg to about 250 mg, such as 240 mg ± 5 mg, such as 240 ± 2.5 mg, such as 240 ± 1.0 mg, such as 240 ± 0.5 mg, such as 240 mg). , fixed capacity). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of about 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is from about 100 mg to about 1000 mg (eg, from about 200 mg to about 900) every 4 weeks. mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 400 mg to about 600 mg, such as about 400 mg to about 550 mg, such as about 420 mg to about 540 mg , such as from about 440 mg to about 520 mg, such as from about 460 mg to about 500 mg, such as from about 470 mg to about 490 mg, such as 480 mg ± 5 mg, such as 480 ± 2.5 mg, such as 480 ± 1.0 mg, such as 480 ± 0.5 mg, such as 480 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is 20 mg to 1000 mg (eg 40 mg to 900 mg, such as 60 mg) every two weeks. to 800 mg, such as 80 mg to 700 mg, such as 80 mg to 600 mg, such as 100 mg to 500 mg, such as 120 mg to 400 mg, such as 140 mg to 300 mg, such as 160 mg to 350 mg, such as 180 mg. to 300 mg, such as 200 mg to 280 mg, such as 220 mg to 260 mg, such as 230 mg to 250 mg, such as 240 mg ± 5 mg, such as 240 ± 2.5 mg, such as 240 ± 1.0 mg, such as 240 ± 0.5 mg, eg 240 mg) (eg, a fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is 100 mg to 1000 mg (eg, 200 mg to 900 mg, eg, every 4 weeks) 300 mg to 800 mg, such as 400 mg to 700 mg, such as 400 mg to 600 mg, such as 400 mg to 550 mg, such as 420 mg to 540 mg, such as 440 mg to 520 mg, such as 460 mg to 500 mg, such as 470 mg to 490 mg, such as 480 mg ± 5 mg, such as 480 ± 2.5 mg, such as 480 ± 1.0 mg, such as 480 ± 0.5 mg, such as 480 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 480 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 480 mg every 4 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, such as an anti TIGIT antagonist antibody disclosed herein, such as tiragolumab). The dose of the antibody (eg, nivolumab)) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 50 mg/kg of the subject's body weight every 3 weeks. kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, For example, about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg ) is the capacity of In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 15 mg/kg of the subject's body weight every 3 weeks. (e.g., about 0.1 mg/kg to about 15 mg/kg, such as about 0.5 mg/kg to about 15 mg/kg, such as about 1 mg/kg to about 15 mg/kg, such as about 2.5 mg/kg to about 15 mg/kg, such as about 5 mg/kg to about 15 mg/kg, such as about 7.5 mg/kg to about 15 mg/kg, such as about 10 mg/kg to about 15 mg/kg, such as , about 12.5 mg/kg to about 15 mg/kg, such as about 14 mg/kg to about 15 mg/kg, such as about 15 ± 1 mg/kg, such as about 15 ± 0.5 mg/kg, such as about 15 ± 0.2 mg/kg, such as about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, an effective amount of an anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of about 15 mg/kg to be administered every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 50 mg/kg of body weight of the subject every 3 weeks ( For example, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as, 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some embodiments, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 15 mg/kg (eg, from 0.01 mg/kg to 15 mg/kg of body weight of the subject every 3 weeks) , 0.1 mg/kg to 15 mg/kg, such as 0.5 mg/kg to 15 mg/kg, such as 1 mg/kg to 15 mg/kg, such as 2.5 mg/kg to 15 mg/kg, such as 5 mg/kg to 15 mg/kg, such as 7.5 mg/kg to 15 mg/kg, such as 10 mg/kg to 15 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 14 mg/kg kg to 15 mg/kg, such as 15 ± 1 mg/kg, such as 15 ± 0.5 mg/kg, such as 15 ± 0.2 mg/kg, such as 15 ± 0.1 mg/kg, such as 15 mg/kg) is the capacity of In some cases, the effective amount of an anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of 15 mg/kg to be administered every 3 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). Doses of an antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) as monotherapy Administered PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab) previously known as lambrolizumab))).

said anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD -1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is administered in one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles) In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (( Dosing cycles of, e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) lose clinical benefit (e.g., disease progression, drug resistance, death, or unacceptable toxicity is identified.) In some cases, the length of each dosing cycle is about 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days. The length of each dosing cycle is about 21 days. In some cases, the length of each dosing cycle is about 14 days. In some cases, the length of each dosing cycle is about 28 days. In some cases, the TIGIT antagonist antibodies (eg, anti-TIGIT antagonists as disclosed herein) The antibody, such as tyragolumab) should be administered on about day 1 (eg, day 1±3) of each dosing cycle. For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of about 600 mg (eg, a fixed dose) on Day 1 of each 21 day cycle (eg, a fixed dose) ( i.e., at a dose of about 600 mg every 3 weeks) should be administered intravenously. Similarly, in some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK) - 3475 (pembrolizumab, formerly known as lambrolizumab) should be administered on about day 1 (eg, day 1±3) of each dosing cycle.For example, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) at a dose of about 1200 mg (eg, a fixed dose) on Day 1 of each 21 day cycle (ie, a dose of about 1200 mg every 3 weeks) For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered at a dose of about 200 mg on day 1 of each 21-day cycle. Doses should be administered intravenously (that is, at a dose of about 200 mg every 3 weeks).For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is each It should be administered intravenously at a dose of about 240 mg (i.e., at a dose of about 240 mg every two weeks) on Day 1 of a 14-day cycle.For example, the PD-1 axis binding antagonist (eg, anti-PD- One antagonist antibody (eg, nivolumab)) should be administered intravenously at a dose of about 480 mg (ie, at a dose of about 480 mg every 4 weeks) on Day 1 of each 28-day cycle. said anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD -1 antagonist antibodies (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) are all administered on about 1 day (eg, 1 day ± 3 days) of each dosing cycle. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody, such as tiragolumab) and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) should all be administered on about day 1 (eg, day 1±3) of the first dosing cycle. For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 600 mg on Day 1 of each 21 day cycle (ie, about every 3 weeks). at a dose of 600 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, nivolumab)) is administered at a dose of about 240 mg on Day 1 of each 14-day cycle. It should be administered intravenously (ie, at a dose of about 240 mg every 2 weeks). For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 600 mg on Day 1 of each 21 day cycle (ie, about every 3 weeks). at a dose of 600 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, nivolumab)) is administered at a dose of about 480 mg on Day 1 of each 28-day cycle. It should be administered intravenously (ie, at a dose of about 480 mg every 4 weeks). In some embodiments, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of 1200 mg (eg, a fixed dose) on Day 1 of each 21-day cycle (eg, a fixed dose) ( ie, at a dose of 1200 mg every 3 weeks) should be administered intravenously. For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered at a dose of 200 mg on Day 1 of each 21 day cycle (ie, 200 every 3 weeks). mg) should be administered intravenously. For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is administered at a dose of 240 mg on Day 1 of each 14-day cycle (ie, 240 mg every 2 weeks). dose) should be administered intravenously. For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is administered at a dose of 480 mg on Day 1 of each 28-day cycle (ie, 480 mg every 4 weeks). dose) should be administered intravenously. In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) are both administered on Day 1 of each dosing cycle (e.g., day 1 ± 3. In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, An anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) All should be administered on Day 1 (eg, Day 1±3) of the first dosing cycle.For example, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered intravenously at a dose of about 600 mg (i.e., at a dose of 600 mg every 3 weeks) on Day 1 of each 21-day cycle and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody ( (e.g., nivolumab)) should be administered intravenously at a dose of 240 mg (i.e., at a dose of 240 mg every 2 weeks) on day 1 of each 14-day cycle.For example, the anti-TIGIT antagonist antibody , an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered intravenously at a dose of 600 mg (ie, at a dose of 600 mg every 3 weeks) on Day 1 of each 21 day cycle, wherein the PD The -1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, nivolumab)) is administered intravenously at a dose of 480 mg (ie, at a dose of 480 mg every 4 weeks) on Day 1 of each 28-day cycle. should be administered

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 60 ± 15 minutes (eg, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes , about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab, formerly known as lambrolizumab) in about 60 ± 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes) , about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes). It should be administered to the subject or population of subjects by intravenous infusion.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 30 ± 10 minutes (eg, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes , about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab, formerly known as lambrolizumab) in about 30 ± 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes) , about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) to the subject or population of subjects by intravenous infusion.

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is combined with the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli). Zumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) to the subject or population of subjects prior to administration. In some cases, for example, after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, , MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)), the method includes an interim first observation period. The PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab) )), formerly known as lambrolizumab, further comprises a second observation period after administration. In some cases, the method includes a first observation period after administration of said anti-TIGIT antagonist antibody and said PD-1 axis binding An antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) )) after administration of the second observation period.In some cases, the first and second observation period are each about 30 minutes to about 60 minutes in length.The first and second observation period are each In cases that are about 60 minutes in length, the method comprises the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab), respectively, during the first and second observation periods. ) or term vitality of the subject or population of subjects about 30 ± 10 minutes after administration of a PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) may include recording signs (eg, pulse rate, respiration rate, blood pressure and temperature). In cases where the first and second observation periods are each about 30 minutes in length, the method comprises the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD- After administration of an L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) recording vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) of the subject or population of subjects at 15±10 minutes.

In other cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab, formerly known as lambrolizumab) should be administered to the subject or population of subjects prior to the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab). In some cases, for example, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or After administration of MK-3475 (pembrolizumab, formerly known as lambrolizumab) and before administration of said anti-TIGIT antagonist antibody, the method comprises an interim first observation period. comprises a second observation period after administration of said anti-TIGIT antagonist antibody In some cases, said method comprises said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD -1 first observation period after administration of antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and second after administration of said anti-TIGIT antagonist antibody includes both observation periods.In some cases, the first and second observation periods are each about 30 minutes to about 60 minutes in length, When the first and second observation periods are each about 60 minutes in length In some cases, the method comprises a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX- 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) and the vital signs of the subject or population of subjects about 30 ± 10 minutes after administration of the anti-TIGIT antagonist antibody may include recording the follow-up (eg, pulse rate, respiration rate, blood pressure and temperature). In cases where the first and second observation periods are each about 30 minutes in length, the method comprises each of the first and second observation periods with a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (such as MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and drug after administration of the anti-TIGIT antagonist antibody recording vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) of the subject or population of subjects at 15±10 minutes.

In other instances, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) should be administered to the subject or population of subjects simultaneously. In some cases, for example, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX- After administration of 1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab), the method comprises an observation period.In some cases, the observation period is about 30 minutes to is about 60 minutes in length.In cases where the observation period is about 60 minutes in length, the method comprises a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) during the observation period) or about 30 ± 10 minutes after administration of an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and said anti-TIGIT antagonist antibody recording the subject's vital signs (e.g., pulse rate, respiration rate, blood pressure and temperature) in the case where the observation period is about 30 minutes in length, the method includes the PD during the observation period -1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly lamb (known as rolizumab)) and the subject's vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) about 15±10 minutes after administration of the anti-TIGIT antagonist antibody.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-L1) for use in a method of treating a subject or population of subjects having cervical cancer) An antagonist antibody (eg, atezolizumab) is provided, wherein the method comprises administering an anti-TIGIT antagonist antibody at a dose of 600 mg (eg, a fixed dose) every 3 weeks and a dose of 1200 mg (eg, a fixed dose) every 3 weeks. administering to the subject or population of subjects one or more dosing cycles of atezolizumab, wherein the anti-TIGIT antagonist antibody is further described below: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-1) for use in a method of treating a subject or population of subjects having cervical cancer An antagonist antibody (eg, pembrolizumab) is provided, wherein the method comprises administering an anti-TIGIT antagonist antibody at a dose of 600 mg (eg, a fixed dose) every 3 weeks and a dose of 200 mg (eg, a fixed dose) every 3 weeks. administering to the subject or population of subjects one or more dosing cycles of pembrolizumab, wherein the anti-TIGIT antagonist antibody is further described below: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-1) for use in a method of treating a subject or population of subjects having cervical cancer Provided is an antagonist antibody (eg, nivolumab), wherein the method comprises a dose of 600 mg (eg, a fixed dose) of an anti TIGIT antagonist antibody every 3 weeks and a dose of 240 mg (eg, a fixed dose) of nibol every 2 weeks administering to said subject or population of subjects one or more dosing cycles of lumab, wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a sequence as further described below: and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases In , the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-1) for use in a method of treating a subject or population of subjects having cervical cancer An antagonist antibody (eg, nivolumab) is provided, wherein the method comprises a dose of 600 mg (eg, a fixed dose) of an anti TIGIT antagonist antibody every 3 weeks and a dose of 480 mg (eg, a fixed dose) of nibol every 4 weeks (eg, a fixed dose) administering to said subject or population of subjects one or more dosing cycles of lumab, wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a sequence as further described below: and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases In , the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-L1) for use in a method of treating a subject or population of subjects having cervical cancer) Provided is an antagonist antibody (eg, atezolizumab), wherein the method comprises a dose of 600 mg (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 1200 mg (eg, a fixed dose) of ate every 3 weeks (eg, a fixed dose) administering to the subject or population of subjects one or more dosing cycles of zolizumab.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-1) for use in a method of treating a subject or population of subjects having cervical cancer An antagonist antibody (eg, MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is provided, wherein the method comprises a dose of 600 mg (eg, a fixed dose) of tiragolumab and 3 every 3 weeks administering to the subject or population of subjects one or more dosing cycles of pembrolizumab at a dose of 200 mg per week (eg, a fixed dose).

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-1) for use in a method of treating a subject or population of subjects having cervical cancer An antagonist antibody (eg, MDX-1106 (nivolumab)) is provided, wherein the method comprises a dose of 600 mg (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 240 mg (eg, a fixed dose) every 2 weeks dose) of at least one dosing cycle of nivolumab to said subject or population of subjects.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti-PD-1) for use in a method of treating a subject or population of subjects having cervical cancer An antagonist antibody (eg, MDX-1106 (nivolumab)) is provided, wherein the method comprises a dose of 600 mg (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 480 mg (eg, a fixed dose) every 4 weeks (eg, a fixed dose) dose) of at least one dosing cycle of nivolumab to said subject or population of subjects.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, , an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament comprises an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist. (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) ))).

In another aspect, the present invention relates to a cancer having a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) ) provides the use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject or population of subjects having one or more dosing cycles of (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) administering to the subject or population of subjects, wherein the medicament is an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD -1 is formulated for administration of an antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)).

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject or population of subjects having cervical cancer) (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)), wherein said method comprises one or more of said medicament and an anti-TIGIT antagonist antibody. administering a dosing cycle to the subject or population of subjects, wherein the medicament is an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody) (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and the anti-TIGIT antagonist antibody to be administered.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 30 mg to about 1200 mg (eg, from about 30 mg to about 1100) every 3 weeks. mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, For example, a dose (eg, a fixed dose) of 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is about 30 mg to about 600 mg (eg, about 50 mg to 600 mg every 3 weeks). , such as about 60 mg to about 600 mg, such as about 100 mg to about 600 mg, such as about 200 mg to about 600 mg, such as about 200 mg to about 550 mg, such as about 250 mg to about 500 mg , such as about 300 mg to about 450 mg, such as about 350 mg to about 400 mg, such as about 375 mg) (eg, 30 mg to 1200 mg (eg, 30 mg to 1100 mg, such as 60 mg to 1000) mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, For example, 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg , such as 600 ± 0.5 mg, such as 600 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is 3 weeks. 30 mg to 600 mg (eg, 50 mg to 600 mg, such as 60 mg to 600 mg, such as 100 mg to 600 mg, such as 200 mg to 600 mg, such as 200 mg to 550 mg, such as 250 mg to 500 mg, such as 300 mg to 450 mg, such as 350 mg to 400 mg, such as 375 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is a dose of about 600 mg every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is a dose of 600 mg every 3 weeks. In some cases, combination therapy (eg, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or Dose of said anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to be administered in combination therapy with MK-3475 (pembrolizumab, formerly known as lambrolizumab) may be reduced compared to a standard dose of the anti-TIGIT antagonist antibody to be administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 80 mg to about) every two weeks. 1950 mg, such as about 80 mg to about 1900 mg, such as about 80 mg to about 1800 mg, such as about 100 mg to about 1700 mg, such as about 200 mg to about 1600 mg, such as about 300 mg to about 1400 mg, such as about 400 mg to about 1300 mg, such as about 500 mg to about 1200 mg, such as about 600 mg to about 1100 mg, such as about 700 mg to about 1000 mg, such as about 740 mg to about 940 mg, such as about 790 mg to about 890 mg, such as about 815 mg to about 865 mg, such as about 830 mg to about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as, 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg) (such as 80 mg to 2000 mg (such as 80 mg to 1950 mg, such as 80 mg to 1900 mg, such as 80 mg to 1800 mg, For example, 100 mg to 1700 mg, such as 200 mg to 1600 mg, such as 300 mg to 1400 mg, such as 400 mg to 1300 mg, such as 500 mg to 1200 mg, such as 600 mg to 1100 mg, such as, 700 mg to 1000 mg, such as 740 mg to 940 mg, such as 790 mg to 890 mg, such as 815 mg to 865 mg, such as 830 mg to 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as, 840 mg))). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 3 weeks. 2000 mg, such as about 200 mg to about 1900 mg, such as about 300 mg to about 1700 mg, such as about 400 mg to about 1600 mg, such as about 500 mg to about 1600 mg, such as about 600 mg to about 1600 mg, such as about 700 mg to about 1600 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 about 1225 mg (eg, 100 mg to 2000 mg, such as 200 mg to 1900 mg, such as 300 mg to 1700 mg, such as 400 mg to 1600 mg, such as 500 mg to 1600 mg, such as 600 mg to 1600 mg, such as 700 mg to 1600 mg, such as 800 mg to 1600 mg, such as 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg), such as about 1190 mg to about 1210 mg (eg 1190 mg to 1210 mg), 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 4 weeks. 2000 mg, such as about 200 mg to about 2000 mg, such as about 300 mg to about 2000 mg, such as about 400 mg to about 2000 mg, such as about 500 mg to about 2000 mg, such as about 600 mg to about 1900 mg, such as about 700 mg to about 1800 mg, such as about 800 mg to about 1800 mg, such as about 900 mg to about 1800 mg, such as about 1000 mg to about 1800 mg, such as about 1100 mg to about 1800 mg, such as about 1200 mg to about 1800 mg, such as about 1300 mg to about 1800 mg, such as about 1400 mg, about 1800 mg, such as about 1500 mg to about 1800 mg, such as about 1580 mg to about 1780 mg, such as about 1630 mg to about 1730 mg, such as about 1655 mg to about 1705 mg, about 1670 mg to about 1690 mg (eg, 100 mg to 2000 mg, such as 200 mg to 2000 mg, such as 300 mg) to 2000 mg, such as 400 mg to 2000 mg, such as 500 mg to 2000 mg, such as 600 mg to 1900 mg, such as 700 mg to 1800 mg, such as 800 mg to 1800 mg, such as 900 mg to 1800 mg, such as 1000 mg to 1800 mg, such as 1100 mg to 1800 mg, such as 1200 mg to 1800 mg, such as 1300 mg to 1800 mg, such as 1400 mg to 1800 mg, such as 1500 mg to 1800 mg, 1580 mg to 1780 mg, such as 1630 mg to 1730 mg, such as 1655 mg to 1705 mg, such as 1670 mg to 1690 mg), such as 1680 mg ± 5 mg, such as 1680 mg ± 2.5 mg, such as 1680 ± 1.0 mg , eg 1680 ± 0.5 mg, eg 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some embodiments, a PD-1 axis binding antagonist (eg, anti-PD-L1) to be administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of an antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is monotherapy may be reduced compared to the standard dose of anti-PD-L1 antagonist antibody to be administered as a

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) is from about 20 mg to about 1000 mg (eg, from about 40 mg to about) every 3 weeks. 900 mg, such as about 60 mg to about 800 mg, such as about 80 mg to about 700 mg, such as about 80 mg to about 600 mg, such as about 100 mg to about 500 mg, such as about 120 mg to about 400 mg, such as about 140 mg to about 300 mg, such as about 160 mg to about 350 mg, such as about 180 mg to about 300 mg, such as about 180 mg to about 250 mg, such as about 180 mg to about 220 mg, such as about 190 mg to about 210 mg (eg, 40 mg to 900 mg, such as 60 mg to 800 mg, such as 80 mg to 700 mg, such as 80 mg to 600 mg, such as 100 mg to 500 mg, such as 120 mg to 400 mg, such as 140 mg to 300 mg, such as 16 mg to 350 mg, such as 180 mg to 300 mg, such as 180 mg to 250 mg, such as 180 mg to 220 mg , such as 190 mg to 210 mg), such as 200 mg ± 0.5 mg, such as 200 ± 2.5 mg, such as 200 ± 1.0 mg, such as 200 ± 0.5 mg, such as 200 mg) (eg, a fixed dose) to be. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, pamprolizumab)) is a dose of about 200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pamprolizumab)) is a dose of 200 mg every 3 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of the antibody (eg, pembrolizumab)) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is from about 20 mg to about 1000 mg (eg, from about 40 mg to about 900) every two weeks. mg, such as about 60 mg to about 800 mg, such as about 80 mg to about 700 mg, such as about 80 mg to about 600 mg, such as about 100 mg to about 500 mg, such as about 120 mg to about 400 mg, such as about 140 mg to about 300 mg, such as about 160 mg to about 350 mg, such as about 180 mg to about 300 mg, such as about 200 mg to about 280 mg, such as about 220 mg to about 260 mg, such as about 230 mg to about 250 mg (eg, 40 mg to 900 mg, such as 60 mg to 800 mg, such as 80 mg to 700 mg, such as 80 mg to 600 mg, such as 100 mg to 500 mg mg, such as 120 mg to 400 mg, such as 140 mg to 300 mg, such as 16 to 350 mg, such as 180 mg to 300 mg, such as 200 mg to 280 mg, such as 220 mg to 260 mg, such as , 230 mg to 250 mg), such as 240 mg ± 5 mg, such as 240 ± 2.5 mg, such as 240 ± 1.0 mg, such as 240 ± 0.5 mg, such as 240 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of about 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 240 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is about 100 mg to about 1000 mg (eg, 100 mg to 1000 mg) every 4 weeks. (e.g., about 200 mg to about 900 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 400 mg to about 600 mg, such as about 400 mg to about 550 mg , such as about 420 mg to about 540 mg, such as about 440 mg to about 520 mg, such as about 460 mg to about 500 mg, such as about 470 mg to about 490 mg (eg, 200 mg to 900 mg, such as , 300 mg to 800 mg, such as 400 mg to 700 mg, such as 400 mg to 600 mg, such as 400 mg to 550 mg, such as 420 mg to 540 mg, such as 440 mg to 520 mg, such as 460 mg to 500 mg, such as 470 mg to 490 mg), such as 480 mg ± 5 mg, such as 480 ± 2.5 mg, such as 480 ± 1.0 mg, such as 480 ± 0.5 mg, such as 480 mg). to be. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 480 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) is a dose of 480 mg every 4 weeks. In some cases, a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, such as an anti TIGIT antagonist antibody disclosed herein, such as tiragolumab). The dose of the antibody (eg, nivolumab)) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 50 mg/kg of the subject's body weight every 3 weeks. kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, For example, about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg ) is the capacity of In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 15 mg/kg of the subject's body weight every 3 weeks. (e.g., about 0.1 mg/kg to about 15 mg/kg, such as about 0.5 mg/kg to about 15 mg/kg, such as about 1 mg/kg to about 15 mg/kg, such as about 2.5 mg/kg to about 15 mg/kg, such as about 5 mg/kg to about 15 mg/kg, such as about 7.5 mg/kg to about 15 mg/kg, such as about 10 mg/kg to about 15 mg/kg, such as , about 12.5 mg/kg to about 15 mg/kg, such as about 14 mg/kg to about 15 mg/kg, such as about 15 ± 1 mg/kg, such as about 15 ± 0.5 mg/kg, such as about 15 ± 0.2 mg/kg, such as about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the effective amount of the anti-PD-L1 antagonist antibody (eg, atezolizumab) is a dose of about 15 mg/kg to be administered every 3 weeks. In some cases, a PD-1 axis binding antagonist (eg, anti-PD-) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). A single dose of an L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is may be reduced compared to standard doses of anti-PD-L1 antagonist antibody administered as therapy.

In any use of the present invention, said anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, , atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) is administered in one or more doses. Period (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles.) In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding An antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly called lambrolizumab) known)), continue until clinical benefit is lost (e.g., disease progression, drug resistance, death, or unacceptable toxicity is identified) In some cases, each dosing cycle of about 14 to 28 days (eg, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days) , 27 days, or 28 days).In some cases, the length of each dosing cycle is about 21 days. In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as , tiragolumab) about 1 day (eg, 1 day ± 3) should be administered. For example, a medicament comprising the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tyragolumab as disclosed herein) may be administered at a dose of about 600 mg (eg, fixed) on Day 1 of each 21-day cycle. dose) (ie, at a dose of about 600 mg every 3 weeks). Similarly, in some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK) - a medicament comprising 3475 (pembrolizumab, formerly known as lambrolizumab) should be administered on about day 1 (eg, day 1±3) of each dosing cycle. For example, the PD- A medicament comprising a uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a fixed dose of about 1200 mg on Day 1 of each 21-day cycle (ie, about every 3 weeks). In a dose of 1200 mg), for example, the agent comprising the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered in each 21-day cycle. It should be administered intravenously at a dose of about 200 mg (i.e., at a dose of about 200 mg every 3 weeks) on Day 1. For example, the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody ( For example, nivolumab)) should be administered intravenously at a dose of about 240 mg (ie, at a dose of about 240 mg every two weeks) on Day 1 of each 14-day cycle. A medicament comprising a PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) is administered at a dose of about 480 mg on Day 1 of each 28-day cycle (ie, about 480 every 4 weeks). In some cases, the anti-TIGIT antagonist antibody (such as anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (such as An anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) All inclusive agents should be administered on about day 1 (eg, day 1 ± 3 days) of each dosing cycle. For example, a medicament comprising the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tyragolumab as disclosed herein) is administered at a dose of about 600 mg on Day 1 of each 21-day cycle (ie, 3 weeks). should be administered intravenously (at a dose of about 600 mg per day) and the medicament comprising the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at the first dose of each 21-day cycle. It should be administered intravenously at a dose of about 1200 mg per day (ie, at a dose of about 1200 mg every 3 weeks). For example, a medicament comprising the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) may be administered at a dose of about 600 mg on Day 1 of each 21-day cycle (i.e., Drugs comprising the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, pembrolizumab)) should be administered intravenously (at a dose of about 600 mg every 3 weeks) and should be administered in a cycle of each 21 days. It should be administered intravenously at a dose of about 200 mg on Day 1 (ie, at a dose of about 200 mg every 3 weeks). For example, a medicament comprising the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) may be administered at a dose of about 600 mg on Day 1 of each 21-day cycle (i.e., should be administered intravenously (in a dose of about 600 mg every 3 weeks), and the medicament comprising the PD-1 axis binding antagonist (eg, anti-PD-1 antagonist antibody (eg, nivolumab)) should be administered as a drug in each 14-day cycle. It should be administered intravenously at a dose of about 240 mg per day (ie, at a dose of about 240 mg every two weeks). For example, a medicament comprising the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) may be administered at a dose of about 600 mg on Day 1 of each 21-day cycle (i.e., should be administered intravenously (at a dose of about 600 mg every 3 weeks), and the medicament comprising the PD-1 axis binding antagonist (eg, an anti-PD-1 antagonist antibody (eg, nivolumab)) should be administered as a drug in each 28-day cycle. It should be administered intravenously at a dose of about 480 mg per day (ie, at a dose of about 480 mg every 4 weeks).

In some cases, the medicament comprising the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 60 ± 15 minutes (eg, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes , about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( pembrolizumab, formerly known as lambrolizumab) in about 60 ± 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes) , about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes. minutes) to the subject or population of subjects by intravenous infusion.

In some cases, the medicament comprising the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 30 ± 10 minutes (eg, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes , about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( pembrolizumab, formerly known as lambrolizumab) in about 30 ± 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes) , about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) by intravenous infusion to the subject or population of subjects.

In some cases, the medicament comprising the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, anti-PD-L1 antagonist antibody) the subject prior to a medicament comprising, e.g., atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) or to the subject population.In some cases, for example, after the administration of the medicament comprising the anti-TIGIT antagonist antibody and prior to the administration of the medicament comprising the anti-PD-L1 antagonist antibody, the method comprises an intermediate agent 1 observation period.In some cases, the method comprises a second observation period after administration of the anti-PD-L1 antagonist antibody.In some cases, the method comprises the anti-TIGIT antagonist antibody includes both the first observation period after administration of the drug and the second observation period after administration of the drug comprising the anti-PD-L1 antagonist antibody, in some cases, the first and second observation period are each from about 30 minutes to about 60 minutes in length.In cases where the first and second observation periods are each about 60 minutes in length, the method comprises a medicament comprising the anti-TIGIT antagonist antibody and the PD during the first and second observation periods. - recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) about 30 ± 10 minutes after administration of the medicament comprising the L1 antagonist antibody. When the 2 observation periods are each about 30 minutes in length, the method comprises administering the medicament comprising the anti-TIGIT antagonist antibody and the medicament comprising the PD-L1 antagonist antibody during the first and second observation periods about 15 after administration. recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) at ±10 minutes.

In other cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab, formerly known as lambrolizumab)) is administered to the subject or population of subjects prior to the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab). In some cases, for example, after administration of the medicament comprising the anti-PD-L1 antagonist antibody and prior to the administration of the medicament comprising the anti-TIGIT antagonist antibody, the method comprises an intervening first observation period. In some cases, the method comprises a second observation period after administration of the medicament comprising the anti-TIGIT antagonist antibody.In some cases, the method comprises the medicament comprising the anti-PD-L1 antagonist antibody. includes both the first observation period after administration of and the second observation period after administration of the medicament comprising the anti-TIGIT antagonist antibody In some cases, the first and second observation periods are each from about 30 minutes to about 60 minutes In cases where said first and second observation periods are each about 60 minutes in length, the method comprises a medicament comprising said anti-PD-L1 antagonist antibody during said first and second observation periods, respectively, and recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) about 30 ± 10 minutes after administration of the medicament comprising the anti-TIGIT antagonist antibody. When the second observation period is each about 30 minutes in length, the method comprises administering the medicament comprising the anti-PD-L1 antagonist antibody and the medicament comprising the anti-TIGIT antagonist antibody, respectively, during the first and second observation periods, respectively. then recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) at about 15±10 minutes.

In other instances, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli medicaments comprising zumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) to the subject or population of subjects simultaneously In some cases, for example, after administration of the medicament comprising the anti-TIGIT antagonist antibody and the medicament comprising the anti-PD-L1 antagonist antibody, the method comprises an observation period. In , the observation period is from about 30 minutes to about 60 minutes in length.In cases where the observation period is about 60 minutes in length, the method comprises a medicament comprising the anti-PD-L1 antagonist antibody, respectively, during the observation period. and recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) about 30±10 minutes after administration of the medicament comprising the anti-TIGIT antagonist antibody. each of about 30 minutes in length, the method comprises administering to the subject about 15±10 minutes after administration of the medicament comprising the anti-PD-L1 antagonist antibody and the medicament comprising the anti-TIGIT antagonist antibody, respectively, during the observation period, respectively. recording vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) of

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab) and an anti-PD-L1 antagonist antibody (eg, , atezolizumab), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is from about 30 mg to about 1200 mg every 3 weeks. a (eg, 30 mg to 1200 mg) dose (eg, a fixed dose) of an anti TIGIT antagonist antibody, and a dose (eg, a fixed dose) of about 80 mg to about 2000 mg (eg, 80 mg to 2000 mg) every 3 weeks A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))).

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab) and an anti-PD-L1 antagonist antibody (eg, , atezolizumab), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is from about 30 mg to about 1200 mg every 3 weeks. a (eg, 30 mg to 1200 mg) dose (eg, a fixed dose) of an anti TIGIT antagonist antibody, and a dose (eg, a fixed dose) of about 80 mg to about 2000 mg (eg, 80 mg to 2000 mg) every two weeks A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))).

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab) and an anti-PD-L1 antagonist antibody (eg, , atezolizumab), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is from about 30 mg to about 1200 mg every 3 weeks. A dose (eg, a fixed dose) of an anti TIGIT antagonist antibody, and a dose (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, a fixed dose) of about 80 mg to about 2000 mg (eg, 80 mg to 2000 mg) every 4 weeks of an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) formulated for administration.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject or population of subjects having cervical cancer) (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)), wherein said method comprises one or more of said medicament and an anti-TIGIT antagonist antibody. administering to the subject or population of subjects a dosing cycle, wherein the medicament is administered at a dose (eg, a fixed dose) of from about 80 mg to about 2000 mg (eg, 80 mg to 2000 mg) of the PD-1 axis every 3 weeks. A binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly called lambrolizumab) known)) and anti-TIGIT antagonist antibody to be administered at a dose (eg, a fixed dose) of about 30 mg to about 1200 mg (eg, 30 mg to 1200 mg) every 3 weeks.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject or population of subjects having cervical cancer) (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)), wherein said method comprises one or more of said medicament and an anti-TIGIT antagonist antibody. administering to the subject or population of subjects a dosing cycle, wherein the medicament is administered at a dose (eg, a fixed dose) of about 80 mg to about 2000 mg (eg, 80 mg to 2000 mg) of the PD-1 axis every 4 weeks. A binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly called lambrolizumab) known)) and anti-TIGIT antagonist antibody to be administered at a dose (eg, a fixed dose) of about 30 mg to about 1200 mg (eg, 30 mg to 1200 mg) every 3 weeks.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody in the manufacture of a medicament for use in a method of treating a subject or population of subjects having cervical cancer) (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)), wherein said method comprises one or more of said medicament and an anti-TIGIT antagonist antibody. administering to the subject or population of subjects a dosing cycle, wherein the medicament is administered at a dose (eg, a fixed dose) of about 80 mg to about 2000 mg (eg, 80 mg to 2000 mg) of the PD-1 axis every two weeks. A binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly called lambrolizumab) known)) and anti-TIGIT antagonist antibody to be administered at a dose (eg, a fixed dose) of about 30 mg to about 1200 mg (eg, 30 mg to 1200 mg) every 3 weeks.

In another aspect, the present invention relates to a cancer having a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) Provided is the use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject or population of subjects having cervical cancer), wherein said method comprises said medicament and a PD-1 axis binding antagonist (eg, anti-PD- one or more doses of an L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) administering to the subject or population of subjects a dosing cycle, wherein the medicament is administered at a dose (eg, a fixed dose) of an anti-TIGIT antagonist antibody from about 30 mg to about 1200 mg (eg, 30 mg to 1200 mg) every 3 weeks. and a dose (eg, a fixed dose) of about 80 mg to about 2000 mg (eg, 80 mg to 2000 mg) of the anti-PD-L1 antagonist antibody every 3 weeks.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject or population of subjects, wherein said method administers one or more dosing cycles of said medicament to said subject or population of subjects. administering, wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of the anti-TIGIT antagonist antibody every 3 weeks and a 1200 mg dose (eg, a fixed dose) of atezolizumab every 3 weeks and wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti TIGIT antagonist antibody and pembrolizumab for use in a method of treating a subject or population of subjects, wherein said method administers one or more dosing cycles of said medicament to said subject or population of subjects. administering, wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of the anti-TIGIT antagonist antibody every 3 weeks and a 200 mg dose (eg, a fixed dose) of pembrolizumab every 3 weeks and wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti TIGIT antagonist antibody and nivolumab for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects one or more dosing cycles of said medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks and a dose of 240 mg (eg, a fixed dose) of nivolumab every 2 weeks wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti TIGIT antagonist antibody and nivolumab for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects one or more dosing cycles of said medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks and a dose of 480 mg (eg, a fixed dose) of nivolumab every 4 weeks wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti TIGIT antagonist antibody for use in a method of treating a subject or population of subjects, wherein said method administers one or more dosing cycles of said medicament and atezolizumab to said subject or population of subjects. administering an anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks (eg, a fixed dose) and atezolizumab to be administered at a dose of 1200 mg every 3 weeks (eg, a fixed dose) , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) provides the use of an anti-TIGIT antagonist antibody for use in a method of treating a subject or population of subjects, wherein said method administers one or more dosing cycles of said medicament and pembrolizumab to said subject or population of subjects. administering an anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks (eg, a fixed dose) and pembrolizumab to be administered at a dose of 200 mg every 3 weeks (eg, a fixed dose) , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the present invention relates to a cancer having a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti-TIGIT antagonist antibody for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said agent and nivolumab. for administration of an anti-TIGIT antagonist antibody at a dose of 600 mg (eg, a fixed dose) every 3 weeks and nivolumab to be administered at a dose of 240 mg (eg, a fixed dose) every 2 weeks and wherein said anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In another aspect, the present invention relates to a cancer having a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti-TIGIT antagonist antibody for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said agent and nivolumab. for administration of an anti-TIGIT antagonist antibody at a dose of 600 mg (eg, a fixed dose) every 3 weeks and nivolumab to be administered at a dose of 480 mg (eg, a fixed dose) every 4 weeks and wherein said anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti TIGIT antagonist antibody for use in a method of treating a subject or population of subjects, wherein said method administers one or more dosing cycles of said medicament and atezolizumab to said subject or population of subjects. administering an anti-TIGIT antagonist antibody at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab to be administered at a dose of 840 mg (eg, a fixed dose) every 2 weeks , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of an anti TIGIT antagonist antibody for use in a method of treating a subject or population of subjects, wherein said method administers one or more dosing cycles of said medicament and atezolizumab to said subject or population of subjects. administering an anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks (eg, a fixed dose) and atezolizumab to be administered at a dose of 1680 mg every 4 weeks (eg, a fixed dose) , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein the method provides at least one dosing cycle of said medicament and an anti-TIGIT antagonist antibody to said subject or population of subjects. administering, wherein the medicament is atezolizumab at a dose of 1200 mg every 3 weeks (eg, a fixed dose) and an anti-TIGIT antagonist antibody to be administered at a dose of 600 mg every 3 weeks (eg, a fixed dose). , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein the method provides at least one dosing cycle of said medicament and an anti-TIGIT antagonist antibody to said subject or population of subjects. administration of an anti-TIGIT antagonist antibody to be administered at a dose of 840 mg (eg, a fixed dose) of atezolizumab every two weeks and a dose of 600 mg (eg, a fixed dose) every three weeks; , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer), wherein the method provides the use of pembrolizumab for use in a method of treating a subject or population of subjects, wherein the method administers one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody to the subject or population of subjects. administering, wherein the medicament is pembrolizumab at a dose of 200 mg every 3 weeks (eg, a fixed dose) and an anti-TIGIT antagonist antibody to be administered at a dose of 600 mg every 3 weeks (eg, a fixed dose). , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer), wherein the method provides the use of nivolumab for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and an anti-TIGIT antagonist antibody. wherein the medicament is nivolumab at a dose of 240 mg every two weeks (eg, a fixed dose) and an anti-TIGIT antagonist antibody to be administered at a dose of 600 mg every three weeks (eg, a fixed dose). and wherein said anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer), wherein the method provides the use of nivolumab for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and an anti-TIGIT antagonist antibody. wherein the medicament is nivolumab at a dose of 480 mg every 4 weeks (eg, a fixed dose) and an anti-TIGIT antagonist antibody to be administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks. and wherein said anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein the method provides at least one dosing cycle of said medicament and an anti-TIGIT antagonist antibody to said subject or population of subjects. administering, wherein the medicament is administered at a 1680 mg dose (eg, a fixed dose) of atezolizumab every 4 weeks and an anti-TIGIT antagonist antibody to be administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks (eg, a fixed dose) , wherein said anti TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects one or more dosing cycles of said medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 1200 mg (eg, a fixed dose) of atezolizumab every 3 weeks do.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects one or more dosing cycles of said medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 840 mg (eg, a fixed dose) of atezolizumab every 2 weeks do.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects one or more dosing cycles of said medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 840 mg (eg, a fixed dose) of atezolizumab every 2 weeks do.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects one or more dosing cycles of said medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of tiragolumab every 3 weeks and a 200 mg dose (eg, a fixed dose) of pembrolizumab every 3 weeks do.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of tiragolumab and nivolumab for use in a method of treating a subject or population of subjects, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 240 mg (eg, a fixed dose) of nivolumab every 2 weeks.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) cervical cancer) provides the use of tiragolumab and nivolumab for use in a method of treating a subject or population of subjects, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament. wherein the medicament is formulated for administration of a 600 mg dose (eg, a fixed dose) of tiragolumab every 3 weeks and a dose of 480 mg (eg, a fixed dose) of nivolumab every 4 weeks.

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and atezolizumab. for administration of tiragolumab at a dose of 600 mg every 3 weeks (eg, a fixed dose) and atezolizumab to be administered at a dose of 1200 mg every 3 weeks (eg, a fixed dose) is formulated

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and atezolizumab. for administration of tiragolumab at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab to be administered at a dose of 840 mg (eg, a fixed dose) every 2 weeks is formulated

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and atezolizumab. for administration of tiragolumab at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab to be administered at a dose of 840 mg (eg, a fixed dose) every 2 weeks is formulated

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and pembrolizumab. for administration of tiragolumab at a dose of 600 mg every 3 weeks (eg, a fixed dose) and pembrolizumab to be administered at a dose of 200 mg every 3 weeks (eg, a fixed dose) is formulated

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and pembrolizumab. wherein the medicament is formulated for administration of tiragolumab at a dose of 600 mg (eg, a fixed dose) every 3 weeks and nivolumab to be administered at a dose of 240 mg (eg, a fixed dose) every 2 weeks. get angry

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer) for use in a method of treating a subject or population of subjects, wherein said method administers to said subject or population of subjects at least one dosing cycle of said medicament and pembrolizumab. wherein the medicament is formulated for administration of tiragolumab at a dose of 600 mg every 3 weeks (eg, a fixed dose) and nivolumab to be administered at a dose of 480 mg (eg, a fixed dose) every 4 weeks. get angry

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer), wherein the method provides the use of atezolizumab for use in a method of treating a subject or population of subjects, wherein the method administers to the subject or population of subjects one or more dosing cycles of the medicament and tiragolumab for administration of atezolizumab at a dose of 1200 mg (eg, a fixed dose) every 3 weeks and tiragolumab to be administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks is formulated

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer), wherein the method provides the use of atezolizumab for use in a method of treating a subject or population of subjects, wherein the method administers to the subject or population of subjects one or more dosing cycles of the medicament and tiragolumab for administration of atezolizumab at a dose of 1200 mg (eg, a fixed dose) every 3 weeks and tiragolumab to be administered at a dose of 840 mg (eg, a fixed dose) every 2 weeks is formulated

In another aspect, the invention provides a cancer with a detectable expression level of PD-L1 (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive uterine cancer) and cervical cancer), wherein the method provides the use of atezolizumab for use in a method of treating a subject or population of subjects, wherein the method administers to the subject or population of subjects one or more dosing cycles of the medicament and tiragolumab for administration of atezolizumab at a dose of 1200 mg (eg, a fixed dose) every 3 weeks and tiragolumab to be administered at a dose of 1680 mg (eg, a fixed dose) every 4 weeks is formulated

In any of the methods, uses, or compositions for use described herein, said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, anti A PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)), or An agent thereof may be administered in combination with one or more additional anti-cancer therapeutic agent(s) (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiotherapy/radiotherapy, and/or an anti-hormonal agent, such as those recited herein above) ( separately or together).

In any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)); or medicament thereof is for treating said subject or subject population with cervical cancer.In some cases, said cervical cancer is stage 4B, metastatic, recurrent or persistent cervical cancer.In some cases, said cervical cancer is It is metastatic and/or recurrent PD-L1 positive cervical cancer.The cancer may be early or late stage.

In some cases, in a method, use, or compositions for use described herein, the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1. In some cases, detectable protein expression levels of PD-L1 were determined by immunohistochemical (IHC) assays. In some cases, the protein expression level of PD-L1 is detected using an anti-PD-L1 antibody suitable for staining. In some cases, the tumor sample is a formalin-fixed, paraffin-embedded (FFPE) tumor sample.

In some cases, in a method, use, or compositions for use described herein, the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1. In some cases, the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. became

In some cases, in any of the methods, uses, or compositions for use described herein, the cervical cancer is squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma. In some cases, the cervical cancer is stage 4B, metastatic, recurrent, or persistent. In some cases, the cervical cancer is metastatic and/or recurrent PD-L1 positive cervical cancer. In some cases, the subject or population of subjects has not received prior therapy. In some cases, the subject or population of subjects has not received at least one line of prior therapy. In some cases, the subject or population of subjects has not received at least two lines of prior therapy. In some cases, the subject or population of subjects has previously received at least one or two or fewer systemic therapy, and/or there is no acceptable standard of care. In some cases, the subject or population of subjects has not received more than two lines of prior therapy. In some cases, the prior therapy is chemotherapy, surgery, and/or radiation therapy. In some cases, the prior therapy is immunotherapy.

In some cases, in any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or Administration of an anti-PD-1 antagonist antibody (such as MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) elicits a clinical response. Clinical response is the increase in the objective response rate (ORR) of a subject or subject population compared to the reference ORR.In some cases, the reference ORR is at least about 14.6% to about 26%.In some cases, the reference ORR is PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (Pembb) without anti-TIGIT antagonist antibody) is the median ORR of a population of subjects receiving treatment with rolizumab (formerly known as lambrolizumab)) In some cases, the clinical response is an increase in PFS in a subject or population of subjects as compared to baseline PFS. In some cases, the baseline PFS time is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106) without an anti TIGIT antagonist antibody. (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) is the median PFS time in a population of subjects treated with. In some cases, the clinical response is compared with a baseline DOR time. to increase the duration of response (DOR) in a subject or population of subjects.In some cases, the reference DOR time is the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly is the median DOR time of a population of subjects receiving treatment including))), known as lambrolizumab. In some cases, the clinical response is an increase in OS.

Diagnostic methods and uses related to cervical cancer

The present invention provides a method for selecting a therapy for a subject or population of subjects having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer). Provided is a method, wherein the therapy is of one or more biomarkers (eg, PD-L1, TIGIT, activated T cells, or cytokines) in a sample (eg, a tumor sample or blood sample) obtained from the subject or population of subjects. Guided by a diagnostic method involving determining the presence and/or expression level/amount.

Disclosed herein are an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475) (pembrolizumab, formerly known as lambrolizumab)) cancers (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or or recurrent PD-L1 positive cervical cancer), wherein the identification is identified in a sample obtained from the subject or population of subjects (eg, a tumor sample or a blood sample) one or more biomarkers Guided by a diagnostic method involving determining the presence and/or expression level/amount of (eg, PD-L1, TIGIT, activated T cells, or cytokines).

Disclosed herein is responsiveness to therapy for a subject or population of subjects having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer). Further provided is a method of assessing, wherein further therapy is administered from one or more biomarkers (eg, PD-L1, TIGIT, activated T cells, or cytokines) are present and/or expression levels/amounts are determined.

Disclosed herein are methods of optimizing therapy for a subject or population of subjects having cancer (eg, cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer). further provided, wherein additionally, the therapy is one or more biomarkers (eg, PD-L1, TIGIT, activated T cells, or cytokines) in a sample (eg, a tumor sample or blood sample) obtained from the subject or population of subjects. is guided by a diagnostic method involving determining the presence and/or expression level/amount of

Biomarkers for use in the methods described herein include genes or gene signatures associated with tumor immunobiology (eg, TEFF), HPV alterations, lymphocyte subpopulations, T cell receptor repertoire, cytokines associated with T cell activation, and plasma-derived cytokines. Tissue (e.g., tumor tissue) or blood (e.g., whole blood), tissue (e.g., tumor tissue) and/or circulating tumor DNA (mutant load, PD-L1 expression on germline and somatic mutations including but not limited to MSI and MMR defects. In some cases, the biomarker is PD-L1. In some cases, the sample is a tumor sample (eg, a formalin fixed, paraffin embedded (FFPE) tumor sample).

In some cases, the method comprises the presence of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects and/or or determining the expression level/amount and administering to the subject or population of subjects a dose (eg, a fixed dose) of an anti TIGIT antagonist antibody (eg, a fixed dose) of about 30 mg to about 1200 mg (eg, 30 mg to 1200 mg) every 3 weeks. One or more dosing cycles of an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab, and every 3 weeks PD- at a dose (eg, a fixed dose) of about 80 mg to about 2000 mg (eg, 80 mg to about 2000 mg) administering one or more dosing cycles of a uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some cases, the method comprises the presence of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects and/or or determining the expression level/amount and administering to the subject or population of subjects a dose (eg, a fixed dose) of about 600 mg (eg, 600 mg) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein) every 3 weeks. one or more dosing cycles of, e.g., tiragolumab) and an 840 mg dose (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) every two weeks) administering one or more dosing cycles. In some cases, the method comprises the presence of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects and/or or determining the expression level/amount and administering to the subject or population of subjects a dose (eg, a fixed dose) of about 600 mg (eg, 600 mg) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein) every 3 weeks. 1 or more dosing cycles of, e.g., tiragolumab) and a 1200 mg dose (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) every 3 weeks) administering one or more dosing cycles. In some cases, the method comprises the presence of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects and/or or determining the expression level/amount and administering to the subject or population of subjects a dose (eg, a fixed dose) of about 600 mg (eg, 600 mg) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein) every 3 weeks. one or more dosing cycles of, e.g., tiragolumab) and a 1680 mg dose (e.g., a fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab) every 4 weeks) administering one or more dosing cycles.

The presence and/or expression level/amount of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) includes, but is not limited to, protein, protein fragment, DNA, mRNA, cDNA, and/or gene copy number. It may be determined qualitatively and/or quantitatively according to any suitable criteria known in the art without limitation.

In some cases, the expression level or amount of a biomarker is a detectable protein expression level of PD-L1 in a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects. In some cases, PD-L1 protein expression levels were determined by immunohistochemical (IHC) analysis. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects has been determined to have a detectable expression level of PD-L1. In some cases, a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects has been determined to have a detectable expression level of PD-L1 in tumor infiltrating immune cells. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, the expression level or amount of a biomarker is a detectable nucleic acid expression level of PD-L1 in a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects. In some cases, the nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MassARRAY ^® technology, in-tissue. (in situ) hybridization (ISH), or a combination thereof. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from a subject or population of subjects/ The amount is an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( selecting said subject or population of subjects as eligible for therapy with pembrolizumab, formerly known as lambrolizumab)), eg, wherein the detectable expression level of PD-L1 is marker.In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample.In some cases, the tissue sample is a tumor sample (eg, a FFPE tumor sample). In some cases, the tumor sample comprises tumor infiltrating immune cells, tumor cells, stromal cells, and any combination thereof In some cases, the tumor sample is a FFPE tumor sample.

In one aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and an anti-TIGIT antagonist administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on PD-L1 expression in the detected tumor sample. cancer (e.g., cervical cancer such as stage 4B, metastatic, recurrent) by identifying said subject and subject population as those who would benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as , or a method of selecting a therapy for a subject or population of subjects having a persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein the anti-TIGIT antagonist antibody is of SEQ ID NO: 17 or 18 It has a VH domain comprising an amino acid sequence and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1680 mg every 4 weeks. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 840 mg every 2 weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. tiragoluumab administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on the detecting, and PD-L1 expression of the detected tumor sample. cancer (e.g., cervical cancer such as stage 4B, metastatic, recurrent) by identifying said subject and subject population as those who would benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as , or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer). In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and an anti-TIGIT antagonist administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on PD-L1 expression in the detected tumor sample. cancer (e.g., cervical cancer such as stage 4B, metastatic, recurrent) by identifying said subject and subject population as those who would benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as , or a method of selecting a therapy for a subject or population of subjects having a persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein the anti-TIGIT antagonist antibody is of SEQ ID NO: 17 or 18 It has a VH domain comprising an amino acid sequence and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1680 mg every 4 weeks. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 840 mg every 2 weeks. In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. tiragoluumab administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on the detecting, and PD-L1 expression of the detected tumor sample. cancer (e.g., cervical cancer such as stage 4B, metastatic, recurrent) by identifying said subject and subject population as those who would benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as , or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer). In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks (eg, a fixed dose) and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on PD-L1 expression in the detected tumor sample. cancer (e.g., cervical cancer such as stage 4B, metastatic, recurrent) by identifying said subject and subject population as those who would benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as , or a method of selecting a therapy for a subject or population of subjects having a persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein the anti-TIGIT antagonist antibody is of SEQ ID NO: 17 or 18 It has a VH domain comprising an amino acid sequence and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1680 mg every 4 weeks. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 840 mg every 2 weeks. In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and at least one dosing cycle of tiragolumab administered at a 600 mg dose every 3 weeks and atezolizumab administered at a 1200 mg dose every 3 weeks based on PD-L1 expression in the detected tumor sample. cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD, -L1-positive cervical cancer) provides a method of selecting a therapy for a subject or population of subjects. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. one or more doses of the anti-TIGIT antagonist administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, artezolith (zumab) or an anti-PD-1 antagonist antibody (such as MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) that may benefit from therapy ( For example, provided is a method of identifying a subject or population of subjects having cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer, wherein the The TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 domain and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the regimen comprises one or more dosing cycles of anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1680 mg every 4 weeks. , the regimen is administered at a dose of 600 mg every 3 weeks. anti-TIGIT antagonist antibody administered and one or more dosing cycles of atezolizumab administered at a dose of 840 mg every two weeks. In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancers that may benefit from therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) (e.g., cervical cancer, such as stage 4B, metastatic, relapsed) Provided is a method for identifying a subject or population of subjects with sexual or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer.In some cases, the method comprises an identified subject or population of subjects In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (e.g., an immunomodulatory agent (e.g., one or more immune co-suppression receptors (e.g., TIGIT, PD-L1) , PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody. (eg, ipilimumab ( ^YERVOY® )) or one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR) or an activating agent such as an OX-40 agonist such as an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above (separately or in combination).

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancers that may benefit from therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) (e.g., cervical cancer, such as stage 4B, metastatic, relapsed) Provided is a method of identifying a subject or population of subjects having sexual or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein said anti-TIGIT antagonist antibody comprises the amino acid sequence of SEQ ID NO: 17 or 18 has a VH domain comprising and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19 In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is 600 every 3 weeks. one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of mg and atezolizumab administered at a dose of 1680 mg every 4 weeks In some cases, the therapy is at a dose of 600 mg every 3 weeks. Anti-TIGIT antagonist antibody administered and 2 weeks one or more dosing cycles of atezolizumab administered at a dose of 840 mg per day. In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancers that may benefit from therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) (e.g., cervical cancer, such as stage 4B, metastatic, relapsed) Provided is a method for identifying a subject or population of subjects with sexual or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer.In some cases, the method comprises an identified subject or population of subjects In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (e.g., an immunomodulatory agent (e.g., one or more immune co-suppression receptors (e.g., TIGIT, PD-L1) , PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody. (eg, ipilimumab ( ^YERVOY® )) or one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR) or an activating agent such as an OX-40 agonist such as an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above (separately or in combination).

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancers that may benefit from therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) (e.g., cervical cancer, such as stage 4B, metastatic, relapsed) Provided is a method of identifying a subject or population of subjects having sexual or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein said anti-TIGIT antagonist antibody comprises the amino acid sequence of SEQ ID NO: 17 or 18 has a VH domain comprising and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19 In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is 600 every 3 weeks. one or more dosing cycles of an anti-TIGIT antagonist antibody administered at a dose of mg and atezolizumab administered at a dose of 1680 mg every 4 weeks In some cases, the therapy is at a dose of 600 mg every 3 weeks. Anti-TIGIT antagonist antibody administered and 2 weeks one or more dosing cycles of atezolizumab administered at a dose of 840 mg per day. In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancers that may benefit from therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) (e.g., cervical cancer, such as stage 4B, metastatic, relapsed) Provided is a method for identifying a subject or population of subjects with sexual or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer.In some cases, the method comprises an identified subject or population of subjects In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (e.g., an immunomodulatory agent (e.g., one or more immune co-suppression receptors (e.g., TIGIT, PD-L1) , PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody. (eg, ipilimumab ( ^YERVOY® )) or one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR) or an activating agent such as an OX-40 agonist such as an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above (separately or in combination).

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent) for therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) A method is provided for assessing the reactivity of a subject or population of subjects having cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein said anti-TIGIT antagonist antibody comprises the amino acid sequence of SEQ ID NO: 17 or 18 has a VH domain and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19 In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is administered at 600 mg every 3 weeks. one or more dosing cycles of anti-TIGIT antagonist antibody administered as a dose and atezolizumab administered at a dose of 1680 mg every 4 weeks In some cases, the therapy is administered at a dose of 600 mg every 3 weeks. Anti-TIGIT antagonist antibody and 840 every 2 weeks one or more dosing cycles of atezolizumab administered in a mg dose. In some aspects, the present invention provides a method for obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent) for therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) Provided is a method for assessing the reactivity of a subject or a population of subjects with cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer.In some cases, the method provides an identified subject or population of Further comprising the step of administering therapy.In some cases, the therapy is one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agent (e.g., one or more immune co-suppression receptors (e.g., TIGIT, PD-L1, PD) -1, an agent that reduces or inhibits one or more immune co-suppression receptors selected from -1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA, such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (such as , ipilimumab ( ^YERVOY® )) or one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR). agents, such as OX-40 agonists, such as OX-40 agonist antibodies), Therapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents such as the agents mentioned herein above) (separately or together) may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent) for therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) A method is provided for assessing the reactivity of a subject or population of subjects having cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein said anti-TIGIT antagonist antibody comprises the amino acid sequence of SEQ ID NO: 17 or 18 has a VH domain and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19 In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is administered at 600 mg every 3 weeks. one or more dosing cycles of anti-TIGIT antagonist antibody administered as a dose and atezolizumab administered at a dose of 1680 mg every 4 weeks In some cases, the therapy is administered at a dose of 600 mg every 3 weeks. Anti-TIGIT antagonist antibody and 840 every 2 weeks one or more dosing cycles of atezolizumab administered in a mg dose. In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent) for therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) Provided is a method for assessing the reactivity of a subject or a population of subjects with cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer.In some cases, the method provides an identified subject or population of Further comprising the step of administering therapy.In some cases, the therapy is one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agent (e.g., one or more immune co-suppression receptors (e.g., TIGIT, PD-L1, PD) -1, an agent that reduces or inhibits one or more immune co-suppression receptors selected from -1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA, such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (such as , ipilimumab (YERVOY ^® )) or one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR). agents, such as OX-40 agonists, such as OX-40 agonist antibodies), Therapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents such as the agents mentioned herein above) (separately or together) may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent) for therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) A method is provided for assessing the reactivity of a subject or population of subjects having cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer, wherein said anti-TIGIT antagonist antibody comprises the amino acid sequence of SEQ ID NO: 17 or 18 has a VH domain and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19 In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is administered at 600 mg every 3 weeks. one or more dosing cycles of anti-TIGIT antagonist antibody administered as a dose and atezolizumab administered at a dose of 1680 mg every 4 weeks In some cases, the therapy is administered at a dose of 600 mg every 3 weeks. Anti-TIGIT antagonist antibody and 840 every 2 weeks one or more dosing cycles of atezolizumab administered in a mg dose. In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. by identifying the subject and subject population as an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, Cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent) for therapy comprising MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) Provided is a method for assessing the reactivity of a subject or a population of subjects with cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer.In some cases, the method provides an identified subject or population of Further comprising the step of administering therapy.In some cases, the therapy is one or more additional anti-cancer therapeutic agent(s) (e.g., immunomodulatory agent (e.g., one or more immune co-suppression receptors (e.g., TIGIT, PD-L1, PD) -1, an agent that reduces or inhibits one or more immune co-suppression receptors selected from -1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA, such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (such as , ipilimumab (YERVOY ^® )) or one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR). agents, such as OX-40 agonists, such as OX-40 agonist antibodies), Therapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents such as the agents mentioned herein above) (separately or together) may be administered.

In some cases, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining, the protein expression level of PD-L1 in the tumor sample. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. a subject having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) by identifying said subject and subject population as or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) in a population of subjects or MK-3475 (pembrolizumab, formerly known as lambrolizumab), wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and has a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is administered at a dose of 600 mg every 3 weeks. one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab administered at a dose of 1680 mg every 4 weeks, in some cases, the therapy is an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks. Antibody and 840 mg every 2 weeks one or more dosing cycles of atezolizumab administered as a dose. In some cases, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining, the protein expression level of PD-L1 in the tumor sample. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. a subject having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) by identifying said subject and subject population as or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) in a population of subjects or MK-3475 (pembrolizumab, formerly known as lambrolizumab). In some cases, the method comprises administering the therapy to an identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppression receptors (eg, TIGIT, PD-L1, PD-1, Agents that decrease or inhibit one or more immune co-suppression receptors selected from CTLA-4, LAG3, TIM3, BTLA, and/or VISTA, such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimu) ^YERVOY® ) or an agent that increases or activates one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR); e.g., an OX-40 agonist such as an OX-40 agonist antibody), a chemotherapeutic agent, Cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents such as the agents mentioned herein above) (separately or in combination).

In some cases, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining, the protein expression level of PD-L1 in the tumor sample. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. a subject having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) by identifying said subject and subject population as or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) in a population of subjects or MK-3475 (pembrolizumab, formerly known as lambrolizumab), wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and has a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is administered at a dose of 600 mg every 3 weeks. one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab administered at a dose of 1680 mg every 4 weeks, in some cases, the therapy is an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks. 840 mg of antibody and every 2 weeks one or more dosing cycles of atezolizumab administered as a dose. In some cases, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining, the protein expression level of PD-L1 in the tumor sample. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. a subject having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) by identifying said subject and subject population as or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) in a population of subjects or MK-3475 (pembrolizumab, formerly known as lambrolizumab). In some cases, the method comprises administering the therapy to an identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppression receptors (eg, TIGIT, PD-L1, PD-1, Agents that decrease or inhibit one or more immune co-suppression receptors selected from CTLA-4, LAG3, TIM3, BTLA, and/or VISTA, such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimu). ^YERVOY® ) or an agent that increases or activates one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR); e.g., OX-40 agonists such as OX-40 agonist antibodies), chemotherapeutic agents, Cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents such as the agents mentioned herein above) (separately or in combination).

In some cases, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining, the protein expression level of PD-L1 in the tumor sample. and one or more dosing cycles of an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. a subject having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) by identifying said subject and subject population as or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) in a population of subjects or MK-3475 (pembrolizumab, formerly known as lambrolizumab), wherein said anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and has a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the therapy is administered at a dose of 600 mg every 3 weeks. one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab administered at a dose of 1680 mg every 4 weeks, in some cases, the therapy is an anti-TIGIT antagonist administered at a dose of 600 mg every 3 weeks. 840 mg of antibody and every 2 weeks one or more dosing cycles of atezolizumab administered as a dose. In some cases, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining, the protein expression level of PD-L1 in the tumor sample. and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. a subject having cancer (e.g., cervical cancer, such as stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer) by identifying said subject and subject population as or an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) in a population of subjects or MK-3475 (pembrolizumab, formerly known as lambrolizumab). In some cases, the method comprises administering the therapy to an identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppression receptors (eg, TIGIT, PD-L1, PD-1, Agents that decrease or inhibit one or more immune co-suppression receptors selected from CTLA-4, LAG3, TIM3, BTLA, and/or VISTA, such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimu) ^YERVOY® ) or an agent that increases or activates one or more immune co-stimulatory receptors (eg, one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR); e.g., OX-40 agonists such as OX-40 agonist antibodies), chemotherapeutic agents, Cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents such as the agents mentioned herein above) (separately or in combination).

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; (e.g., OX-40 agonist antibody), chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents, such as the agents mentioned herein above (separately or in combination) may be administered.

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; (e.g., OX-40 agonist antibody), chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents, such as the agents mentioned herein above (separately or in combination) may be administered.

In some cases, in any of the diagnostic methods or uses described herein, the cervical cancer is stage 4B, metastatic, recurrent, or persistent cervical cancer. The cancer may be early or late.

A. Treatment methods and uses associated with breast cancer

breast cancer

Breast cancer is the most frequently diagnosed cancer in women, with an estimated 2.08 million new cases reported worldwide in 2018. Breast cancer accounts for about 15% of all cancer deaths (about 626,700 cases), and is the most common cause of cancer-related deaths in women, with a 5-year survival rate of about 15% after metastasis diagnosis. Although most patients are diagnosed with focal breast cancer, about 6% of patients with new metastatic disease and 10% to 40% of patients with focal breast cancer have systemic recurrence. In the early stages of breast cancer (1-3, early breast cancer), most are asymptomatic, usually surgical and curative.

Breast cancer is a heterogeneous disease involving about 15 different types of carcinoma further classified according to the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) for therapeutic reasons. This subgroup has important implications for treatment choice, treatment outcome, recurrence rate, and risk of death. Triple negative breast cancer (TNBC) is characterized by lack of expression of ER, PR and HER2. Overall, about 15% to 20% of all breast cancers are classified as TNBC. Although large-scale comprehensive genomic analyzes have characterized the heterogeneous nature of TNBC and its diverse gene expression patterns and underlying genomic changes, these insights still provide clear guidance for the identification of clinically effective targeted therapies that are currently under laboratory stage and clinical investigation. can't do it

TNBCs are more likely to have aggressive features such as high proliferation rates. Patients with metastatic TNBC generally show particularly poor clinical outcomes with rapid progression and a median OS rate of about 16 months. Despite recent treatment improvements, the prognosis for TNBC patients is far from optimal, and in fact, the 5-year survival rate after metastatic diagnosis is about 15%.

Therefore, there is a high unmet need for improved medical interventions in TNBC, including early TNBC (eTNBC).

Methods and uses for the treatment of breast cancer

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) , and a subject or population of subjects who have received a taxane (eg, a taxane (eg, nap-paclitaxel or paclitaxel)) are being treated for breast cancer (eg, HER2+ breast cancer and TNBC). In some cases, the anti-TIGIT antagonist antibody is tyragolumab. In some cases, the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. In some cases, the anti-PD-L1 antagonist antibody is atezolizumab. In some cases, the chemotherapy is a taxane. In some cases, the taxane is nap-paclitaxel or paclitaxel. In some cases, the taxane is nap-paclitaxel. In some cases, the breast cancer is TNBC. In some cases, the TNBC is a PD-L1 positive TNBC. In some cases, the TNBC is unresectable locally advanced or metastatic. In some cases, the PD-L1 positive TNBC is unresectable locally advanced or metastatic. In some embodiments, the subject or population of subjects has not received prior systemic therapy for breast cancer. In some embodiments, the subject or population of subjects has not received prior systemic therapy for metastatic breast cancer.

Methods and uses for the treatment of eTNBC

Disclosed herein are methods and uses for treating early TNBC (eTNBC) in a subject or population of subjects, comprising an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and an effective amount of PD-1 An axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly lambrolizumab) Methods and uses are provided comprising treating said subject or subject population by administering to said subject or subject population a dosing regimen comprising one or more dosing cycles

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab). methods and uses involving administration to a subject or population of subjects in need thereof. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) is one or more chemotherapeutic agents (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and/or non-platinum-based chemotherapeutic agents (eg, alkylating agents (eg, cyclophosphamide), taxanes (eg, paclitaxel)) ), eg, nap-paclitaxel) and/or a topoisomerase II inhibitor (eg, doxorubicin))). In some cases, the method further comprises one or more surgeries (eg, mastectomy and/or axillary lymph node surgery). In some cases, the surgery is performed after administering a dosing regimen comprising the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the one or more chemotherapeutic agents, and/or G-CSF or GM-CSF. . In some cases, the surgery is a mastectomy and/or axillary lymph node surgery. In some cases, the surgery is performed between 2 and 6 weeks (eg, 2 weeks, 3 weeks, 4 weeks, 5 weeks, and 6 weeks) after the last dose of the dosing regimen.

In some cases, any method and use for treating eTNBC in a subject or population of subjects may result in pCR. In some cases, any method and use for treating eTNBC in a subject or population of subjects may result in an increase in OS or event-free survival (EFS).

Dosage regimen and administration

In one aspect, the treatment methods and uses of the invention described herein comprise an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX) -1106 (nivolumab) or MK-3475) (pembrolizumab (formerly known as lambrolizumab)) and an anti-TIGIT antagonist antibody (eg, tyragolumab) in a subject or population of subjects with eTNBC In some cases, the treatment methods and uses of the invention described herein comprise an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti A PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) are combined with one or more chemical agents. Therapeutic agents (eg, platinum-based chemotherapeutic agents (eg, carboplatin or cisplatin) and/or non-platinum-based chemotherapeutic agents (eg, alkylating agents (eg, cyclophosphamide), taxanes (eg, paclitaxel, such as nap-paclitaxel)) ) and/or a topoisomerase II inhibitor (eg, doxorubicin)) and/or to a subject or population of subjects having eTNBC with or without G-CSF or GM-CSF. In , the topoisomerase II inhibitor is doxorubicin In some embodiments, doxorubicin is administered at a dose of about 60 mg/m ² .

The pharmaceutical compositions described herein may be formulated for administration as described in Section III(K).

dosing of chemotherapeutic agents

Therapeutically effective amounts of various chemotherapeutic agents are known in the art and are contemplated by the present invention. In certain instances, one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an alkylating agent (eg, cyclophosphamide)); The taxane (eg, paclitaxel, eg, nap-paclitaxel) and/or topoisomerase II inhibitor (eg, doxorubicin)) is administered according to the doses mentioned in Section III(K) herein.

Cancer characterization and selection

In any of the methods, uses, or compositions for use described herein, the cancer can be breast cancer. In some cases, the breast cancer is TNBC. In some cases, the TNBC is an eTNBC. In some cases, the eTNBC is presented as a T2-4d TNBC. In some cases, the eTNBC is presented as cT2-cT4, cN0-cN3, and cM0 TNBC. In some cases, the eTNBC is PD-L1 positive. In some cases, the eTNBC is PD-L1 negative. In some cases, the subject or population of subjects has not been previously treated for eTNBC. In some cases, the subject or population of subjects has not received prior systemic treatment for breast cancer (eg, TNBC, eg, eTNBC).

In some cases, in any of the methods, uses, or compositions for use described herein, the subject or population of subjects has a PD-L1-selected tumor (eg, occupied by PD-L1-expressing tumor infiltrating immune cells (IC)). proportion of tumor area is greater than or equal to 1% in said tumor sample as determined by IHC with SP142 antibody). In some cases, the PD-L1 selected tumor is a tumor in which the proportion of tumor area occupied by PD-L1 expressing IC is determined by immunohistochemical (IHC) analysis to be greater than or equal to 1%. In some cases, the IHC assay uses anti-PD-L1 antibodies SP142, SP263, 22C3, or 28-8. In some cases, the IHC assay uses anti-PD-L1 antibody SP142. In some cases, the IC was determined to be greater than or equal to 1% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, PD-L1 expression levels are detected using anti-PD-L1 antibody 22C3. In some cases, the detectable expression level of PD-L1 has a composite positive score (CPS) of 1 or greater in a sample from the subject.

In some cases, in a method, use, or compositions for use described herein, a tumor sample obtained from an individual has a detectable nucleic acid expression level of PD-L1. In some cases, the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. became In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some cases, the tissue sample is a tumor sample. In some cases, the tumor sample comprises tumor infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

In some cases, a tumor sample from the subject or population of subjects has been determined to be PD-L1 positive. In some cases, the tumor sample from the subject or population of subjects has been determined to be PD-L1 negative. In some cases, the majority of samples from the subject or population of subjects have been determined to be PD-L1 negative. In some cases, all samples from the subject or population of subjects were determined to be PD-L1 negative.

response to treatment

In some embodiments of any of the methods described herein, the response of a subject or population of subjects to a therapy can be characterized by one or more measures. In some embodiments, the treatment results in CR or PR.

In some cases, the treatment is compared to treatment with a PD-1 axis binding antagonist, eg, in the absence of an anti TIGIT antagonist antibody, or compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist, such as in the subject or population of subjects. increased event-free survival. For example, in embodiments where no chemotherapeutic agent is administered (eg, only an anti TIGIT antagonist antibody (eg, tyragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), the Treatment may include, for example, an increase in event-free survival of a subject or population of subjects as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. generate one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an alkylating agent (eg, cyclophosphamide), a taxane (eg, paclitaxel)) (eg, nap-paclitaxel), and/or topoisomerase II inhibitors (eg, doxorubicin) and/or anti-TIGIT antagonist antibodies (eg, tyragolumab) and PD- in combination with G-CSF or GM-CSF In embodiments in which a uniaxial binding antagonist (eg, atezolizumab) is administered, the treatment comprises (i) a PD-1 axis binding antagonist and one or more chemotherapeutic agents and/or G-CSF or GM in the absence of an anti-TIGIT antagonist antibody. - compared to treatment with CSF; (ii) compared to treatment with an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents and/or G-CSF or GM-CSF in the absence of a PD-1 axis binding antagonist; and/or (iii) results in an increase in event-free survival in a subject or population of subjects as compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

In some cases, the treatment of the subject or population of subjects, eg, compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. Extend the OS. For example, in embodiments where no chemotherapeutic agent is administered (eg, only an anti-TIGIT antagonist antibody (eg, tyragolumab) in combination with a PD-1 axis binding antagonist (eg, atezolizumab) is administered), the Treatment results in an increase in OS of a subject or population of subjects, e.g., as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist . one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an alkylating agent (eg, cyclophosphamide), a taxane (eg, paclitaxel)) (eg, nap-paclitaxel), and/or topoisomerase II inhibitors (eg, doxorubicin) and/or anti-TIGIT antagonist antibodies (eg, tyragolumab) in combination with G-CSF or GM-CSF and PD- In embodiments in which a uniaxial binding antagonist (eg, atezolizumab) is administered, the treatment comprises (i) a PD-1 axis binding antagonist and one or more chemotherapeutic agents and/or G-CSF or GM in the absence of an anti-TIGIT antagonist antibody. - compared to treatment with CSF; (ii) compared to treatment with an anti-TIGIT antagonist antibody and one or more chemotherapeutic agents and/or G-CSF or GM-CSF in the absence of a PD-1 axis binding antagonist; and/or (iii) results in an increase in OS in a subject or population of subjects as compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

The obligatory event-free survival of the subject or population of subjects is described in Eisenhauer et al., Eur. J. Cancer . 2009, 45:228-47 according to RECIST v1.1 criteria as described. In some embodiments, EFS is measured as the period from initiation of treatment to the first occurrence of disease progression as determined by RECIST v1.1 criteria. In some embodiments, EFS is measured as the time from initiation of treatment to death. .

In some embodiments, the treatment described herein reduces the EFS of the subject or population of subjects by at least about 2.4 months (eg, by 2.4 to 120 months, by 2.5 to 100 months, by 3.0 to 80 months, by 4.0 to 60 months). , by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months , 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the EFS of the subject or population of subjects by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 by -48 months, by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months , 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the EFS of the subject or population of subjects by at least about 2 months (eg, by 2 to 120 months, by 3 to 100 months, by 4 to 80 months, by 6 to 60 months, 8 by -48 months, by 9-36 months, by 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months , 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, OS is measured as the period from initiation of treatment to death. In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 2 months (eg, by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6- by 60 months, by 7-48 months, by 8-36 months, by 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months , 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 3.3 months (eg, by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7- by 48 months, by 8-36 months, or by 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 5.1 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months , 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 5.3 months (eg, by 5.3 to 120 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 by -24 months, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months , 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment lasts for at least about 20 months (eg, from about 20 months to about 36 months (eg, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months) of the subject population.In some embodiments, the treatment is about 25.0 months yields the median OS of the subject population of

In some embodiments, the treatment is at least about 53% (eg, about 53% to about 100% (eg, about 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%) , 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) ) of the subject population. In some embodiments, the treatment is at least about 53% (eg, about 65% to about 100% (eg, 65%, 65.5%, 66%, 66.5%, 67%, 67.5%, 68%, 68.5%, 69%, 69.5%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 85%, 90%, 95%, or 100 %)) of the subject population. In some embodiments, the treatment is at least about 53% to at least about 67.5% (e.g., at least about 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, or 67.5%) of the subject population.

A. Treatment methods and diagnosis and use associated with head and neck cancer

head and neck cancer

Head and neck cancer is a leading cause of serious morbidity and mortality, accounting for 890,000 new cases and 450,000 deaths worldwide in 2018. Head and neck cancer is a heterogeneous group consisting of cancers that originate on the mucosal surface of the upper aerodigestive tract and affect the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx. The dominant histological type is squamous cell carcinoma (SCC), accounting for more than 90% of all malignant diseases of the head and neck region of the body.

Despite advances in the diagnosis and treatment of early stage or locally advanced head and neck squamous cell carcinoma (SCCHN), more than 65% of these patients will develop recurrent or metastatic disease. Additionally, approximately 10% of SCCHN patients appear to have metastatic SCCHN at initial diagnosis. For patients with locally recurrent disease, salvage surgery is only curative for some patients with resectable local recurrence, and re-irradiation is often limited by prior radiation therapy history and associated toxicity and morbidity. Consequently, for patients with relapsed or metastatic SCCHN, systemic therapy is the standard of care (SOC) therapy and is key to remission. In the case of the above patients, the prognosis is poor with an average survival period of 6 to 15 months in most clinical trials depending on the patient and disease-related factors.

Therefore, there is a high unmet need for improved medical interventions in head and neck cancer, especially SCCHN.

Methods and uses for the treatment of head and neck cancer

Disclosed herein are methods and uses for treating SCCHN (eg, relapsed and/or metastatic SCCHN (eg, PD-L1 positive and/or HPV positive relapsed and/or metastatic SCCHN)) in a subject or population of subjects, comprising an effective amount of PD -1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX 1106 (nivolumab)), MK-3475 (pembrolizumab, formerly lambrolizumab) known as zumab), MEDI-0680 (AMP-514), PDR001 (spartalizumab), REGN2810 (semipliumab), BGB-108, prolgolimab, camrelizumab, scintilimab, tislelizumab or torifalimab)) and an anti-TIGIT antagonist (eg, an anti-TIGIT antagonist antibody, such as tiragolumab, as described in Bonwoer), by administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles. Methods and uses are provided comprising treating a population. Also disclosed herein is a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and about 80 mg to about 1600 every 3 weeks. A method is provided comprising administering to the subject one or more dosing cycles of a mg dose of a PD-1 axis binding antagonist. Also disclosed herein is a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising a dose of about 600 mg tiragolumab every 3 weeks and a dose of about 1200 mg atezolizumab once every 3 weeks. A method is provided comprising administering to the subject at least one dosing cycle.

The present invention provides an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab) and an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab). methods and uses involving administration to a subject or population of subjects in need thereof. In some cases, the present invention provides an effective amount of a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) and an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) to a subject or population of subjects in need thereof.

In some cases, any method and use for treating SCCHN in a subject or population of subjects may result in CR or PR. In some cases, any method and use for treating SCCHN in a subject or population of subjects may result in an increase in the objective response rate (ORR) of the subject or population of subjects. In some cases, any method and use for treating SCCHN in a subject or population of subjects may result in an increase in PFS, Duration of Response (DOR), and/or OS in the subject or population of subjects.

In some cases, the SCCHN is a SCCHN having a detectable expression level of PD-L1. In some cases, a tumor sample obtained from the subject or population of subjects comprises a detectable expression level of PD-L1 (eg, a detectable protein and/or nucleic acid expression level of PD-L1 (eg, a tumor associated immune cell (TIC) ) was determined to have 5% or more)). In some cases, the detectable protein expression level of PD-L1 is a TIC in the tumor sample of at least 5% (eg, PD-L1 positive), at least 5% and less than 20% (eg, PD-L1 low), or greater than 20% (eg, high in PD-L1). In some cases, the detectable protein expression level of PD-L1 is at least 10%, at least 10% and less than 50%, or at least 50% of the TIC in the tumor sample.

In some cases, the treatment is first-line treatment. In some cases, the subject or population of subjects has not received prior therapy. In some cases, the subject or population of subjects has not received prior systemic therapy for recurrent and/or metastatic disease.

Dosage regimen and administration

In one aspect, the treatment methods and uses of the invention described herein comprise an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX) one or more dosing cycles of -1106 (nivolumab) or MK-3475) (pembrolizumab (formerly known as lambrolizumab)), and an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT as disclosed herein). administering to the subject or population of subjects having SCCHN (eg, recurrent and/or metastatic SCCHN) a dosing regimen comprising one or more dosing cycles of an antagonist antibody, such as tyragolumab.

The pharmaceutical compositions described herein may be formulated for administration as described in Section III(K).

Diagnostic methods and uses for head and neck cancer

The invention provides a method of selecting a therapy (eg, one line therapy) for a subject or population of subjects having SCCHN (eg, recurrent and/or metastatic SCCHN), wherein the therapy is obtained from the subject or population of subjects. one or more biomarkers (eg, PD-L1 (eg, as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (eg, p16 IHC, ISH or is guided by a diagnostic method involving determining the presence and/or expression level/amount of )))) as determined by PCR.

Disclosed herein are an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475) (pembrolizumab, formerly known as lambrolizumab), MEDI-0680 (AMP-514), PDR001 (spartalizumab), REGN2810 (semipliumab), BGB-108, prolgolimab, camrelizumab Further provided is a method of identifying a subject or population of subjects with SCCHN (e.g., recurrent and/or metastatic SCCHN) that may benefit from treatment including wherein the identification is one or more biomarkers (eg, PD-L1 (eg, as determined by PD-L1 protein and/or nucleic acid expression) in a sample (eg, a tumor sample or blood sample) obtained from the subject or population of subjects. or by a diagnostic method involving determining the presence and/or expression level/amount of HPV status (eg, as determined by p16 IHC, ISH or PCR).

Further provided herein is a method of assessing responsiveness to therapy for a subject or population of subjects having SCCHN (eg, relapsed and/or metastatic SCCHN), wherein the therapy is a sample obtained from the subject or population of subjects (eg, one or more biomarkers (eg, PD-L1 (eg, as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (eg, determined by p16 IHC, ISH or PCR) in a tumor sample or blood sample) as))) and/or is further guided by a diagnostic method involving determining the level/amount of expression.

Further provided herein is a method of optimizing therapy for a subject or population of subjects having SCCHN (eg, recurrent and/or metastatic SCCHN), wherein the therapy is a sample obtained from the subject or population of subjects (eg, a tumor sample or one or more biomarkers (e.g., as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (e.g., as determined by p16 IHC, ISH or PCR) in a blood sample) ) is further guided by a diagnostic method involving determining the presence and/or expression level/amount.

Biomarkers for use in the methods described herein include WGS, a gene or gene signature analysis associated with tumor immunobiology, HPV alteration, lymphocyte subpopulations, T cell receptor repertoire, cytokines associated with T cell activation and plasma-derived cytokines and/or or circulating tumor DNA in tissue (e.g., tumor tissue) or blood (e.g., whole blood), tissue (e.g., tumor tissue) and/or blood identified via NGS (including, but not limited to, mutant load, MSI and MMR defects) PD-L1 expression on germline and somatic mutations of In some cases, the biomarker is PD-L1. In some cases, a tumor sample obtained from the subject or population of subjects comprises a detectable expression level of PD-L1 (eg, a detectable protein and/or nucleic acid expression level of PD-L1 (eg, a tumor associated immune cell (TIC) ) was determined to have 5% or more)). In some cases, the detectable protein expression level of PD-L1 is at least 5% (eg, PD-L1 positive), at least 5% and less than 20% (eg, PD) of tumor associated immune cells (TICs) in the tumor sample. -L1 low), or greater than 20% (eg, PD-L1 high). In some cases, the detectable protein expression level of PD-L1 is at least 10%, at least 10% and less than 50%, or at least 50% of the TIC in the tumor sample. In some cases, the sample is a tumor sample (eg, a formalin fixed, paraffin embedded (FFPE) tumor sample). In some cases, the tumor sample is a tumor tissue sample.

In some cases, the method comprises (eg, as determined by PD-L1 (eg, PD-L1 protein and/or nucleic acid expression) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects. or determining the presence and/or expression level/amount of HPV status (eg, as determined by p16 IHC, ISH or PCR) and administering to the subject or population of subjects from about 30 mg to about 1200 mg every 3 weeks ( For example, from 30 mg to 1200 mg) at a dose (eg, a fixed dose) of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) at one or more dosing cycles and about 80 mg to every 3 weeks One or more dosing cycles of about 2000 mg (eg, 80 mg to about 2000 mg) dose (eg, fixed dose) of a PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) It includes the step of administering. In some cases, the method comprises (eg, as determined by PD-L1 (eg, PD-L1 protein and/or nucleic acid expression) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects. or determining the presence and/or expression level/amount of HPV status (e.g., as determined by p16 IHC, ISH or PCR) and giving said subject or population of subjects about 600 mg (e.g., 600 mg every 3 weeks) ) at least one dosing cycle of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a dose of 840 mg every two weeks of a PD-1 axis binding antagonist (eg, anti-PD-L1) administering one or more dosing cycles of the antagonist antibody (eg, atezolizumab). In some cases, the method comprises (eg, as determined by PD-L1 (eg, PD-L1 protein and/or nucleic acid expression) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects. or determining the presence and/or expression level/amount of HPV status (e.g., as determined by p16 IHC, ISH or PCR) and giving said subject or population of subjects about 600 mg (e.g., 600 mg every 3 weeks) ) at least one dosing cycle of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tyragolumab as disclosed herein) and a 1200 mg dose of a PD-1 axis binding antagonist (eg, anti-PD-L1 every 3 weeks) administering one or more dosing cycles of the antagonist antibody (eg, atezolizumab). In some cases, the method comprises (eg, as determined by PD-L1 (eg, PD-L1 protein and/or nucleic acid expression) in a sample (eg, a tumor sample or blood sample) from the subject or population of subjects. or determining the presence and/or expression level/amount of HPV status (e.g., as determined by p16 IHC, ISH or PCR) and giving said subject or population of subjects about 600 mg (e.g., 600 mg every 3 weeks) ) at least one dosing cycle of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tyragolumab as disclosed herein) and a 1680 mg dose of a PD-1 axis binding antagonist (eg, anti-PD-L1 every 4 weeks) administering one or more dosing cycles of the antagonist antibody (eg, atezolizumab).

Presence and/or expression level of (eg, PD-L1 (eg, as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (eg, as determined by p16 IHC, ISH or PCR)) The /amount can be determined qualitatively and/or quantitatively according to any suitable criterion known in the art, including, but not limited to, protein, protein fragment, DNA, mRNA, cDNA, and/or gene copy number.

In some cases, the expression level or amount of a biomarker is a detectable protein expression level of PD-L1 in a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects. In some cases, the PD-L1 protein expression level was determined by IHC analysis. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects has been determined to have a detectable expression level of PD-L1. In some cases, a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects has been determined to have a detectable expression level of PD-L1 in tumor infiltrating immune cells. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, the expression level or amount of a biomarker is a detectable nucleic acid expression level of PD-L1 in a tumor sample (eg, a FFPE tumor sample) from the subject or population of subjects. In some cases, the nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MassARRAY ^® technology, in-tissue. (in situ) hybridization (ISH), or a combination thereof. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, in a sample (eg, a tumor sample or blood sample) from a subject or population of subjects (eg, as determined by PD-L1 (eg, PD-L1 protein and/or nucleic acid expression) or HPV status ( The presence and/or expression level/amount of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) ) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) as eligible for therapy with the subject or population of subjects. selecting, e.g., wherein the detectable expression level of PD-L1 is a biomarker for selection of an individual, in some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample In some cases, the tissue sample is a tumor sample (such as FFPE tumor sample).In some cases, the tumor sample comprises tumor infiltrating immune cells, tumor cells, stromal cells, and any combination thereof. In some cases, the tumor sample is a FFPE tumor sample.

In one aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks (eg, a fixed dose) and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on PD-L1 expression in the detected tumor sample. with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying said subject and subject population as those who may benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as A method of selecting a therapy for a subject or population of subjects is provided. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1680 mg every 4 weeks. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 840 mg every 2 weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on PD-L1 expression in the detected tumor sample. providing a method of selecting a therapy for a subject or subject population having SCCHN (eg, recurrent and/or metastatic SCCHN) by identifying said subject and subject population as those who may benefit from a therapy comprising do. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks (eg, a fixed dose) and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on PD-L1 expression in the detected tumor sample. with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying said subject and subject population as those who may benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as A method of selecting a therapy for a subject or population of subjects is provided. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1680 mg every 4 weeks. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 840 mg every 2 weeks. In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on PD-L1 expression in the detected tumor sample. providing a method of selecting a therapy for a subject or subject population having SCCHN (eg, recurrent and/or metastatic SCCHN) by identifying said subject and subject population as those who may benefit from a therapy comprising do. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks (eg, a fixed dose) and a dose of 1200 mg every 3 weeks (eg, a fixed dose) based on PD-L1 expression in the detected tumor sample. with SCCHN (e.g., recurrent and/or metastatic SCCHN) by identifying said subject and subject population as those who may benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as A method of selecting a therapy for a subject or population of subjects is provided. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1680 mg every 4 weeks. In some cases, the regimen comprises one or more dosing cycles of the anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 840 mg every 2 weeks. In another aspect, the invention provides a method for determining the protein expression level of PD-L1 in a tumor sample by obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, by IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting, and one or more dosing cycles of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on PD-L1 expression in the detected tumor sample. providing a method of selecting a therapy for a subject or subject population having SCCHN (eg, recurrent and/or metastatic SCCHN) by identifying said subject and subject population as those who may benefit from a therapy comprising do. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, ate SCCHN that may benefit from therapy comprising zolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) Provided is a method for identifying a subject or population of subjects with (eg, recurrent and/or metastatic SCCHN). In some cases, the therapy comprises an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 4 weeks. one or more dosing cycles of atezolizumab administered at a dose of 1680 mg per day In some cases, the regimen includes an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 840 mg every 2 weeks. one or more dosing cycles of atezolizumab administered as a dose, in some aspects, the present invention provides an anti-PD-L1 antibody suitable for staining, comprising the steps of obtaining a tumor sample (eg, biopsy) from a subject or population of subjects. detecting the protein expression level of PD-L1 in the tumor sample by IHC analysis using the subject and population of subjects as those who may benefit from a therapy comprising one or more dosing cycles of by identifying an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) provide a way In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, ate SCCHN that may benefit from therapy comprising zolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) Provided is a method for identifying a subject or population of subjects with (eg, recurrent and/or metastatic SCCHN). In some cases, the therapy comprises an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 4 weeks. one or more dosing cycles of atezolizumab administered at a dose of 1680 mg per day In some cases, the regimen includes an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 840 mg every 2 weeks. one or more dosing cycles of atezolizumab administered as a dose, in some aspects, the present invention provides an anti-PD-L1 antibody suitable for staining, comprising the steps of obtaining a tumor sample (eg, biopsy) from a subject or population of subjects. detecting the protein expression level of PD-L1 in the tumor sample by IHC analysis using may benefit from a therapy comprising one or more dosing cycles of atezolizumab administered as a fixed dose (eg, a fixed dose). an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, SCCHN (e.g., recurrent and/or metastatic SCCHN) that may benefit from therapy comprising, e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) A method for identifying a subject or population of subjects with In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, ate SCCHN that may benefit from therapy comprising zolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) Provided is a method for identifying a subject or population of subjects with (eg, recurrent and/or metastatic SCCHN). In some cases, the therapy comprises an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 4 weeks. one or more dosing cycles of atezolizumab administered at a dose of 1680 mg per day In some cases, the regimen includes an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 840 mg every 2 weeks. one or more dosing cycles of atezolizumab administered as a dose, in some aspects, the present invention provides an anti-PD-L1 antibody suitable for staining, comprising the steps of obtaining a tumor sample (eg, biopsy) from a subject or population of subjects. detecting the protein expression level of PD-L1 in the tumor sample by IHC analysis using the subject and population of subjects as those who may benefit from a therapy comprising one or more dosing cycles of by identifying an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) provide a way In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agent; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, ate SCCHN (e.g., relapse) for therapy comprising zolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) Provided is a method for assessing the reactivity of a subject or population of subjects with sexual and/or metastatic SCCHN) In some cases, the therapy comprises an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 1680 every 4 weeks. one or more dosing cycles of atezolizumab administered at a dose of mg.In some cases, the regimen comprises an anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and a dose of 840 mg every 2 weeks. one or more dosing cycles of atezolizumab to be administered.In some aspects, the invention provides a method for obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, using an anti-PD-L1 antibody suitable for staining. detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis, and 1 of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. identifying said subject and subject population as those who would benefit from a therapy comprising more than one dosing cycle; By system, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK) Provided are methods for assessing the responsiveness of a subject or population of subjects having SCCHN (eg, recurrent and/or metastatic SCCHN) to therapy comprising -3475 (pembrolizumab, formerly known as lambrolizumab)). . In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, ate SCCHN (e.g., relapse) for therapy comprising zolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) Provided is a method for assessing the reactivity of a subject or population of subjects with sexual and/or metastatic SCCHN) In some cases, the therapy comprises an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 1680 every 4 weeks. one or more dosing cycles of atezolizumab administered at a dose of mg.In some cases, the regimen comprises an anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and a dose of 840 mg every 2 weeks. one or more dosing cycles of atezolizumab to be administered.In some aspects, the invention provides a method for obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, using an anti-PD-L1 antibody suitable for staining. detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis, and 1 of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. identifying said subject and subject population as those who would benefit from a therapy comprising more than one dosing cycle; By system, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK) Provided are methods for assessing the responsiveness of a subject or population of subjects having SCCHN (eg, recurrent and/or metastatic SCCHN) to therapy comprising -3475 (pembrolizumab, formerly known as lambrolizumab)). . In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, ate SCCHN (e.g., relapse) for therapy comprising zolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) Provided is a method for assessing the reactivity of a subject or population of subjects with sexual and/or metastatic SCCHN) In some cases, the therapy comprises an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 1680 every 4 weeks. one or more dosing cycles of atezolizumab administered at a dose of mg.In some cases, the regimen comprises an anti-TIGIT antagonist antibody at a dose of 600 mg every 3 weeks and a dose of 840 mg every 2 weeks. one or more dosing cycles of atezolizumab to be administered.In some aspects, the invention provides a method for obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, using an anti-PD-L1 antibody suitable for staining. detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis, and 1 of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks. identifying said subject and subject population as those who would benefit from a therapy comprising more than one dosing cycle; By system, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK) Provided are methods for assessing the responsiveness of a subject or population of subjects having SCCHN (eg, recurrent and/or metastatic SCCHN) to therapy comprising -3475 (pembrolizumab, formerly known as lambrolizumab)). . In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; (e.g., OX-40 agonist antibody), chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapeutic agents, and/or anti-hormonal agents, such as the agents mentioned herein above (separately or in combination) may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. an anti TIGIT antagonist antibody and in a subject or subject population having SCCHN (eg, recurrent and/or metastatic SCCHN), by identifying said subject and subject population as those who may benefit from a therapy comprising a dosing cycle; A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) In some cases, the therapy is an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and a dose of 1680 mg every 4 weeks. one or more dosing cycles of atezolizumab administered to one or more dosing cycles of zolizumab.In some aspects, the invention provides for obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, for IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting the protein expression level of PD-L1 in said tumor sample by means of one or more doses of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks identifying said subject and subject population as those who may benefit from a therapy comprising a cycle; , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD in a subject or population of subjects with SCCHN (eg, relapsed and/or metastatic SCCHN)) A method of optimizing therapy comprising a -1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is provided. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. an anti TIGIT antagonist antibody and in a subject or subject population having SCCHN (eg, recurrent and/or metastatic SCCHN), by identifying said subject and subject population as those who may benefit from a therapy comprising a dosing cycle; A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) In some cases, the therapy is an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and a dose of 1680 mg every 4 weeks. one or more dosing cycles of atezolizumab administered to one or more dosing cycles of zolizumab.In some aspects, the invention provides for obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, for IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting the protein expression level of PD-L1 in said tumor sample by means of one or more doses of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks identifying said subject and subject population as those who may benefit from a therapy comprising a cycle; , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD in a subject or population of subjects with SCCHN (eg, relapsed and/or metastatic SCCHN)) A method of optimizing therapy comprising a -1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is provided. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some aspects, the invention provides a method for obtaining a tumor sample (eg, a biopsy) from a subject or population of subjects, the protein expression level of PD-L1 in the tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining. and one or more doses of anti-TIGIT antagonist antibody administered at a dose of 600 mg (eg, a fixed dose) every 3 weeks and atezolizumab administered at a dose of 1200 mg (eg, a fixed dose) every 3 weeks. an anti TIGIT antagonist antibody and in a subject or subject population having SCCHN (eg, recurrent and/or metastatic SCCHN), by identifying said subject and subject population as those who may benefit from a therapy comprising a dosing cycle; A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab))) In some cases, the therapy is an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and a dose of 1680 mg every 4 weeks. one or more dosing cycles of atezolizumab administered to one or more dosing cycles of zolizumab.In some aspects, the invention provides for obtaining a tumor sample (eg, biopsy) from a subject or population of subjects, for IHC analysis using an anti-PD-L1 antibody suitable for staining. detecting the protein expression level of PD-L1 in said tumor sample by means of one or more doses of tiragolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks identifying said subject and subject population as those who may benefit from a therapy comprising a cycle; , an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD in a subject or population of subjects with SCCHN (eg, relapsed and/or metastatic SCCHN)) A method of optimizing therapy comprising a -1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is provided. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy comprises one or more additional anti-cancer therapeutic agent(s) (eg, an immunomodulatory agent (eg, one or more immune co-suppressive receptors (eg, TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3) , BTLA, and/or one or more immune co-suppression receptors selected from VISTA), such as a CTLA-4 antagonist, such as an anti-CTLA-4 antagonist antibody (eg, ipilimumab ( ^YERVOY® )), or an agent that increases or activates one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR), such as an OX-40 agonist; In combination with (separately or in combination with, e.g., an OX-40 agonist antibody), a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, a radiotherapy/radiotherapeutic agent, and/or an anti-hormonal agent, such as the agents mentioned herein above). may be administered.

In some cases, in any of the diagnostic methods or uses described herein, the SCCHN is recurrent and/or metastatic SCCHN. The cancer may be early or late. In some cases, the therapy is a one-line therapy. In some cases, the subject or population of subjects has not received prior therapy. In some cases, the prior therapy is prior systemic therapy for recurrent and/or metastatic disease.

Cancer characterization and selection

In any of the methods, uses, or compositions for use described herein, the cancer may be SCCHN (eg, recurrent and/or metastatic SCCHN). In some cases, the SCCHN is recurrent and/or metastatic SCCHN. In some cases, the SCCHN is PD-L1 positive. In some cases, the SCCHN is HPV positive. In some cases, the SCCHN is HPV negative. In some cases, the SCCHN is PD-L1 positive and HPV positive. In some cases, the SCCHN is PD-L1 positive and HPV negative. In some cases, the subject or population of subjects has not received prior therapy. In some cases, the prior therapy is prior systemic therapy for recurrent and/or metastatic disease.

In some cases, in any method, use, or composition for use described herein, the subject or population of subjects is a PD-L1 selected tumor (eg, a tumor having a detectable expression level of PD-L1 (eg, has a detectable protein expression level of PD-L1 (eg, at least 5% tumor-associated immune cells (TIC)) In some cases, a sample obtained from the subject or population of subjects (eg, a tumor sample (eg, a tumor tissue sample)) has a detectable protein expression level (eg, a TIC of at least 5%) of PD-L1 In some cases, the PD-L1 selected tumor has a detectable expression level of PD-L1 (eg, PD- has a detectable protein expression level of L1 (eg, greater than or equal to 5% TIC) In some cases, the detectable expression level of PD-L1 is a detectable expression level of PD-L1 (eg, greater than or equal to 5% TIC) In some cases, the detectable protein expression level of PD-L1 has a TIC of at least about 5% (eg, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75% , 80%, 90% or greater) In some cases, the detectable protein expression level of PD-L1 has a TIC of about 5% to less than 20% (eg, 5%, 6%, 7%, 8 %, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%) In some cases, 5% or more 20 A TIC of less than % is defined as PD-L1 low In some cases, the detectable protein expression level of PD-L1 is a TIC of about 20% or greater (e.g., 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 40%, 45%, 50%, 5 5%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%). In some cases, a TIC of 20% or more is defined as PD-L1 high. In some cases, the detectable protein expression level of PD-L1 has a TIC of at least about 10% (eg, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18 %, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90% or more). In some cases, the detectable protein expression level of PD-L1 has a TIC of at least about 10% and less than 50% (eg, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17 %, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 46%, 47%, 48%, 49%, 49.5%, 49.9%, or 49.99%). In some cases, the detectable protein expression level of PD-L1 has a TIC of at least about 50% (eg, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58 %, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 95% , 99%, or 99.99%).

In some cases, the IHC assay uses anti-PD-L1 antibodies SP263, SP142, 22C3, or 28-8. In some cases, the IHC assay uses the anti-PD-L1 antibody SP263. In some cases, the TIC was determined to be greater than or equal to 5% (eg, using a Ventana (SP263) PD-L1 IHC assay). In some cases, the TIC was determined to be greater than or equal to 5% and less than 20% (eg, using a Ventana (SP263) PD-L1 IHC assay). In some cases, the TIC was determined to be greater than or equal to 20% (eg, using a Ventana (SP263) PD-L1 IHC assay). In some cases, the TIC was determined to be greater than or equal to 10% (eg, using a Ventana (SP263) PD-L1 IHC assay). In some cases, the TIC was determined to be greater than or equal to 10% and less than 50% (eg, using a Ventana (SP263) PD-L1 IHC assay). In some cases, the TIC was determined to be greater than or equal to 50% (eg, using a Ventana (SP263) PD-L1 IHC assay).

In some cases, in a method, use, or composition for use described herein, a sample obtained from the subject or population of subjects (eg, a tumor sample) has a detectable nucleic acid expression level of PD-L1. In some instances, the detectable nucleic acid expression level of PD-L1 was determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. . In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some cases, the tissue sample is a tumor sample. In some cases, the tumor sample comprises tumor infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

In some cases, in any of the methods, uses, or compositions for use described herein, the subject or population of subjects has a tumor with detectable HPV. In some cases, in any of the methods, uses, or compositions for use described herein, the subject or population of subjects has a tumor free of detectable HPV. In some cases, the HPV is detected directly or indirectly. In some cases, the HPV is detected by protein expression level (eg, p16 or HPV viral protein). In some cases, the HPV is detected by the level of nucleic acid expression. In some cases, HPV status is determined by p16 IHC, in situ or PCR. In some cases, the HPV is HPV16. In some cases, the HPV is HPV18.

response to treatment

In some embodiments of any of the methods described herein, the response of a subject or population of subjects to a therapy can be characterized by one or more measures. In some embodiments, the treatment results in CR or PR. In some cases, any method and use for treating SCCHN in a subject or population of subjects may result in an increase in the objective response rate (ORR) of the subject or population of subjects. In some cases, any method and use for treating SCCHN in a subject or population of subjects may result in an increase in PFS, Duration of Response (DOR), and/or OS in the subject or population of subjects.

In some cases, in any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or Administration of an anti-PD-1 antagonist antibody (such as MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) elicits a clinical response. The clinical response is an increase in ORR in a subject or a population of subjects compared to a reference ORR In some cases, the baseline ORR is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, an anti-PD-L1 antagonist antibody) without anti-TIGIT antagonist antibody. , atezolizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) ORR in a Population of Subjects In some cases, the baseline ORR is at least about 19% (eg, between about 19% and about 80%, such as between about 19% and about 60% (eg, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%) In some cases, the baseline ORR is at least about 36% (eg, about 36%). to about 80%, such as from about 36% to about 60% (eg, 36%, 37%, 38%, 39%, 40%, 45%, 50%, 55%, or 60%). In , the baseline ORR is at least about 19% to about 36%.In some cases, the clinical response is an increase in PFS in a subject or population compared to baseline PFS.In some cases, the baseline PFS time is a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (e.g., MDX-1106 (nivolumab) Pembrolizumab, formerly lambrolizumab is the median PFS time of a population of subjects receiving treatment including Zumab)). In some cases, the clinical response is an increase in DOR in a subject or population of subjects as compared to a baseline DOR time. In some cases, the baseline DOR time is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106) without an anti-TIGIT antagonist antibody. (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab) is the median DOR time of a population of subjects receiving treatment. In some cases, the baseline DOR time is at least about 4 months. (e.g., from about 4 months to about 42 months (e.g., from about 6 months to about 30 months (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months , 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months or 30 months)) In some cases, the baseline DOR time is at least about 6.7 months (eg, at least about 6.7 months, 6.8 months, 6.9 months, 7.0 months, 8.0 months, 9.0 months, 10.0 months, 11.0 months, or 12.0 months). In some cases, the reference DOR time is at least about 6.7 months to about 23.4 months In some cases, the reference DOR time is at least about 23.4 months (eg, at least about 23.4 months, 23.5 months, 23.6 months, 23.7 months) , 23.8 months, 23.9 months, 24 months, 25 months, 26 months, 28 months, 30 months, or 32 months) In some cases, the clinical response is an increase in OS.

In some cases, the treatment is greater than 15% (eg, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43% , 44%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90% or more). In some cases, the treatment results in an ORR greater than the baseline ORR. In some cases, the baseline ORR is 19%. In some cases, the baseline ORR is 24.4%. In some cases, the baseline ORR is 28.8%. In some cases, the baseline ORR is 35%.

In some cases, the treatment is compared to treatment with a PD-1 axis binding antagonist, eg, in the absence of an anti TIGIT antagonist antibody, or compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist, such as in the subject or population of subjects. causes an increase in PFS, DOR, or OS.

In some embodiments, OS is measured as the period from initiation of treatment to death. In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 2 months (eg, by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6- by 60 months, by 7-48 months, by 8-36 months, by 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months , 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 3.3 months (eg, by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7- by 48 months, by 8-36 months, or by 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 5.1 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months , 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, the treatment reduces the OS of the subject or population of subjects by at least about 5.3 months (eg, by 5.3 to 120 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 by -24 months, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months , 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some cases, the treatment results in an increase in OS compared to baseline OS time. In some cases, the baseline OS time is at least about 8 months (eg, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months) to be. In some cases, the baseline OS time is at least about 14.9 months (eg, 15 months, 16 months, 17 months, 18 months, 19 months, or 20 months). In some cases, the baseline OS time is at least about 11.6 months to about 14.9 months.

In some embodiments, the treatment described herein reduces the PFS of the subject or population of subjects by at least about 2.4 months (eg, by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months). , by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months , 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the PFS of the subject or population of subjects by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, 8 by -48 months, by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months , 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the PFS of the subject or population of subjects by at least about 2 months (eg, by 2 to 120 months, by 3 to 100 months, by 4 to 80 months, by 6 to 60 months, 8 by -48 months, by 9-36 months, by 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months , 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, the treatment described herein increases the DOR of the subject or population of subjects by at least about 2.4 months (eg, by 2.4 to 120 months, by 2.5 to 100 months, by 3.0 to 80 months, by 4.0 to 60 months). , by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months , 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment increases the DOR of the subject or population of subjects by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, 8 by -48 months, by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months , 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment increases the DOR of the subject or population of subjects by at least about 2 months (eg, by 2 to 120 months, by 3 to 100 months, by 4 to 80 months, by 6 to 60 months, 8 by -48 months, by 9-36 months, by 10-24 months, such as at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months , 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some cases, the treatment is administered to the patient as measured by the Patient Reported Outcomes Measurement Information System ^® (PROMIS) ^® IItem Bank v2.0-Physical Functioning-Short Form 10b. time to confirmed deterioration (TTCD) in bodily function reported by In some cases, the treatment is PROMIS ^® Item Bank v2.0 - Quick Form 10b for Body Functions, PROMIS ^® Item Bank v1.0 - Quick Form 4a for Fatigue, PROMIS ^® Item Bank v1.0 - Quick Form for Fatigue Interference Baseline of body function, fatigue and/or pain as measured by the Pain Interference Short Form 4a, and the PROMIS ^® Numeric Rating Scale v1.0-Pain Intensity 1a. improve

D. Treatment methods and uses associated with liver cancer

liver cancer

Liver cancer is the fifth most common cancer and the second most common cancer-related cause of death worldwide, with 854,000 new cases and 810,000 deaths annually. At diagnosis, most patients with primary liver cancer present with advanced disease, a stage at which curative treatment is not recommended. The World Health Organization (WHO) estimates that more than one million people will die of liver cancer by 2030, presenting a significant global public health problem.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and accounts for approximately 90% of all primary liver cancers. Hepatocellular carcinoma (HCC) is the most lethal disease of any solid tumor with a mortality rate of 0.98. Up to 80% of patients initially presenting with hepatocellular carcinoma (HCC) have progressed to unresectable or metastatic disease due to the late onset of symptoms. In the United States, the 5-year overall survival (OS) rate of patients with hepatocellular carcinoma (HCC) is 17% and drops significantly to 3% with distant metastasis.

Accordingly, there is an unmet need in the field of development of effective immunotherapy for the treatment of liver cancer, such as HCC, such as locally advanced HCC, metastatic HCC, or unresectable HCC.

Methods and uses for the treatment of liver cancer

Disclosed herein are methods and uses for treating or delaying the progression of liver cancer, including locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC), in a subject or population of subjects, comprising: an effective amount of a PD-1 axis binding antagonist ( Methods and uses are provided comprising administering to the subject or population of subjects a treatment regimen comprising, e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) wherein the subject or population of subjects has not previously received systemic treatment for liver cancer (eg, HCC). Also provided herein are methods and uses for treating or delaying the progression of liver cancer, including locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC), in a subject or population of subjects, comprising an effective amount of a PD-1 axis binding Treatments comprising an antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) and an anti-TIGIT antagonist antibody (eg, tyragolumab) Methods and uses are provided comprising administering therapy to the subject or population of subjects. In some embodiments, the treatment regimen is one dose of an effective amount of a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)) and an anti TIGIT antagonist antibody (eg, tyragolumab) more than one dosing cycle. In other embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) )), and one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tyragolumab).

Also disclosed herein is a method of enhancing immune function in a subject or population of subjects having liver cancer (eg, HCC including locally advanced or metastatic and/or unresectable HCC), comprising an effective amount of a PD-1 axis binding antagonist (eg, anti-PD). Methods are provided comprising administering to the subject or population of subjects a treatment regimen comprising an -L1 antagonist antibody (eg, atezolizumab)) and an anti TIGIT antagonist antibody (eg, tiragolumab). In some embodiments, the treatment regimen is one dose of an effective amount of a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)) and an anti TIGIT antagonist antibody (eg, tyragolumab) more than one dosing cycle.

For example, disclosed herein are methods and uses for treating or delaying the progression of liver cancer (eg, HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects, comprising an effective amount of a PD-1 axis binding antagonist Methods and uses comprising administering to the subject or population of subjects a treatment regimen comprising (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an anti-TIGIT antagonist antibody (eg, tiragolumab) provided In some embodiments, the treatment regimen is one dose of an effective amount of a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)) and an anti TIGIT antagonist antibody (eg, tyragolumab) more than one dosing cycle.

Also disclosed herein is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, an anti-PD-L1 antagonist antibody) for use in treating liver cancer (eg, HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects. , atezolizumab)), wherein said treatment comprises a treatment regimen comprising administration of said PD-1 axis binding antagonist in combination with said anti-TIGIT antagonist antibody (eg, tiragolumab). do. In some embodiments, the treatment regimen is one dose of an effective amount of a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)) and an anti TIGIT antagonist antibody (eg, tyragolumab) more than one dosing cycle.

Also disclosed herein is a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, an anti-PD-L1 antagonist antibody) for use in treating liver cancer (eg, HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects. , atezolizumab)), wherein the treatment is in combination with a VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) and an anti TIGIT antagonist antibody (eg, tiragolumab) treatment regimens comprising administration of one of said PD-1 axis binding antagonists. In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) )), and one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tyragolumab).

In another example, disclosed herein is a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) for use in treating liver cancer (eg, HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects. ) is provided, wherein the treatment comprises a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an anti-TIGIT antagonist antibody (eg, tyragolumab) treatment regimens comprising administration of said VEGF antagonist in combination with In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) )), and one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tyragolumab).

In another example, disclosed herein is a pharmaceutical comprising an anti-TIGIT antagonist antibody (eg, tyragolumab) for use in treating liver cancer (eg, HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects. An antagonist composition is provided, wherein the treatment comprises a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab))) treatment regimens including administration of the anti-TIGIT antagonist antibody in combination with In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) )), and one or more dosing cycles of an anti-TIGIT antagonist antibody (eg, tyragolumab).

In some embodiments of any method, use, or composition for use described herein, the liver cancer may be early or late. In some embodiments, the liver cancer is HCC (eg, locally advanced or metastatic and/or unresectable HCC). In some cases, the liver cancer is locally advanced or metastatic and/or unresectable HCC. In some embodiments, the liver cancer is high risk liver cancer (eg, high risk locally advanced or metastatic and/or unresectable HCC). In some embodiments, the high-risk liver cancer comprises one or more of the following characteristics: VP4 PVTT, bile duct infiltration, and/or tumor occupancy >50% of the liver.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the treatment elicits a response in the subject or population of subjects following treatment. For example, in some embodiments, the treatment increases the likelihood that the subject or population of subjects will have an objective response, prolongs the PFS of the subject or population of subjects, and the OS of the subject or subject as compared to reference treatment prolongs the time to radiation progression (TTRP) of the subject or population of subjects, prolongs the duration of response (DOR) of the subject or population of subjects, and/or reduces the risk of death. In some embodiments, the treatment is at least about 5.6 months (eg, 5.6 to 14 months (eg, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6 months, 7 months, 8 months, 9 months, 10 months) , 11 months, 12 months, 13 months, or 14 months)))). In some embodiments, the treatment provides for a median PFS of a population of subjects of at least about 6.83 months (eg, 6.9 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, or 14 months). causes In some embodiments, the treatment is at least about 5.6 months to at least about 6.83 months (e.g., at least about 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.1 months, 6.2 months, 6.3 months, 6.4 months, 6.5 months, 6.6 months, 6.7 months, 6.8 months, or 6.83 months). In some embodiments, the standard of care comprises current standard of care. In some embodiments, the standard of care comprises a PD-1 axis binding antagonist (eg, atezolizumab) and a VEGF antagonist (eg, bevacizumab) without an anti-TIGIT antagonist antibody. In some embodiments, the reference of treatment comprises a PD-1 axis binding antagonist and a VEGF antagonist. In some embodiments, the standard of care comprises a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without a VEGF antagonist. In some embodiments, the standard of care comprises a VEGF antagonist and an anti TIGIT antagonist antibody without a PD-1 axis binding antagonist. In some embodiments, the reference of treatment comprises a PD-1 axis binding antagonist without a VEGF antagonist and an anti-TIGIT antagonist antibody. In some embodiments, the standard of care comprises an anti-TIGIT antagonist antibody and a VEGF antagonist without a PD-1 axis binding antagonist. In some embodiments, the standard of care comprises an anti-TIGIT antagonist antibody without a VEGF antagonist and a PD-1 axis binding antagonist.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the therapeutic response(s) may be improved as compared to any suitable standard cancer treatment regimen. In some embodiments, the standard of care cancer treatment regimen is standard liver cancer (eg, HCC including locally advanced or metastatic and/or unresectable HCC) treatment regimen. In some embodiments, the standard of care for liver cancer (eg, HCC) treatment regimen comprises a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a multiple kinase inhibitor. In some embodiments, the multikinase inhibitor is sorafenib or lenvatinib. In some embodiments, the multikinase inhibitor is sorafenib.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab), PD- The uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)), or an agent thereof, is one or more additional anti-cancer therapeutic agent(s) ) (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiotherapy/radiotherapy, and/or anti-hormonal agents, such as those recited herein above) (separately or together), or It may be used in manufacture or formulated for administration.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the subject or population of subjects has previously had the liver cancer (e.g., locally advanced or metastatic and/or unresectable HCC comprising HCC) has never been treated. In some cases, the subject or population of subjects has not received prior therapy. In some cases, the subject or population of subjects has not received at least one line of prior therapy. In some cases, the subject or population of subjects has not received at least two lines of prior therapy. In some cases, the subject or population of subjects has previously received at least one or two or fewer systemic therapies, and/or there is no acceptable standard of care. In some cases, the subject or population of subjects has not received more than two lines of prior therapy. In some cases, the prior therapy is chemotherapy, surgery, and/or radiation therapy. In some cases, the prior therapy is immunotherapy. In some embodiments, the subject or population of subjects has not previously been treated for the liver cancer (eg, HCC (eg, locally advanced or metastatic and/or unresectable HCC)). In some embodiments, the subject or population of subjects has previously been treated for HCC. In some embodiments, the subject or population of subjects has not previously received treatment for locally advanced or metastatic and/or unresectable HCC.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the subject or population of subjects is suffering from liver cancer (eg, HCC including locally advanced or metastatic and/or unresectable HCC). No prior prior therapy for In some embodiments, the subject or population of subjects has not received prior systemic therapy for liver cancer (eg, HCC).

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the subject or population of subjects has received prior treatment with a PD-1 axis binding antagonist, VEGF antagonist, or anti-TIGIT antagonist antibody. never received

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the subject or population of subjects may have any suitable child-per-liver function. For example, in some embodiments, the subject or population of subjects has child-fur class A liver function.

Any suitable PD-1 axis binding antagonist, VEGF antagonist, or anti-TIGIT antagonist antibody can be used in the methods, uses, or pharmaceutical compositions for use described herein. For example, any PD-1 axis binding antagonist, VEGF antagonist, or anti TIGIT antagonist antibody known in the art or described herein can be used in a method, use, or pharmaceutical composition for use described herein. In some embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody or an anti-PD-1 antibody. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the VEGF antagonist is an anti-VEGF antibody. In some embodiments, the anti-VEGF antibody is bevacizumab. In some embodiments, the anti-TIGIT antagonist antibody is tyragolumab.

Exemplary methods

In one aspect, the invention provides a subject or one or more dosing cycles of a 600 mg dose (eg, a fixed dose) of an anti TIGIT antagonist antibody every 3 weeks and a 1200 mg dose (eg, a fixed dose) of atezolizumab every 3 weeks. Provided is a method of treating a subject or population of subjects having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the subject population, wherein the anti-TIGIT antagonist antibody comprises a sequence as further described below a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the subject or population of subjects has not previously received treatment for HCC, such as locally advanced or metastatic and/or unresectable HCC.

In another embodiment, the invention provides a 600 mg dose (eg, fixed dose) of anti-TIGIT antagonist antibody every 3 weeks, a 1200 mg dose (eg, fixed dose) of atezolizumab every 3 weeks, and 15 mg/kg every 3 weeks Provided is a method of treating a subject or population of subjects having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more dosing cycles of a dose of bevacizumab, wherein The anti-TIGIT antagonist antibody comprises a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19 as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another embodiment, the present invention provides a subject or subject with one or more dosing cycles of a 600 mg dose (eg, a fixed dose) tiragolumab every 3 weeks and a 1200 mg dose (eg, a fixed dose) atezolizumab every 3 weeks. Provided is a method of treating said subject or population of subjects having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the population.

In another embodiment, the present invention provides a dose of 600 mg (eg, a fixed dose) tiragolumab every 3 weeks, a 1200 mg dose (eg, a fixed dose) of atezolizumab every 3 weeks, and a 15 mg/kg dose every 3 weeks. Provided is a method of treating a subject or population of subjects having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more dosing cycles of bevacizumab of

In another embodiment, the invention provides a subject or subject one or more dosing cycles of a 420 mg dose (eg, a fixed dose) tiragolumab every 2 weeks and a 840 mg dose (eg, a fixed dose) atezolizumab every 2 weeks. Provided is a method of treating said subject or population of subjects having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the population.

In another embodiment, the present invention provides a dose of 420 mg (eg, a fixed dose) tiragolumab every 2 weeks, a 840 mg dose (eg, a fixed dose) of atezolizumab every 2 weeks, and 5 mg/kg every 2 weeks, The subject or subject having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more dosing cycles of bevacizumab at a dose of 7.5 mg/kg, or 10 mg/kg. A method of treating a population of

In another embodiment, the invention provides a subject or subject one or more dosing cycles of an 840 mg dose (eg, a fixed dose) of tiragolumab every 4 weeks and a 1680 mg dose (eg, a fixed dose) of atezolizumab every 4 weeks. Provided is a method of treating said subject or population of subjects having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the population.

In another embodiment, the present invention provides a dose of 840 mg (eg, a fixed dose) tiragolumab every 4 weeks, a 1680 mg dose (eg, a fixed dose) of atezolizumab every 4 weeks, and 5 mg/kg every 2 weeks, The subject or subject having HCC (eg, locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more dosing cycles of bevacizumab at a dose of 7.5 mg/kg, or 10 mg/kg. A method of treating a population of

In another aspect, the invention provides an anti-TIGIT antagonist antibody ( For example, provided are an anti TIGIT antagonist antibody, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)) disclosed herein, wherein the method comprises an effective amount of an anti administering to the subject or population of subjects one or more dosing cycles of a TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In another aspect, the invention provides an anti-TIGIT antagonist antibody ( For example, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab), a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and a VEGF antagonist (eg, an anti-VEGF antibody (eg, , bevacizumab)), wherein the method comprises an effective amount of an anti TIGIT antagonist antibody, an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and an effective amount of VEGF administering to the subject or population of subjects one or more dosing cycles of an antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)).

Exemplary medicaments and uses thereof

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. providing the use of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered at a dose (eg, a fixed dose) of about 30 mg to about 1200 mg (eg, a fixed dose) of anti-TIGIT every 3 weeks. Formulations for administration of an antagonist antibody, and a dose of about 80 mg to about 2000 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 3 weeks get angry In some embodiments, the medicament is a 30 mg to 1200 mg dose (eg, a fixed dose) of the anti-TIGIT antagonist antibody every 3 weeks and a PD-1 axis binding at a 80 mg to 2000 mg dose (eg, a fixed dose) every 3 weeks It is formulated for administration of an antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, such as tyragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)), and VEGF antagonists (eg, , an anti-VEGF antibody (eg, bevacizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered for 3 weeks. at a dose of about 30 mg to about 1200 mg per (eg, fixed dose) anti-TIGIT antagonist antibody, every 3 weeks at a dose of about 80 mg to about 2000 mg (eg, fixed dose) of PD-1 axis binding antagonist (eg, anti-PD) -L1 antagonist antibody (eg, atezolizumab)), and formulations for administration of a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) at a dose of about 0.1 mg/kg to 50 mg/kg every 3 weeks get angry In some aspects, the medicament is a 30 mg to 1200 mg dose (eg, fixed dose) of anti-TIGIT antagonist antibody every 3 weeks, a 80 mg to 2000 mg dose (eg, a fixed dose) of PD-1 axis binding every 3 weeks An antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) at a dose of about 0.1 mg/kg to 50 mg/kg every 3 weeks) ) is formulated for administration.

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. providing the use of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered at a dose (eg, a fixed dose) of about 30 mg to about 600 mg every two weeks (eg, a fixed dose) of anti-TIGIT. Formulations for administration of an antagonist antibody, and a dose of about 80 mg to about 1200 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every two weeks get angry In some embodiments, the medicament is a 30 mg to 600 mg dose (eg, a fixed dose) of anti-TIGIT antagonist antibody every 2 weeks and a PD-1 axis binding at a dose of 80 mg to 1200 mg (eg, a fixed dose) every 2 weeks. It is formulated for administration of an antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, such as tyragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)), and VEGF antagonists (eg, , an anti-VEGF antibody (eg, bevacizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered for 2 weeks. at a dose of about 30 mg to about 600 mg per (eg, fixed dose) anti-TIGIT antagonist antibody, every two weeks at a dose of about 80 mg to about 1200 mg (eg, fixed dose) of PD-1 axis binding antagonist (eg, anti-PD) -L1 antagonist antibody (eg, atezolizumab)), and formulations for administration of a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) at a dose of about 0.1 mg/kg to 50 mg/kg every two weeks get angry In some embodiments, the medicament is a 30 mg to 600 mg dose (eg, fixed dose) of anti-TIGIT antagonist antibody every 2 weeks, a 80 mg to 1200 mg dose (eg, a fixed dose) of PD-1 axis binding every 2 weeks An antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), and a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab) at a dose of 0.1 mg/kg to 50 mg/kg every two weeks) formulated for administration.

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. providing the use of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered at a dose of about 600 mg to about 1200 mg (eg, a fixed dose) of anti-TIGIT every 4 weeks. Formulations for administration of an antagonist antibody, and a dose of about 1200 mg to about 2000 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 4 weeks get angry In some embodiments, the medicament is a 600 mg to 1200 mg dose (eg, a fixed dose) of the anti-TIGIT antagonist antibody every 4 weeks and a 1200 mg to 2000 mg dose (eg, a fixed dose) of the PD-1 axis binding every 4 weeks It is formulated for administration of an antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, such as tyragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)), and VEGF antagonists (eg, , an anti-VEGF antibody (eg, bevacizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered for 4 weeks. at a dose of about 600 mg to about 1200 mg per (eg, fixed dose) anti-TIGIT antagonist antibody, every 4 weeks at a dose of about 1200 mg to about 2000 mg (eg, fixed dose) of PD-1 axis binding antagonist (eg, anti-PD) -L1 antagonist antibody (eg, atezolizumab)), and formulations for administration of a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) at a dose of about 0.1 mg/kg to 50 mg/kg every two weeks get angry In some embodiments, the medicament is a 600 mg to 1200 mg dose (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 4 weeks, a 1200 mg to 2000 mg dose (eg, a fixed dose) of the PD-1 axis binding every 4 weeks An antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), and a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) at a dose of 0.1 mg/kg to 50 mg/kg every 2 weeks) formulated for administration.

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. providing the use of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the agent and an anti-TIGIT antagonist antibody, wherein the agent is administered at a dose of about 80 mg to about 2000 mg every 3 weeks (eg, a fixed dose). dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a dose of about 30 mg to about 1200 mg (e.g., a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks formulated for administration. In some aspects, the medicament is administered at a dose of 80 mg to 2000 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 3 weeks and 3 weeks It is formulated for administration of an anti TIGIT antagonist antibody to be administered in a 30 mg to 1200 mg dose (eg, a fixed dose) per hour.

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, such as tyragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)), and VEGF antagonists (eg, , an anti-VEGF antibody (eg, bevacizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the agent and an anti-TIGIT antagonist antibody, The agent is administered at a dose of about 80 mg to about 2000 mg every 3 weeks (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), about 30 every 3 weeks. Anti-TIGIT antagonist antibody at a dose of mg to about 1200 mg (eg, a fixed dose), and a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab) at a dose of about 0.1 mg/kg to 50 mg/kg every 3 weeks) formulated for administration. In some aspects, the medicament is administered at a dose of 80 mg to 2000 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 3 weeks, 3 weeks An anti-TIGIT antagonist antibody to be administered at a dose of 30 mg to 1200 mg per (eg, a fixed dose), and a dose of about 0.1 mg/kg to 50 mg/kg of a VEGF antagonist (eg, anti-VEGF antibody (eg, bevaciz) every 3 weeks mob))).

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. providing the use of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)), wherein the method comprises administering to the subject or population of subjects at least one dosing cycle of the agent and an anti-TIGIT antagonist antibody, wherein the agent is administered at a dose of about 80 mg to about 1200 mg every two weeks (e.g., a fixed dose) dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) and a dose of about 30 mg to about 600 mg (e.g., a fixed dose) of an anti TIGIT antagonist antibody every two weeks formulated for administration. In some aspects, the medicament is administered at a dose of 80 mg to 1200 mg (eg, a fixed dose) every 2 weeks of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and 2 weeks It is formulated for administration of an anti-TIGIT antagonist antibody to be administered in a 30 mg to 600 mg dose (eg, a fixed dose) per dose.

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, such as tyragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)), and VEGF antagonists (eg, , an anti-VEGF antibody (eg, bevacizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the agent and an anti-TIGIT antagonist antibody, The agent is administered at a dose of about 80 mg to about 1200 mg every two weeks (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), about 30 every two weeks. Anti-TIGIT antagonist antibody at a dose of mg to about 600 mg (eg, a fixed dose), and a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab) at a dose of about 0.1 mg/kg to 50 mg/kg every two weeks) formulated for administration. In some embodiments, the medicament is administered at a dose of 80 mg to 1200 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 2 weeks, 2 weeks An anti-TIGIT antagonist antibody to be administered at a dose of 30 mg to 600 mg per (eg, a fixed dose), and a dose of about 0.1 mg/kg to 50 mg/kg of a VEGF antagonist (eg, anti-VEGF antibody (eg, bevaciz) every two weeks mob))).

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. providing the use of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), wherein the method comprises administering to the subject or population of subjects at least one dosing cycle of the agent and an anti-TIGIT antagonist antibody, wherein the agent is administered at a dose of about 1200 mg to about 2000 mg every 4 weeks (e.g., a fixed dose) dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and a dose of about 600 mg to about 1200 mg every 4 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody formulated for administration. In some aspects, the medicament is administered at a dose of 1200 mg to 2000 mg (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 4 weeks and 4 weeks It is formulated for administration of an anti-TIGIT antagonist antibody to be administered in a 600 mg to 1200 mg dose (eg, a fixed dose) per dose.

In another aspect, the invention provides a medicament for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in the manufacture of a medicament. anti-TIGIT antagonist antibodies (eg, anti-TIGIT antagonist antibodies disclosed herein, such as tyragolumab), PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, atezolizumab)), and VEGF antagonists (eg, , an anti-VEGF antibody (eg, bevacizumab)), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the agent and an anti-TIGIT antagonist antibody, The agent is administered at a dose of about 1200 mg to about 2000 mg every 4 weeks (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), about 600 every 4 weeks Anti-TIGIT antagonist antibody at a dose of mg to about 1200 mg (eg, a fixed dose), and a VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab) at a dose of about 0.1 mg/kg to 50 mg/kg every two weeks) formulated for administration. In some aspects, the medicament is a 1200 mg to 2000 mg dose (eg, a fixed dose) of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 4 weeks, 4 weeks An anti-TIGIT antagonist antibody to be administered at a dose of 600 mg to 1200 mg per day (eg, a fixed dose), and a dose of about 0.1 mg/kg to 50 mg/kg of a VEGF antagonist (eg, anti-VEGF antibody (eg, bevaciz) every two weeks mob))).

In another aspect, the present invention provides an anti-TIGIT antagonist antibody and Provided is the use of atezolizumab, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered at a 600 mg dose (e.g., fixed dose) of an anti TIGIT antagonist antibody and a 1200 mg dose (eg, a fixed dose) of atezolizumab every 3 weeks, wherein the anti TIGIT antagonist antibody is further described in SEQ ID NO: 17 or a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides an anti-TIGIT antagonist antibody for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC); Provided is a use of atezolizumab, and bevacizumab, wherein the method comprises administering to the subject or population of subjects at least one dosing cycle of the medicament, wherein the medicament is 600 mg every 3 weeks. Formulated for administration of a dose (eg, a fixed dose) of an anti TIGIT antagonist antibody, a 1200 mg dose (eg, a fixed dose) of atezolizumab every 3 weeks, a 15 mg/kg dose of bevacizumab every 3 weeks, The anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, as further described below. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides an anti-TIGIT antagonist antibody and Provided is the use of atezolizumab, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered at a dose of 420 mg every two weeks (e.g., a fixed dose) of an anti TIGIT antagonist antibody and an 840 mg dose (eg, a fixed dose) of atezolizumab every two weeks, wherein the anti TIGIT antagonist antibody is further described in SEQ ID NO: 17 or a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides an anti-TIGIT antagonist antibody for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC); Provided is a use of atezolizumab, and bevacizumab, wherein the method comprises administering to the subject or population of subjects at least one dosing cycle of the medicament, wherein the medicament is 420 mg every two weeks. A dose (eg, a fixed dose) of the anti-TIGIT antagonist antibody, a dose of 840 mg (eg, a fixed dose) of atezolizumab every 2 weeks, and a dose of 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every 2 weeks bevacizumab, wherein the anti-TIGIT antagonist antibody is further described below: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19 includes In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the present invention provides an anti-TIGIT antagonist antibody and Provided is the use of atezolizumab, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, wherein the medicament is administered at a dose of 840 mg every 4 weeks (e.g., a fixed dose) of an anti TIGIT antagonist antibody and a 1680 mg dose (eg, a fixed dose) of atezolizumab every 4 weeks, wherein the anti TIGIT antagonist antibody is further described in SEQ ID NO: 17 or a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

In another aspect, the invention provides an anti TIGIT antagonist antibody for use in a method of treating a subject or population of subjects having liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC); Provided is a use of atezolizumab, and bevacizumab, wherein the method comprises administering to the subject or population of subjects at least one dosing cycle of the medicament, wherein the medicament is 840 mg every 4 weeks. A dose (eg, a fixed dose) of the anti-TIGIT antagonist antibody, a 1680 mg dose (eg, a fixed dose) of atezolizumab every 4 weeks, and a 5 mg/kg, 7.5 mg/kg, or 10 mg/kg dose every 2 weeks bevacizumab, wherein the anti-TIGIT antagonist antibody is further described below: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19 includes In some cases, the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 and a VL domain having the amino acid sequence of SEQ ID NO: 19. In some cases, the anti TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19.

Dosage regimen and administration

In one aspect, the therapeutic methods and uses of the invention described herein comprise an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), a VEGF antagonist (eg, an anti-VEGF antagonist ( treatment regimens including bevacizumab), and an anti-TIGIT antagonist antibody (eg, tiragolumab) with liver cancer (eg, hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC). administering to a subject or population of subjects.

The pharmaceutical compositions described herein may be formulated for administration as described below and in Section III(K).

effective amount

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of the VEGF antagonist (eg, anti-VEGF antibody (eg, beva) described in Section III(K). shizumab))) (e.g., combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), wherein the dose is administered as a monotherapy. Can be reduced compared to standard dose of antagonist antibody Dosing of anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, and VEGF antagonist is described in section III(K).

dosing cycle

In any of the methods and uses of the invention, said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody) (eg, atezolizumab)), or the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered in one or more dosing cycles (eg, 1, 2, 3, 4, 5). , 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, ate jolizumab)), and/or the dosing cycle of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) results in loss of clinical benefit (eg, disease progression, drug resistance, death, or unacceptable toxicity). In some cases, the length of each dosing cycle is between about 14 days and 28 days (eg, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days) In some cases, the length of each dosing cycle is about 21 days. In some cases, each dosing The length of the cycle is about 14 days.In some cases, the length of each dosing cycle is about 28 days. In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as Tyra) Goluumab) is administered on about day 1 (eg, day 1±3) of each dosing cycle.For example, the anti-TIGIT antagonist antibody (eg, the anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) ) is administered intravenously at a dose of about 600 mg (eg, a fixed dose) (ie, a dose of about 600 mg every 3 weeks) on Day 1 of each 21-day cycle. The axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered on about day 1 (eg, day 1±3) of each dosing cycle. For example, the PD-1 axis The binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered intravenously at a dose of about 1200 mg (ie, at a dose of about 1200 mg every 3 weeks) on Day 1 of each 21-day cycle. In some cases, the VEGF antagonist (eg, anti-VEGF antibody (eg, Bevacizumab) mob)) is administered on about day 1 (eg, day 1 ± 3 days) of each dosing cycle. For example, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered at a dose of about 15 mg/kg on Day 1 of each 21-day cycle (ie, about 15 mg/kg every 3 weeks). dose) administered intravenously. In some cases, for example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 600 mg (eg, fixed) on Day 1 of each 21-day cycle. dose) (ie, at a dose of 600 mg every 3 weeks). In some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered on Day 1 (eg, Day 1±3) of each dosing cycle. For example, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of 1200 mg on Day 1 of each 21 day cycle (ie, 1200 every 3 weeks). mg) administered intravenously. In some cases, the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) is administered on Day 1 (eg, Day 1±3) of each dosing cycle. For example, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered at a dose of 15 mg/kg on Day 1 of each 21 day cycle (ie, a dose of 15 mg/kg every 3 weeks). ) administered intravenously.

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) )), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered on about 1 day (eg, 1 day±3 days) of each dosing cycle.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 600 mg on Day 1 of each 21-day cycle (ie, every 3 weeks). at a dose of about 600 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist (eg, atezolizumab)) is administered at a dose of about 1200 mg on Day 1 of each 21-day cycle. administered intravenously (ie, at a dose of about 1200 mg every 3 weeks), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered at about 15 mg on Day 1 of each 21-day cycle. It is administered intravenously at a dose of /kg (ie, at a dose of about 15 mg/kg every 3 weeks). In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 600 mg on Day 1 of each 21 day cycle (ie, 600 every 3 weeks). Administered intravenously (in a dose of mg), the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist (eg, atezolizumab)) is administered at a dose of 1200 mg on Day 1 of each 21-day cycle (i.e., , at a dose of 1200 mg every 3 weeks), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered at a dose of 15 mg/kg on Day 1 of each 21-day cycle. It is administered intravenously (ie, at a dose of 15 mg/kg every 3 weeks).

In other cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 420 mg (ie, every 2 weeks) on Day 1 of each 14-day cycle. at a dose of about 420 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist (eg, atezolizumab)) is administered at a dose of about 840 mg on Day 1 of each 14-day cycle. administered intravenously (ie, at a dose of about 840 mg every 2 weeks), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered at about 5 mg on Day 1 of each 14-day cycle. It is administered intravenously at a dose of /kg, 7.5 mg/kg, or 10 mg/kg (ie, at a dose of about 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every two weeks). In other cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 420 mg on Day 1 of each 14-day cycle (ie, 420 every 2 weeks). Administered intravenously (in a dose of mg), the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist (eg, atezolizumab)) is administered at a dose of 840 mg on Day 1 of each 14-day cycle (i.e., , at a dose of 840 mg every 2 weeks), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered at 5 mg/kg, 7.5 mg on Day 1 of each 14-day cycle. /kg, or at a dose of 10 mg/kg (ie, at a dose of 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every 2 weeks).

In other instances, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 840 mg on Day 1 of each 28-day cycle (ie, every 4 weeks). at a dose of about 840 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist (eg, atezolizumab)) is administered at a dose of about 1680 mg on Day 1 of each 28-day cycle. (ie, at a dose of about 1680 mg every 4 weeks), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered on days 1 and 15 of each 28-day cycle. It is administered intravenously at a dose of about 5 mg/kg, 7.5 mg/kg, or 10 mg/kg (ie, at a dose of about 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every two weeks). In other cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 840 mg on Day 1 of each 28-day cycle (ie, 840 every 4 weeks). Administered intravenously (in a dose of mg), the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist (eg, atezolizumab)) is administered at a dose of 1680 mg on Day 1 of each 28-day cycle (i.e., , at a dose of 1680 mg every 4 weeks), and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered at 5 mg/kg on days 1 and 15 of each 28-day cycle. , at a dose of 7.5 mg/kg, or 10 mg/kg (ie, at a dose of 5 mg/kg, 7.5 mg/kg, or 10 mg/kg every 2 weeks).

Dosing sequence and observation period

In some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is combined with the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) and/or prior to said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to said subject or population of subjects. In some cases, for example, after administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) and the VEGF antagonist (eg, an anti-VEGF antibody (eg, beva) shizumab)) or the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab), the method includes an interim first observation period. In some cases, for example, after administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), the VEGF antagonist (eg, an anti-VEGF antibody (eg, beva) shizumab)) is administered to said subject or population of subjects prior to said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab). In other cases, following administration of the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)), the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein) , such as tiragolumab) is administered to the subject or population of subjects prior to the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)). In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is first administered to the subject or population of subjects, and the VEGF antagonist (eg, anti-VEGF antibody) (eg, bevacizumab)) is administered to said subject or population of subjects after administration of said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), wherein said anti-TIGIT antagonist An antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tiragolumab) is administered to the subject or population of subjects after administration of the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab). In some instances In , the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is first administered to the subject or population of subjects, and the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody (eg, an anti- A TIGIT antagonist antibody, such as tyragolumab) is administered to the subject or population of subjects following administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), wherein the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab) is administered to the subject or population of subjects following administration of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab).

In some cases, the method comprises administering the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) or the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab). Further comprising a second observation period after administration. In some cases, the method comprises the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab))) , and a third observation period after administration of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody, such as tyragolumab as disclosed herein).

In some cases, the method comprises a first observation period following administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), and the VEGF antagonist (eg, anti-VEGF antibody). (eg, bevacizumab)) or a second observation period after administration of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tiragolumab as disclosed herein). In some cases, the method comprises a first observation period following administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), the VEGF antagonist (eg, an anti-VEGF antibody ( eg bevacizumab)) or a second observation period following administration of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody, such as tiragolumab as disclosed herein), and the TIGIT antagonist antibody, the PD-1 axis a third observation period following administration of the binding antagonist and said VEGF antagonist. In some cases, the first, second, and/or third observation periods are each between about 30 minutes and about 120 minutes in length (eg, between about 30 minutes and 60 minutes in length, between 60 minutes and 90 minutes in length, and / or between 90 minutes and 120 minutes in length). In instances where the first, second, and third observation periods are each about 60 minutes, the method comprises administering the PD-1 axis binding antagonist (eg, anti-PD-) during the first, second, or third observation period. L1 antagonist antibody (eg, atezolizumab)), said anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), or said VEGF antagonist (eg, anti-VEGF antibody (eg, beva) recording the subject's vital signs (eg, pulse, respiration rate, blood pressure, body temperature) at about 30 ± 10 minutes after administration of shizumab)). In cases where the first, second, and third observation periods are each about 30 minutes, the method comprises, during the first, second, or third observation period, the PD-1 axis binding antagonist (eg, anti-PD- L1 antagonist antibody (eg, atezolizumab)), said anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), or said VEGF antagonist (eg, anti-VEGF antibody (eg, beva) recording the subject's vital signs (eg, pulse, respiration rate, blood pressure, body temperature) at about 15±10 minutes after administration of shizumab)).

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is combined with the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli). zumab) or the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) to the subject or population of subjects prior to administration.

In some cases, for example, after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or the VEGF antagonist (eg, anti-VEGF) Prior to administration of the antibody (eg, bevacizumab)), the method includes an intermediate first observation period.In some cases, for example, after administration of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to said subject or population of subjects prior to said VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)). In, for example, after administration of the anti-TIGIT antagonist antibody, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is combined with the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody ( For example, atezolizumab)) is administered to said subject or population of subjects before.In some cases, said anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is first administered to said administered to a subject or population of subjects, wherein said PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to said anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist as disclosed herein) administered to the subject or population of subjects after an antibody, such as tyragolumab, wherein the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered to the PD-1 axis binding antagonist (eg, anti-PD- After administration of the L1 antagonist antibody (eg, atezolizumab) is administered to the subject or population of subjects, in some cases, the anti-TIGIT antagonist antibody (eg, the anti-TIGIT antagonist antibody as disclosed herein, such as tyragol) Luumab) is first administered to the subject or population of subjects, and the VEGF antagonist (eg, anti-V An EGF antibody (eg, bevacizumab)) is administered to the subject or population of subjects after the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), wherein the PD-1 An axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to the subject or population of subjects after administration of the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) .

In some cases, the method comprises the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) or the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab))) and a second observation period after administration of In some cases, the method comprises the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, , atezolizumab)), and a third observation period after administration of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)).

In some cases, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) or VEGF antagonist (eg, , a second observation period after administration of an anti-VEGF antibody (eg, bevacizumab)). In some cases, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) or the VEGF antagonist ( For example, a second observation period following administration of an anti-VEGF antibody (eg, bevacizumab)) and a third observation period following administration of the TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the VEGF antagonist. In some cases, the first, second, and third observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first, second, and third observation periods each have a length of about 60 minutes, the method comprises the anti-TIGIT antagonist antibody, the PD-1 during each of the first, second, or third observation period About 30 ± 10 minutes after administration of an axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab), or the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) to the subject or recording vital signs (e.g., pulse rate, respiration rate, blood pressure and temperature) of the subject population, where the first, second, and third observation periods are each about 30 minutes in length; The method comprises, during the first, second, or third observation period, the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), or the recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure and temperature) of the subject or population of subjects about 15 ± 10 minutes after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) may include

In some cases, the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) is the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) or the PD- A uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to the subject or population of subjects prior to. In some cases, for example, after administration of the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) and the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyra Prior to administration of goluumab) or the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), the method includes an interim first observation period. In some cases, for example, after administration of the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)), the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyra golumab) is administered to the subject or population of subjects prior to the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)). In other cases, for example, after administration of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)), the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, ate jolizumab)) is administered to said subject or population of subjects prior to said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab). In some cases, the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) is first administered to the subject or population of subjects, and the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, For example, tiragolumab) is administered to the subject or population of subjects after administration of the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)), and the PD-1 axis binding antagonist (eg, anti-PD-L1) The antagonist antibody (eg, atezolizumab)) is administered to the subject or population of subjects following administration of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, such as tyragolumab). In some cases, the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) is first administered to the subject or population of subjects, and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody) (eg, atezolizumab)) is administered to said subject or population of subjects after said VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)), wherein said anti TIGIT antagonist antibody (eg, an anti A TIGIT antagonist antibody, such as tiragolumab) is administered to the subject or population of subjects following administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In some cases, the method comprises the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) or the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, , a second observation period after administration of atezolizumab)). In some cases, the method comprises the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)), the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab), and a third observation period following administration of said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In some cases, the method comprises a first observation period after administration of the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)), and the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist as disclosed herein). a second observation period following administration of the antibody (eg, tiragolumab) or the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some cases, the method comprises a first observation period after administration of the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)), the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein). a second observation period following administration of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), and the TIGIT antagonist antibody, the PD-1 axis a third observation period following administration of the binding antagonist, and said VEGF antagonist. In some cases, the first, second, and third observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first, second, and third observation periods are each about 60 minutes, the method comprises the VEGF antagonist (eg, anti-VEGF antibody (eg, Beva) during the first, second, or third observation period. shizumab)), the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), or the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, ate recording the subject's vital signs (eg, pulse, respiration rate, blood pressure, body temperature) at about 30 ± 10 minutes after administration of zolizumab). In cases where the first, second, and third observation periods are each about 30 minutes, the method comprises the VEGF antagonist (eg, anti-VEGF antibody (eg, Beva) during the first, second, or third observation period. shizumab)), the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab), or the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, ate recording the subject's vital signs (eg, pulse, respiration rate, blood pressure, body temperature) at about 15±10 minutes after administration of zolizumab).

In other instances, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) are administered to the subject or administered simultaneously to a population of subjects. In some cases, for example, following administration of the anti-TIGIT antagonist antibody and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)), the method comprises an observation period.

In other instances, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab)) is administered to said subject or population of subjects simultaneously. In some cases, e.g., after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)), the method comprises a period of observation do.

In other instances, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) are administered to the subject or simultaneously administered to a population of subjects. In some cases, for example, the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) ), the method includes an observation period.

In some cases, the observation period is between about 30 minutes and about 60 minutes in length. In cases where the observation period is about 60 minutes in length, the method comprises recording vital signs (eg, pulse rate, respiration rate, blood pressure, and temperature) of the subject or population of subjects at about 30 ± 10 minutes after administration. may include In cases where the observation period is about 30 minutes in length, the method may comprise recording the subject's vital signs (e.g., pulse rate, respiration rate, blood pressure, and temperature) at about 15 ± 10 minutes after administration. can

In other instances, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as Tyra). golumab) and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) after simultaneous administration.

In some cases, the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) comprises the anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD- Administered following concurrent administration of a uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is combined with the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli). Zumab) and the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) after simultaneous administration.

In some cases, for example, the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)), the anti-TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) , and after administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)), the method includes a second observation period. In some cases, for example, the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) ), the method includes a second observation period. In some cases, the second observation period is between about 30 minutes and about 60 minutes in length. In cases where the second observation period is about 60 minutes in length, the method comprises recording the subject's vital signs (e.g., pulse rate, respiration rate, blood pressure, and temperature) at about 30 ± 10 minutes after administration. may include In cases where the second observation period is about 30 minutes in length, the method comprises recording the subject's vital signs (e.g., pulse rate, respiration rate, blood pressure, and temperature) at about 15 ± 10 minutes after administration. may include

E. Treatment methods and uses associated with urothelial cancer

urothelial cell carcinoma

Urinary tract epithelial cancer (UC) is the most common urinary tract cancer worldwide. Most cases occur in the bladder. UC can be diagnosed as a non-muscle invasive, muscle invasive, or metastatic disease, with 1 in 3 new cases diagnosed as a muscle invasive disease (cT2-T4a Nx M0 according to tumor, nodule and metastasis (TNM) classification) . Muscle invasive UC (MIUC) is a generic term for muscle invasive bladder cancer (MIBC) and muscle invasive urothelial carcinoma (UTUC). In 2018, it was estimated that there were 549,393 new bladder cancer cases and 199,922 deaths worldwide. In Europe, it is estimated that there are 197,110 new bladder cancer cases and 64,970 deaths, including 164,450 new cases and 52,930 deaths in the 28 member states of the European Union. In the United States, it is estimated that there will be 81,400 new bladder cancer cases and 17,980 deaths in 2020. The median age of patients diagnosed with UC in the United States is 73 years, the highest age at diagnosis of any tumor type.

A therapeutic approach for the treatment of MIBC is particularly urgently needed. MIBC represents about 30% of new cases of urothelial cancer. The 5-year survival rate of MIBC is 25-50% (European Urology Association EAU Guideline 2013), with little improvement over the past 30 years, in the disease area (Surveillance, Epidemiology, and End Results (SEER) program. Cancer Statistical Information: Bladder Cancer, 2020) has seen little improvement over the past 30 years due to the lack of effective new therapies. Therefore, the unmet need for improved medical intervention is high.

Methods and uses for the treatment of urothelial cancer

Disclosed herein are methods and uses for treating UC (eg, bladder cancer (eg, MIBC)) in a subject or population of subjects, comprising an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab). ) and one or more dosing cycles of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab) to the subject or population of subjects. Methods and uses comprising administering are provided. The subject is preferably a human. In some cases, the subject or population of subjects has not previously been treated for cancer immunotherapy.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or including methods and uses involving administering an anti-PD-1 antagonist antibody, such as pembrolizumab), to a subject or group of subjects in need thereof every three weeks (eg, on Day 1 of each 21-day dosing cycle) do.

The present invention provides a method of treating a subject or population of subjects having MIBC, the method comprising a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody and about 80 mg to about 80 mg every 3 weeks. administering to the subject or population of subjects at least one dosing cycle of an about 1600 mg dose (eg, a fixed dose) of a PD-1 axis binding antagonist, wherein the subject or population of subjects is subjected to platinum-based chemotherapy methods and uses that are ineligible for treatment with an agent (eg, cisplatin). In some aspects, the method comprises a 30 mg to 1200 mg dose (eg, a fixed dose) of anti-TIGIT antagonist antibody every 3 weeks and a PD-1 axis binding at a 80 mg to 1600 mg dose (eg, a fixed dose) every 3 weeks administering to the subject or population of subjects one or more dosing cycles of the antagonist, wherein the subject or population of subjects is ineligible for treatment with a platinum-based chemotherapeutic agent (eg, cisplatin).

The present invention provides methods and uses for treating a subject or population of subjects with MIBC, the method comprising: a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody and about 80 every 3 weeks administering to the subject or population of subjects one or more dosing cycles of a mg to about 1600 mg dose (eg, a fixed dose) of a PD-1 axis binding antagonist, wherein the subject or population of subjects is <60 and methods and uses, having a creatinine clearance rate of mL/min, a grade 2 or greater hearing loss, and/or a grade 2 or greater neuropathy. In some aspects, the method comprises a 30 mg to 1200 mg dose (eg, a fixed dose) of anti-TIGIT antagonist antibody every 3 weeks and a PD-1 axis binding at a 80 mg to 1600 mg dose (eg, a fixed dose) every 3 weeks administering to the subject or population of subjects one or more dosing cycles of the antagonist, wherein the subject or population of subjects has a creatinine clearance of <60 mL/min, a grade 2 or greater hearing loss, and/or a grade 2 have more than one neuropathy.

The present invention provides methods and uses for treating a subject or population of subjects with MIBC, the method comprising: a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody and about 80 every 3 weeks A method comprising administering to the subject or population of subjects one or more dosing cycles of a mg to about 1600 mg dose (eg, a fixed dose) of a PD-1 axis binding antagonist, wherein the treatment is perioperative treatment. and use. In some aspects, the method comprises a 30 mg to 1200 mg dose (eg, a fixed dose) of anti-TIGIT antagonist antibody every 3 weeks and a PD-1 axis binding at a 80 mg to 1600 mg dose (eg, a fixed dose) every 3 weeks administering to the subject or population of subjects one or more dosing cycles of the antagonist, wherein the treatment is perioperative treatment.

The present invention provides methods and uses for treating a subject or a population of subjects with operable MIBC, the method comprising: a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody and every 3 weeks methods and uses comprising administering to said subject or population of subjects one or more dosing cycles of a PD-1 axis binding antagonist at a dose (eg, a fixed dose) of about 80 mg to about 1600 mg. In some aspects, the method comprises a 30 mg to 1200 mg dose (eg, a fixed dose) of anti-TIGIT antagonist antibody every 3 weeks and a PD-1 axis binding at a 80 mg to 1600 mg dose (eg, a fixed dose) every 3 weeks administering to the subject or population of subjects one or more dosing cycles of the antagonist.

The PD-1 axis binding antagonist and anti-TIGIT antagonist antibodies may be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody may be administered sequentially (on different days) or simultaneously (on the same day or during the same treatment cycle). In some cases, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody may be administered on the same day. In some cases, the PD-1 axis binding antagonist is administered prior to the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered after the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered concurrently with the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist may be administered prior to the anti-TIGIT antagonist antibody administered on the same day. In some cases, the PD-1 axis binding antagonist may be administered after the anti-TIGIT antagonist antibody administered on the same day. In still other instances, the PD-1 axis binding antagonist is administered at the same time as the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered in a separate composition from the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered in the same composition as the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered via a separate intravenous line from any other therapeutic agent administered to the patient on the same day. The PD-1 axis binding antagonist and anti-TIGIT antagonist antibody may be administered by the same route of administration or by different routes of administration. In some cases, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, implanted, inhaled, intrathecally, intraventricularly, or intranasally. In some cases, the anti TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, implanted, inhaled, intrathecally, intraventricularly or intranasally. In some cases, the anti TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, implanted, inhaled, intrathecally, intraventricularly or intranasally. In some cases, the anti TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, implanted, inhaled, intrathecally, intraventricularly or intranasally. In some cases, there is a first observation period after administration of the PD-1 axis binding antagonist. In some cases, there is a second observation period following administration of the PD-1 axis binding antagonist. In some cases, there is a first observation period following administration of the anti-TIGIT antagonist antibody. In some cases, there is a second observation period following administration of the anti-TIGIT antagonist antibody. In some examples, the observation period is from about 30 minutes to about 60 minutes in length. In some cases, the anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist is administered intravenously or subcutaneously. In some cases, the intravenous infusion is administered over 30 ± 10 minutes and/or 60 ± 15 minutes. In one example, atezolizumab may be administered intravenously over 60 minutes; If the first infusion is allowed, all subsequent infusions may be delivered over 30 minutes. In some embodiments, the PD-1 axis binding antagonist is not administered as an intravenous push or bolus. In one example, tiragolumab may be administered intravenously over 60 minutes; If the first infusion is allowed, all subsequent infusions may be delivered over 30 minutes. In some embodiments, the anti-TIGIT antagonist antibody is not administered as an intravenous push or bolus.

In some cases, the first dosing cycle is initiated prior to surgery. In some cases, one or more dosing cycles are completed prior to surgery. In some cases, at least 1, 2, or 3 dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, or more dosing cycles) completed before surgery. In some cases, one or more dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13) , 14, 15, 16, 17, 18, 19, 20 or more dosing cycles) are initiated post-operatively. In some cases, 1 to 17 dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) , 13, 14, 15, 16, or 17 dosing cycles) are completed postoperatively. In some cases, at least one dosing cycle is initiated between about 4 to 6 weeks (eg, about 4 weeks, about 5 weeks, or about 6 weeks) post surgery. In some cases, the treatment comprises surgery. In some cases, the surgery is a cystectomy and/or axillary lymph node surgery.

In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab) results in pCR. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in relapse-free survival (RFS), such as major RFS (eg, major RFS at 12 months, 18 months, or 24 months). In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in event-free survival (EFS), such as major EFS (eg, major EFS at 12 months, 18 months, or 24 months). In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in OS, such as major OS (eg, major OS at 12 months, 18 months, or 24 months). In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) causes an increase in the pathological staging rate. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) results in an increase in pCR in a subject or population of subjects, e.g., compared to treatment with a PD-1 axis binding antagonist without said anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without said PD-1 axis binding antagonist. make it In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) is, e.g., the EFS (e.g., major EFS) of a subject or population of subjects as compared to treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. extend the In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) is, e.g., the RFS (e.g., major RFS) of a subject or population of subjects as compared to treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. extend the In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ), e.g., the OS (e.g., major OS) of a subject or population of subjects as compared to treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. extend the

The present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject or population of subjects in need thereof every 4 weeks (eg, the first of each 28-day dosing cycle). per day) and methods and uses involving administration. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered every 4 weeks (eg, on Day 1 of each 28-day dosing cycle), A PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or an anti-PD-1 antagonist antibody, such as, eg, pembrolizumab) is administered every two weeks (eg, each 28-day dosing cycle). on days 1 and 15), every 3 weeks (eg, on Day 1 of each 21-day dosing cycle), or every 4 weeks (eg, on Day 1 of each 28-day dosing cycle). In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in a CR or PR. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in pCR in a subject or population of subjects as compared to baseline PFS. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in EFS and/or RFS. In some cases, administration of an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) prolongs the OR in a subject or population of subjects.

The present invention provides an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab, or a method involving administering an anti-PD-1 antagonist antibody, such as pembrolizumab), to a subject or population of subjects in need thereof every two weeks (eg, on days 1 and 15 of each 28-day dosing cycle) and provide use. In some cases, an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as ate Zolizumab) results in pCR. In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) can be administered to a subject or population of subjects with EFS and/or RFS compared to, for example, treatment with a PD-1 axis binding antagonist without said anti-TIGIT antagonist antibody or treatment with said anti-TIGIT antagonist antibody without said PD-1 axis binding antagonist. causes an increase in In some cases, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) prolongs Os in a subject or population of subjects, e.g., as compared to treatment with a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. .

In certain instances, the present invention provides an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) to a subject or population of subjects in need thereof every two weeks (eg, each 28 on days 1 and 15 of a dosing cycle). In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in pCR. In some cases, administration of an effective amount of said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) results in an increase in EFS and/or RFS in a subject or population of subjects as compared to baseline PFS. causes In some cases, administration of an effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) prolongs the OR in a subject or population of subjects.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) ) is being treated for MIBC.

In some cases, the treatment may further comprise an additional therapy. Any suitable additional therapy known in the art or described herein may be used. The additional therapy may be radiation therapy, surgery (eg, cystectomy), gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, gamma irradiation, or a combination of the foregoing. can

In some cases, the additional therapy is a side-effect limiting agent (eg, an agent intended to reduce the incidence and/or severity of side effects of treatment, such as an anti-nausea agent, a corticosteroid (eg, prednisone or equivalent, such as 1-2 mg/ kg/day), and hormone replacement drug(s), etc.).

In any preceding example, each dosing cycle can be of any suitable length, such as about 7 days, about 14 days, about 21 days, about 28 days or more. In some cases, each dosing cycle is about 21 days.

Also disclosed herein is a method of treating MIBC in a subject or population of subjects, comprising an effective amount of a PD-1 axis binding antagonist (eg, atezolizumab) and/or an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist as disclosed herein). Methods are provided comprising administering an antibody, such as tyragolumab) in combination with another anti-cancer agent or cancer therapy. For example, a PD-1 axis binding antagonist may include additional chemotherapy or chemotherapeutic agents (see definition above); targeted therapy or targeted therapeutics; immunotherapy or immunotherapeutic agents such as monoclonal antibodies; one or more cytotoxic agents (see definition above); Or it may be administered in combination with a combination thereof.

In some cases where the patient has metastatic urothelial cancer (mUC) and the mUC has progressed during or after platinum-containing therapy, the methods provided herein can be performed after the subject or population of subjects experiences disease progression or unacceptable toxicity. and administering a second dosing regimen to the subject or population of subjects. In some cases, the second dosing regimen comprises one or more dosing cycles of the PD-1 axis binding antagonist and the antibody-drug conjugate (ADC). In some cases, the ADC is (a) enfortumab vedotin or (b) sacituzumab gobitecan.

Also disclosed herein is a method of treating a subject or population of subjects having mUC, comprising administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein: (a) the agent one dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks (eg, a fixed dose) and atezolizumab at a dose of about 1200 mg every 3 weeks (eg, a fixed dose); and (b) said second dosing regimen comprises one or more dosing cycles of atezolizumab at a dose of about 1200 mg (eg, a fixed dose) every 3 weeks, and (i) enfortumab vedotin is administered for 2 weeks. administered at a weekly dose of 1.25 mg/kg with a weekly break of one week, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg with a two-week dosing/1 week off, wherein the second dosing regimen is A method is provided, wherein the subject or population of subjects is administered to the subject or population of subjects after experiencing disease progression or unacceptable toxicity during the first dosing regimen. In some aspects, disclosed herein is a method of treating a subject or population of subjects having mUC, comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein: (a ) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a 600 mg dose (eg, a fixed dose) every 3 weeks and atezolizumab at a 1200 mg dose (eg, a fixed dose) every 3 weeks; and (b) said second dosing regimen comprises one or more dosing cycles of atezolizumab at a 1200 mg dose (eg, a fixed dose) every 3 weeks, and (i) enfortumab vedotin is administered for 2 weeks/ administered at a weekly dose of 1.25 mg/kg with a one-week break, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg with a two-week dosing/week break, wherein the second dosing regimen is A method is provided, wherein the subject or population of subjects is administered to the subject or population of subjects after experiencing disease progression or unacceptable toxicity during the first dosing regimen.

In some cases, the treatment results in an ORR in the subject population of at least about 13.4% to at least about 15% (eg, at least about 13.5%, 14%, 14.5%, or 15%).

In some embodiments, the treatment is at least about 7.9 months (eg, 8.0 months, 8.1 months, 8.2 months, 8.3 months, 8.4 months, 8.5 months, 8.6 months, 8.7 months, 8.8 months, 8.9 months, 9 months, 9.5 months months, 10 months, 11 months, 12 months, 13 months, or 14 months). In some cases, the treatment lasts for at least about 8.6 months (eg, 8.6 months, 8.7 months, 8.8 months, 8.9 months, 9 months, 9.5 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months) or 16 months) of the subject population. In some cases, the treatment results in a median OS of the subject population of about 7.9 months to about 8.6 months (eg, about 8.0 months, 8.1 months, 8.2 months, 8.3 months, 8.4 months, 8.5 months, or 8.6 months). .

In some cases, the treatment is at least about 13.4% to at least about 31% (eg, at least about 13.5%, 14%, 15%, 18%, 17%, 18%, 19%, 20%, 21%, 22 %, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or 31%) of the subject population. In some cases, the treatment is at least about 31% (eg, about 31% to about 100%, such as about 31% to about 60% (eg, 35%, 40%, 45%, 50%, 55%, or 60%) of the subject population.

In some cases, the treatment lasts for at least about 7.9 months (eg, between about 7.9 and about 36 months (eg, between about 7.9 and about 24 months (eg, 8 months, 10 months, 12 months, 14 months, 16 months, 18 months)). , 20 months, 22 months, or 24 months) in the subject population. to about 24 months (eg, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months)). , said treatment is at least about 7.9 months to about 16.3 months (eg, 8 months, 8.5 months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 12.5 months, 13 months, 13.5 months , 14 months, 14.5 months), 15 months, 15.5 months, 16 months, or 16.3 months, such as 7.9-9 months, 9-10 months, 10-11 months, 11-12 months, 12-13 months, 13- 14 months, 14-15 months, 15-16 months, or greater than 16 months).

Dosing of Anti-TIGIT Antagonist Antibodies

Dosing of anti-TIGIT antagonist antibodies is described in Section III(K).

Dosing of PD-1 axis binding antagonists

Dosing of PD-1 axis binding antagonists is described in Section III(K).

Cancer characterization and selection

In some cases, in any method, use, or composition for use described herein, the UC (eg, bladder cancer (eg, MIBC)) is surgically operable (eg, a UC suitable for cystectomy (eg, Bladder cancer (eg, MIBC) In some cases, in any of the methods, uses, or compositions for use described herein, the MIBC is surgically operable (eg, a MIBC suitable for cystectomy).

In some embodiments, in a method, use, or compositions for use described herein, the subject is ineligible for platinum-based chemotherapy (eg, eligible for cisplatin). In some cases, the subject is ineligible for cisplatin. In some cases, the subject has a creatinine clearance of less than 60 mL/min. In some cases, the subject has a creatinine clearance of at least 30 mL/min. In some cases, the subject has a hearing loss of grade 2 or greater. In some cases, the subject has grade 2 or greater neuropathy. In some cases, a subject with a creatinine clearance of less than 60 mL/min, a grade 2 or greater hearing loss, and/or a grade 2 or greater neuropathy is cisplatin ineligible. In some cases, a subject with a creatinine clearance of less than 60 mL/min is cisplatin ineligible. In some cases, subjects with a hearing loss of Grade 2 or greater are ineligible for cisplatin. In some cases, subjects with grade 2 or higher neuropathy are cisplatin ineligible. In some cases, a subject who refuses cisplatin-based chemotherapy is cisplatin ineligible. In some cases, the subject has an Eastern Corporate Oncology Group (ECOG) systemic activity (PS) of 0 or 1.

In some cases, in any method, use, or composition for use described herein, the presence or level of circulating tumor DNA (ctDNA) can be assessed. In some cases, the ctDNA is evaluated in a sample from the subject (eg, a blood sample. In some cases, the ctDNA is evaluated in a first dosing cycle (eg, a first dose of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist) in the sample from the subject before 1 day of cycle).In some cases, the ctDNA is evaluated in the sample of the subject before surgery (eg, cystectomy).In some cases, ctDNA is evaluated in the sample of the subject before surgery (eg, bladder resection). After surgery (eg, cystectomy), ctDNA is evaluated in the sample of the subject 4-6 weeks (eg, 4 weeks, 5 weeks, or 6 weeks) after surgery (eg, cystectomy) in the sample from the subject. In some cases, ctDNA is evaluated in a sample from the subject 6 months after surgery (eg, cystectomy).

Assessment of PD-L1 expression

Expression of PD-L1 can be assessed as described in section III(L).

response to treatment

In some embodiments of any of the methods described herein, the subject's response to therapy can be characterized by one or more measures. In some embodiments, the treatment results in pCR. In some embodiments, the treatment results in an increase in recurrence-free survival (RFS), event-free survival (EFS), or OS. In some embodiments, the treatment results in an increase in major RFS, major EFS, or major OS. In some embodiments, the treatment results in an increase in the rate of major pathological staging.

In some cases, the treatment increases the pCR of the subject, eg, as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. causes

In some cases, the treatment prolongs the subject's OS, eg, as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. make it In some cases, the treatment prolongs the subject's EFS, e.g., as compared to treatment with a PD-1 axis binding antagonist without an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody without a PD-1 axis binding antagonist. make it In some cases, the treatment prolongs the RFS of the subject, e.g., as compared to treatment with a PD-1 axis binding antagonist in the absence of an anti TIGIT antagonist antibody or as compared to treatment with an anti TIGIT antagonist antibody in the absence of a PD-1 axis binding antagonist. make it In some cases, the treatment is the pathological stage of the subject, eg, compared to treatment with a PD-1 axis binding antagonist without an anti TIGIT antagonist antibody or compared to treatment with an anti TIGIT antagonist antibody without a PD-1 axis binding antagonist. Increase the downward ratio.

In some embodiments, the treatment described herein lowers the subject's pCR by at least about 2 months (eg, by 2 to 120 months, by 2.5 to 100 months, by 3.0 to 80 months, by 4.0 to 60 months, by 5.0 to by 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months , 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment lowers the subject's pCR by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months) by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, treatment reduces the subject's EFS by at least about 2 months (eg, by 2 to 120 months, by 2.5 to 100 months, by 3.0 to 80 months, by 4.0 to 60 months, by 5.0 to 48 months) , by 6.0-36 months, by 8.0-24 months, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months , 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the subject's EFS by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months). by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, treatment reduces the subject's RFS by at least about 2 months (eg, by 2 to 120 months, by 2.5 to 100 months, by 3.0 to 80 months, by 4.0 to 60 months, by 5.0 to 48 months) , by 6.0-36 months, by 8.0-24 months, or by 10-12 months, such as at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months , 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment reduces the subject's RFS by at least about 4 months (eg, by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months) by 9-36 months, or by 10-24 months, such as at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months , 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, OS is measured as the period from initiation of treatment to death. In some cases, the treatment reduces the subject's OS by at least about 2 months (eg, by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months) , by 7-48 months, by 8-36 months, by 10-24 months, such as at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months , 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 Months, 20 Months, 21 Months, 22 Months, 23 Months, 24 Months, 25 Months, 26 Months, 27 Months, 28 Months, 29 Months, 30 Months, 31 Months, 32 Months, 33 Months, 34 Months, 35 Months, or by 36 months). In some cases, the treatment reduces the subject's OS by at least about 3.3 months (eg, by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months) , by 8-36 months, or by 10-24 months, such as at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months , 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, by 34 months, 35 months, or 36 months). In some cases, the treatment reduces the subject's OS by at least about 5.3 months (eg, by 5.3 to 120 months, by 6 to 60 months, by 7 to 48 months, by 8 to 36 months, or by 10 to 24 months). by, such as at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months , by 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

F. Treatment methods and uses associated with pancreatic cancer

pancreatic cancer

80% of pancreatic cancer patients present with advanced disease at initial diagnosis. Even in patients who underwent radical surgery, the disease recurs, and the 5-year survival rates of patients with nodular-negative and nodular-positive disease in pancreaticoduodenectomy are 25-30% and 10%, respectively. Patients with locally advanced and unresectable disease often receive radiochemotherapy with a median OS of 9 to 13 months, but long-term survival is rare.

Therefore, the unmet need for improved medical intervention is high.

Methods and uses for treating pancreatic cancer

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab), a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody, such as atezolizumab) , an antimetabolite (eg, gemcitabine), and a taxane (eg, paclitaxel), a subject or population of subjects receiving treatment for pancreatic cancer (eg, pancreatic ductal adenocarcinoma (PDAC), such as metastatic PDAC (mPDAC)). are receiving

The present invention provides a method of treating a subject or population of subjects having pancreatic cancer, comprising: tyragolumab at a dose of about 420 mg on days 1 and 15 of each 28-day dosing cycle, Day 1 of each 28-day dosing cycle and atezolizumab at a dose of about 840 mg on day 15, gemcitabine at a dose of about 1000 mg/m ² on days 1, 8, and 15 of each 28-day dosing cycle, and a dosing cycle of about 28 days each. A method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 28-day dosing cycles of nap-paclitaxel at a dose of about 125 mg/m ² on days 1, 8, and 15 include In some cases, the method comprises tiragolumab at a dose of 420 mg on days 1 and 15 of each 28-day dosing cycle, and atezoli at a dose of 840 mg on days 1 and 15 of each 28-day dosing cycle. Zumab, gemcitabine at a dose of 1000 mg/m ² on days 1, 8, and 15 of each 28-day dosing cycle, and drug on days 1, 8, and 15 of each 28-day dosing cycle administering to the subject or population of subjects a dosing regimen comprising one or more 28-day dosing cycles of nap-paclitaxel at a dose of 125 mg/m ² . In some cases, the pancreatic cancer is a PDAC, such as mPDAC. In some aspects, the subject or subjects have not received prior systemic therapy for metastatic breast cancer.

In some cases, the treatment comprises at least about 41.7% to at least about 46.7% (e.g., 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, or 46.7% (eg, 41.7%-43%, 43%-45%, or 45%-46.7%) of the subject population.In some cases, the treatment comprises an anti-TIGIT antagonist antibody and PD-1 Produces an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nap-paclitaxel without an axis binding antagonist In some cases, the treatment is at least about 5.5 months (e.g., between about 5.5 months and 14 months) (e.g., 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, or 14 months)). develop a median PFS of a population of subjects of at least about 7 months (eg, between about 7 months and 14 months (eg, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, or 14 months)) In some cases, the treatment is at least about 5.5 months to about 7 months (e.g., 6 months, 6.2 months, 6.4 months, 6.6 months, 6.8 months, 7 months, or greater than 7 months) of the median PFS of the subject population. In some cases, the treatment is at least about 8.5 months (eg, between about 8.5 months and 16 months (8.5 months, 9 months, 9.5 months, 10 months, 10.5 months, 11 months, 12 months, 13 months, 14 months, 15 months, or 16 months) of the subject population) In some cases, the treatment produces at least about 10.6 months (eg, between about 10.6 months and 16 months (10.6 months, 11 months, 12 months) months, 13 months, 14 months, 15 months, or 16 months)) in the subject population, in some cases, the treatment is at least about 8.5 months to about 10.6 months (eg, 8.7 months, 9.0 months). , 9.2 months, 9.4 months, 9.6 months, 9.8 months, 10 months, 10.2 months, 10.4 months, 10.6 months, 15 months, or 10.6 months).

dosing of the formulation

Dosing of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, antimetabolites, and taxanes is described in Section III(K).

G. Treatment methods and uses associated with esophageal cancer

The present invention provides a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising about 30 mg to about 1200 mg (e.g., about 550 mg to about 650 mg, e.g., 600 mg) on Day 1 of each dosing cycle. Anti TIGIT antagonist antibody at a dose of ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg). , and about 80 mg to about 1600 mg (e.g., about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as, on Day 1 of each dosing cycle, about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, administering to said subject or population of subjects a dosing regimen comprising one or more 21 day dosing cycles of, e.g., 1200 mg ± 0.05 mg, e.g., 1200 mg) of a dose (e.g., a fixed dose) of a PD-1 axis binding antagonist. A method comprising In some cases, the method comprises about 500 mg to about 700 mg (eg, about 550 mg to about 650 mg, eg, 600 mg±10 mg, eg, 600±6 mg, eg, on Day 1 of each dosing cycle) , 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg) of the anti-TIGIT antagonist antibody, and about 900 on day 1 of each dosing cycle mg to about 1500 mg (e.g., about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 mg ± 0.05 mg, such as 1200 mg ) administering to the subject or population of subjects a dosing regimen comprising at least one 21 day dosing cycle of a dose (eg, a fixed dose) of a PD-1 axis binding antagonist. In some aspects, the method comprises 500 mg to 700 mg (eg, 550 mg to 650 mg, eg, 600 mg±10 mg, eg, 600±6 mg, eg, 600±5) on Day 1 of each dosing cycle. mg, e.g., 600 ± 3 mg, e.g., 600 ± 1 mg, e.g., 600 ± 0.5 mg, e.g., 600 mg) of the anti-TIGIT antagonist antibody, and 900 mg to 1500 mg ( For example, 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg, such as, 1200 mg ± 5 mg, e.g., 1200 ± 2.5 mg, e.g., 1200 ± 1.0 mg, e.g., 1200 mg ± 0.05 mg, e.g., 1200 mg) dose (e.g., a fixed dose) of a PD-1 axis binding antagonist once administering to said subject or population of subjects a dosing regimen comprising at least a 21 day dosing cycle.

The present invention provides a method of treating a subject or population of subjects having esophageal cancer, wherein on Day 1 of each dosing cycle, from about 500 mg to about 700 mg (eg, from about 550 mg to about 650 mg, eg, 600 mg±10 mg). , eg, 600±6 mg, eg, 600±5 mg, eg, 600±3 mg, eg, 600±1 mg, eg, 600±0.5 mg, eg, 600 mg) of an anti-TIGIT antagonist antibody, and each About 900 mg to about 1500 mg (e.g., about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg, on Day 1 of the dosing cycle) to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 administering to the subject or population of subjects a dosing regimen comprising one or more 21 day dosing cycles of a dose (eg, a fixed dose) of a mg ± 0.05 mg, eg, 1200 mg, of a PD-1 axis binding antagonist, wherein the subject or the population of subjects has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. In some aspects, the method comprises 500 mg to 700 mg (eg, 550 mg to 650 mg, eg, 600 mg±10 mg, eg, 600±6 mg, eg, 600±5) on Day 1 of each dosing cycle. mg, e.g., 600 ± 3 mg, e.g., 600 ± 1 mg, e.g., 600 ± 0.5 mg, e.g., 600 mg) of the anti-TIGIT antagonist antibody, and 900 mg to 1500 mg ( For example, 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg, such as, 1200 mg ± 5 mg, e.g., 1200 ± 2.5 mg, e.g., 1200 ± 1.0 mg, e.g., 1200 mg ± 0.05 mg, e.g., 1200 mg) dose (e.g., a fixed dose) of a PD-1 axis binding antagonist once A method comprising administering to the subject or population of subjects a dosing regimen comprising at least a 21 day dosing cycle, wherein the subject or population of subjects has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. includes

In some instances, the subject or subjects have previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. In some cases, the subject or population of subjects experienced disease progression or unacceptable toxicity during a previous treatment.

In some cases, the 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. In some cases, the platinum-based chemotherapeutic agent is omitted from the dosing regimen after 6 doses.

In some cases, the platinum-based chemotherapeutic agent is cisplatin. In some cases, cisplatin is administered at a dose of about 80 mg/m ² on Day 1 of each dosing cycle. In some cases, cisplatin is administered at a dose of 80 mg/m ² on Day 1 of each dosing cycle.

In some cases, the non-platinum-based chemotherapeutic agent is an antimetabolite. In some cases, the antagonist is 5-fluorouracil. In some cases, 5-fluorouracil is administered at a dose of about 800 mg/m ² /24 hours on days 1-5 of each 21-day cycle.

In some cases, the esophageal cancer is advanced or metastatic esophageal cancer.

In some cases, the subject or subjects have not received prior treatment for metastatic esophageal cancer.

The present invention provides a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising: tyragolumab at a dose of about 600 mg (eg, a fixed dose) on Day 1 of each dosing cycle, Day 1 of each dosing cycle at a dose of about 1200 mg (eg, a fixed dose) of atezolizumab, cisplatin at a dose of about 80 mg/m ² on Day 1 of each dosing cycle, and about 800 mg on Days 1-5 of each 21-day cycle. administering to said subject or population of subjects a dosing regimen comprising at least one 21 day dosing cycle of 5-fluorouracil at a /m ² /24 hour dose, wherein cisplatin is administered in said dosing regimen after 6 doses. omitted, including the method. In some cases, the method comprises administering an about 600 mg dose (eg, a fixed dose) of tiragolumab on Day 1 of each dosing cycle, a dose of about 1200 mg (eg, a fixed dose) on Day 1 of each dosing cycle. Atezolizumab, cisplatin at a dose of about 80 mg/m ² on day 1 of each dosing cycle, and 5-fluoro at a dose of about 800 mg/m ² /24 hours on days 1-5 of each 21-day cycle administering to the subject or population of subjects a dosing regimen comprising at least one 21 day dosing cycle of uracil, wherein cisplatin is omitted from the dosing regimen after 6 doses.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is from about 10 mg to about 1000 mg (eg, about 20) every two weeks (Q2W). mg to about 1000 mg, such as about 50 mg to about 900 mg, such as about 100 mg to about 850 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 600 mg, such as about 400 mg to about 500 mg, such as about 405 mg to about 450 mg, such as about 410 mg to about 430 mg, such as about 420 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 10 mg to 1000 mg (eg, 20 mg to 1000) every two weeks (Q2W). mg, such as 50 mg to 900 mg, such as 00 mg to 850 mg, such as 200 mg to 800 mg, such as 300 mg to 600 mg, such as 400 mg to 500 mg, such as 405 mg to 450 mg, For example, a dose (eg, a fixed dose) of 410 mg to 430 mg, such as 420 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about 420 mg every 2 weeks (eg, 420 mg ± 10 mg every 2 weeks, For example, a dose of 420 ± 6 mg, such as 420 ± 5 mg, such as 420 ± 3 mg, such as 420 ± 1 mg, such as 420 ± 0.5 mg, such as 420 mg).

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 200 mg to about 2000 mg (eg, about 200 mg) every 4 weeks (Q4W). to about 1600 mg, such as about 250 mg to about 1600 mg, such as about 300 mg to about 1600 mg, such as about 400 mg to about 1500 mg, such as about 500 mg to about 1400 mg, such as about 600 mg to about 1200 mg, such as about 700 mg to about 1100 mg, such as about 800 mg to about 1000 mg, such as about 800 mg to about 900 mg, such as about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 200 mg to 2000 mg (eg, 200 mg to 1600) every 4 weeks (Q4W). mg, such as 250 mg to 1600 mg, such as 300 mg to 1600 mg, such as 400 mg to 1500 mg, such as 500 mg to 1400 mg, such as 600 mg to 1200 mg mg, such as 700 mg to 1100 mg , such as 800 mg to 1000 mg, such as 800 mg to 900 mg, such as 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, or 900 mg).

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 80 mg to about) every two weeks. 1950 mg, such as about 80 mg to about 1900 mg, such as about 80 mg to about 1800 mg, such as about 100 mg to about 1700 mg, such as about 200 mg to about 1600 mg, such as about 300 mg to about 1400 mg, such as about 400 mg to about 1300 mg, such as about 500 mg to about 1200 mg, such as about 600 mg to about 1100 mg, such as about 700 mg to about 1000 mg, such as about 740 mg to about 940 mg, such as about 790 mg to about 890 mg, such as about 815 mg to about 865 mg, such as about 830 mg to about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as, 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 4 weeks. 2000 mg, such as about 200 mg to about 2000 mg, such as about 300 mg to about 2000 mg, such as about 400 mg to about 2000 mg, such as about 500 mg to about 2000 mg, such as about 600 mg to about 1900 mg, such as about 700 mg to about 1800 mg, such as about 800 mg to about 1800 mg, such as about 900 mg to about 1800 mg, such as about 1000 mg to about 1800 mg, such as about 1100 mg to about 1800 mg, such as about 1200 mg to about 1800 mg, such as about 1300 mg to about 1800 mg, such as about 1400 mg to about 1800 mg, such as about 1500 mg to about 1800 mg, such as about 1580 mg to about 1780 mg, such as about 1630 mg to about 1730 mg, such as about 1655 mg to about 1705 mg, such as about 1670 mg to about 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as, 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 80 mg to 1950 mg, such as every two weeks) , 80 mg to 1900 mg, such as 80 mg to 1800 mg, such as 100 mg to 1700 mg, such as 200 mg to 1600 mg, such as 300 mg to 1400 mg, such as 400 mg to 1300 mg, such as 500 mg to 1200 mg, such as 600 mg to 1100 mg, such as 700 mg to 1000 mg, such as 740 mg to 940 mg, such as 790 mg to 890 mg, such as 815 mg to 865 mg, such as 830 mg to 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 100 mg to 2000 mg, such as every 4 weeks) , 200 mg to 2000 mg, such as 300 mg to 2000 mg, such as 400 mg to 2000 mg, such as 500 mg to 2000 mg, such as 600 mg to 1900 mg, such as 700 mg to 1800 mg, such as 800 mg to 1800 mg, such as 900 mg to 1800 mg, such as 1000 mg to 1800 mg, such as 1100 mg to 1800 mg, such as 1200 mg to 1800 mg, such as 1300 mg to 1800 mg, such as 1400 mg to 1800 mg, such as 1500 mg to 1800 mg, such as 1580 mg to 1780 mg, such as 1630 mg to 1730 mg, such as 1655 mg to 1705 mg, such as 1670 mg to 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks. In some cases, a PD-1 axis binding antagonist (eg, anti-PD) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody (eg, tyragolumab) disclosed herein). The dose of the -L1 antagonist antibody (eg, atezolizumab) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy.

The present invention provides a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, the method comprising administering to the subject or population a first dosage regimen and a second dosage regimen, wherein: (a) the agent One dosing regimen consisted of a dose of about 80 mg/m ² of cisplatin on Day 1 of each dosing cycle and of 5-fluorouracil at a dose of 800 mg/m ² /24 hours on Days 1-5 of each 21-day cycle. at least one 21 day dosing cycle, wherein cisplatin is omitted from said dosing regimen after 6 doses; and (b) said second dosing regimen is one or more 21 day doses of about 600 mg of tiragolumab on Day 1 of each dosing cycle and about 1200 mg of atezolizumab on Day 1 of each dosing cycle. a method comprising a cycle.

In some aspects of any of the above methods, the treatment results in an ORR of at least about 14% of a subject population (eg, at least about 14%, 15%, 16%, 17%, 18%, 19%). , 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, e.g., 14%-16%, 16%-18%, 18%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%- 70%, 70%-80%, 80%-90%, or 90%-100% ORR).

H. Diagnostic methods and uses related to cancer

The present invention relates to cancer (eg, lung cancer (eg, early stage lung cancer (eg, resectable lung cancer), SCLC (eg, ES-SCLC), NSCLC (eg, squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, stage IIIB) NSCLC, relapsed or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., the subject has not been previously treated for stage IV NSCLC) if absent)); )) or HER2-positive breast cancer); , MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; ovarian cancer; gastric cancer (eg, gastroesophageal junction cancer); or CRC ( Provided is a method of selecting a therapy for a subject having (eg, MSS or low MSI CRC)), wherein the therapy is one or more biomarkers (eg, PD) in a sample (eg, a tumor sample or a blood sample) obtained from the subject. -L1, TIGIT, activated T cells, or cytokines) are guided by a diagnostic method involving determining the presence and/or expression level/amount.

Additionally, disclosed herein is cancer (eg, early lung cancer (eg, resectable lung cancer), SCLC (eg ES-SCLC), NSCLC (eg, squamous or non-squamous NSCLC, locally advanced unresectable NSCLC, stage IIIB NSCLC, recurrent) or metastatic NSCLC (e.g., locally advanced unresectable or metastatic nonsquamous NSCLC (e.g., stage IV nonsquamous NSCLC)), or stage IV NSCLC (e.g., if the subject has not been previously treated for stage IV NSCLC)) cervical cancer (eg, stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1 positive cervical cancer); breast cancer (eg, TNBC (eg, TNBC (eg, eTNBC)); or HER2 positive breast cancer); head and neck cancer (eg SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); liver cancer (eg, HCC, such as locally advanced or metastatic HCC and/or unresectable HCC); bladder cancer (eg, MIBC, locally advanced UC or mUC); or low MSI CRC), an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as ate Methods of identifying a subject that may benefit from treatment comprising zolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab, are provided, wherein the identifying comprises a sample obtained from the subject (e.g., a tumor sample or blood sample) is guided by a diagnostic method involving determining the presence and/or expression level/amount of one or more biomarkers (eg, PD-L1, TIGIT, activated T cells, or cytokines) in the sample.

Additionally, herein disclosed herein are cancers (eg, lung cancer (eg, early stage lung cancer (eg, resectable lung cancer), SCLC (eg, ES-SCLC), NSCLC (eg, squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, IIIB) Stage NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously been treated for stage IV NSCLC) cervical cancer (e.g., stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (e.g., TNBC (e.g., early TNBC) eTNBC)) or HER2 positive breast cancer); head and neck cancer (eg SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); liver cancer (eg, HCC, such as locally advanced or metastatic HCC and/or unresectable HCC); bladder cancer ( e.g., MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; A method of assessing responsiveness to therapy for a subject having (eg, MSS or low MSI CRC) is provided, wherein additionally the therapy is administered in a sample obtained from the subject (eg, a tumor sample or a blood sample) in one or more biologics. Guided by a diagnostic method involving determining the presence and/or expression level/amount of a marker (eg, PD-L1, TIGIT, activated T cells, or cytokines).

Additionally, herein disclosed herein are cancers (eg, lung cancer (eg, early stage lung cancer (eg, resectable lung cancer), SCLC (eg, ES-SCLC), NSCLC (eg, squamous NSCLC or non-squamous NSCLC, locally advanced unresectable NSCLC, IIIB) Stage NSCLC, relapsed or metastatic NSCLC (eg, locally advanced unresectable or metastatic nonsquamous NSCLC (eg, stage IV nonsquamous NSCLC)), or stage IV NSCLC (eg, the subject has previously been treated for stage IV NSCLC) cervical cancer (e.g., stage 4B, metastatic, recurrent, or persistent cervical cancer, such as metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (e.g., TNBC (e.g., early TNBC) eTNBC)) or HER2 positive breast cancer); head and neck cancer (eg SCCHN, such as recurrent/metastatic PD-L1 positive SCCHN); liver cancer (eg, HCC, such as locally advanced or metastatic HCC and/or unresectable HCC); bladder cancer ( e.g., MIBC, locally advanced UC or mUC); esophageal cancer; pancreatic cancer (eg, PDAC, such as metastatic PDAC); kidney cancer (eg, RCC); melanoma; A method of optimizing therapy for a subject with (eg, MSS or low MSI CRC) is provided, wherein the therapy additionally comprises one or more biomarkers (eg, a tumor sample or a blood sample) in a sample obtained from the subject (eg, a tumor sample or a blood sample). , PD-L1, TIGIT, activated T cells, or cytokines) are guided by a diagnostic method involving determining the presence and/or expression level/amount.

Biomarkers for use in the methods described herein may include tumor immunobiology (eg, TEFF), lymphocyte subpopulations, T cell receptor repertoire, cytokines associated with T cell activation, and gene or gene signature analysis (eg, associated with plasma-derived cytokines). , CD274) in tissues (eg, tumor tissue) or blood (eg, whole blood), tissue (eg, tumor tissue) and/or circulating tumor DNA (mutant load, MSI and MMR) in blood (eg, tumor tissue) identified via WGS and/or NGS PD-L1 expression on germline and somatic mutations (including but not limited to defects). In some cases, the biomarker is PD-L1. In some cases, the sample is a tumor sample (eg, a formalin fixed, paraffin embedded (FFPE) tumor sample).

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount, and an effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tyragolumab as disclosed herein) and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as administering to the subject one or more dosing cycles of atezolizumab, or an anti-PD-1 antagonist antibody, such as pembrolizumab, according to any of the methods or uses described in Section III(A).

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount and administering to the subject a dose of about 700 mg to about 1000 mg (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 4 weeks and a dose of about 1400 mg to about 2000 mg (eg, a fixed dose) every 4 weeks. administering a dosing regimen comprising one or more dosing cycles of the PD-1 axis binding antagonist. In some cases, the dosing regimen is a 700 mg to 1000 mg dose (eg, a fixed dose) of the anti TIGIT antagonist antibody every 4 weeks and a 1400 mg to 2000 mg dose (eg, a fixed dose) of the PD-1 axis every 4 weeks (eg, a fixed dose) one or more dosing cycles of the binding antagonist.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount and giving the subject a dose of about 300 mg to about 600 mg every two weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody and a dose of about 600 mg to about 1200 mg every two weeks (eg, a fixed dose) administering a dosing regimen comprising one or more dosing cycles of the PD-1 axis binding antagonist of In some cases, the method administers to the subject a 300 mg to 600 mg dose (eg, a fixed dose) of an anti-TIGIT antagonist antibody every two weeks and a 600 mg to 1200 mg dose (eg, a fixed dose) of PD- every two weeks. administering a dosing regimen comprising one or more dosing cycles of the uniaxial binding antagonist.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount and giving the subject a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody, a dose of about 80 mg to about 1600 mg every 3 weeks (eg, a fixed dose) administering a dosing regimen comprising at least one dosing cycle of a PD-1 axis binding antagonist of In some cases, the method comprises a 30 mg to 1200 mg dose (eg, a fixed dose) of an anti TIGIT antagonist antibody every 3 weeks, a PD-1 axis binding at a 80 mg to 1600 mg dose (eg, a fixed dose) every 3 weeks administering to the subject a dosing regimen comprising at least one dosing cycle of the antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount and dosing to the subject comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and an anti-PD-1 antagonist antibody at a dose of about 200 mg every 3 weeks administering therapy, wherein the anti-PD-1 antagonist antibody is pembrolizumab. In some cases, the method administers to the subject a dosing regimen comprising one or more dosing cycles of an anti TIGIT antagonist antibody at a dose of 30 mg to 1200 mg every 3 weeks and an anti-PD-1 antagonist antibody at a dose of 200 mg every 3 weeks. administering, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount and administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein said pembrolizumab is administered in an amount of from about 100 mg to about 1000 mg every 6 weeks. administered in dose. In some cases, the pembrolizumab is administered at a dose of about 400 mg every 6 weeks.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount, and giving the subject a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody, a dose of about 80 mg to about 1600 mg every 3 weeks (eg, a fixed dose) of a PD-1 axis binding antagonist, and a dose (eg, a fixed dose) of about 10 mg/m ² to about 10000 mg/m ² orally twice daily every 3 weeks of a 2 week dosing/1 week washout. administering a dosing regimen comprising one or more dosing cycles of the antimetabolite. In some cases, the method administers to the subject a dose of 30 mg to 1200 mg (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks, a dose of 80 mg to 1600 mg (eg, a fixed dose) every 3 weeks. PD-1 axis binding antagonist, and 1 dose of 10 mg/m ² to 10000 mg/m ² dose (eg, fixed dose) of an antimetabolite orally twice daily for every 3 weeks of 2 weeks dosing/week rest administering a dosing regimen comprising more than one dosing cycle.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount and administering to the subject a dose of about 30 mg to about 1200 mg (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks, a dose of about 80 mg to about 1600 mg (eg, a fixed dose) every 3 weeks. administering a dosing regimen comprising one or more dosing cycles of the PD-1 axis binding antagonist, gemcitabine, and nap-paclitaxel. In some cases, the method administers to the subject a 30 mg to 1200 mg dose (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks, a PD- at a 80 mg to 1600 mg dose (eg, a fixed dose) every 3 weeks administering a dosing regimen comprising one or more dosing cycles of the uniaxial binding antagonist, gemcitabine, and nap-paclitaxel.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount, and giving the subject a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti TIGIT antagonist antibody, a dose of about 80 mg to about 1600 mg every 3 weeks (eg, a fixed dose) of a PD-1 axis binding antagonist, and administering a dosing regimen comprising one or more dosing cycles of the VEGF antagonist at a dose of about 1 mg/kg to about 35 mg/kg every 3 weeks. In some cases, the method administers to the subject a dose of 30 mg to 1200 mg (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks, a dose of 80 mg to 1600 mg (eg, a fixed dose) every 3 weeks. administering a dosing regimen comprising a PD-1 axis binding antagonist and one or more dosing cycles of a VEGF antagonist at a dose of 1 mg/kg to 35 mg/kg every 3 weeks.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount, and administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein: (a) the induction phase comprises a dose of about 30 mg to about 1200 mg every 3 weeks (eg, a fixed dose) of an anti-TIGIT antagonist antibody, a dose of about 80 mg to 1600 mg every 3 weeks (eg, a fixed dose) of a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks. comprising one or more dosing cycles; (b) said maintenance phase comprises at least one additional dosing cycle of said anti-TIGIT antagonist antibody every 3 weeks, said PD-1 axis binding antagonist every 3 weeks, and said non-platinum-based chemotherapeutic agent every 3 weeks, wherein said maintenance The phase does not include administration of said platinum-based chemotherapeutic agent. In some cases, (a) the induction phase is a 30 mg to 1200 mg dose (eg, a fixed dose) of an anti-TIGIT antagonist antibody every 3 weeks, a PD at a dose of 80 mg to 1600 mg every 3 weeks (eg, a fixed dose) - one or more dosing cycles of the axis binding antagonist, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks; (b) said maintenance phase comprises at least one additional dosing cycle of said anti-TIGIT antagonist antibody every 3 weeks, said PD-1 axis binding antagonist every 3 weeks, and said non-platinum-based chemotherapeutic agent every 3 weeks, wherein said maintenance The phase does not include administration of said platinum-based chemotherapeutic agent.

In some cases, the method comprises the presence and/or expression level of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample (eg, a tumor sample or blood sample) from the subject. /determining the amount, and administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein: (a) the induction phase comprises a dose of about 500 mg to about 700 mg every 3 weeks (eg, a fixed dose) of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks (eg, a fixed dose), a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks one or more dosing cycles of (b) the maintenance phase comprises one or more additional dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks; , wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent. In some cases, (a) the induction phase is a 500 mg to 700 mg dose (eg, a fixed dose) of an anti TIGIT antagonist antibody every 3 weeks, PD at a dose of 900 mg to 1500 mg every 3 weeks (eg, a fixed dose) - one or more dosing cycles of the axis binding antagonist, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks; (b) said maintenance phase comprises one or more additional dosing cycles of anti-TIGIT antagonist antibody at a dose of 700 mg to 1000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of 1400 mg to 2000 mg every 4 weeks, wherein said The maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent.

The presence and/or expression level/amount of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) includes, but is not limited to, protein, protein fragment, DNA, mRNA, cDNA, and/or gene copy number. It may be determined qualitatively and/or quantitatively according to any suitable criteria known in the art without limitation. In some cases, the biomarker is PD-L1. Expression of PD-L1 can be assessed as described in section III(L). In some cases, the biomarker is TIGIT. Expression of TIGIT can be assessed as described in section III(M). In some cases, the biomarker is above EGFR and/or ALK. EGFR and/or ALK abnormalities can be assessed as described in Section III(N).

In some cases, the expression level or amount of the biomarker is a detectable protein expression level of PD-L1 in a tumor sample from the subject (eg, a FFPE tumor sample). In some cases, the PD-L1 protein expression level was determined by immunohistochemical (IHC) analysis. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, a tumor sample from the subject (eg, a FFPE tumor sample) has been determined to have a detectable expression level of PD-L1. In some cases, a tumor sample from the subject (eg, a FFPE tumor sample) has been determined to have a detectable expression level of PD-L1 in tumor infiltrating immune cells. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, the expression level or amount of the biomarker is a detectable nucleic acid expression level of PD-L1 in a tumor sample (eg, FFPE tumor sample) from the subject. In some cases, the nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MassARRAY ^® technology, in-tissue. (in situ) hybridization (ISH), or a combination thereof. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, the presence and/or expression level/amount of a biomarker (eg, PD-L1, TIGIT, activated T cell, or cytokine) in a sample from the subject (eg, a tumor sample or blood sample) is anti-TIGIT selecting the subject as eligible for therapy with an antagonist antibody and a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody such as atezolizumab or an anti-PD-1 antagonist antibody such as pembrolizumab), e.g. For example, wherein the detectable expression level of PD-L1 is a biomarker for selection of an individual. In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some cases, the tissue sample is a tumor sample (eg, a FFPE tumor sample). In some examples, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combination thereof. In some cases, the tumor sample is a FFPE tumor sample.

In some cases, the method further comprises administering the therapy to the identified subject. In some cases, the therapy comprises one or more additional therapeutic agent(s) (eg, anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (eg, anti-PD-L1 antibody), VEGF antagonist, chemotherapeutic agent (eg, platinum-based) chemotherapeutic or non-platinum chemotherapeutic agent), ADC (e.g. enfortumab vedotin or sacituzumab gobitecan), or CSF (e.g. pegfilgrastim, filgrastim or sagramostim) may be included or administered in combination (separately or together).

In some cases, in any of the diagnostic methods or uses described herein, the cancer is a solid tumor and/or a locally advanced or metastatic cancer.

I. dosage

i. Dosing of Anti-TIGIT Antagonist Antibodies

As a general suggestion, a therapeutically effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tiragolumab as disclosed herein) administered to a human, whether by one or more administrations, is approximately one dose of the patient's body weight. 0.01 to about 50 mg/kg. In some embodiments, a therapeutically effective amount of an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tiragoluumab as disclosed herein) administered to a human is the weight of the patient, whether by one or more administrations. in the range of 0.01 to 50 mg/kg of

In some exemplary embodiments, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered, eg, daily, weekly, every 2 weeks, every 3 weeks, or every 4 weeks. about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about per 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg. In exemplary embodiments, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered, eg, daily, weekly, every 2 weeks, every 3 weeks, or every 4 weeks. 0.01 to 45 mg/kg, 0.01 to 40 mg/kg, 0.01 to 35 mg/kg, 0.01 to 30 mg/kg, 0.01 to 25 mg/kg, 0.01 to 20 mg/kg, 0.01 to 15 mg/kg, 0.01 to 10 mg/kg, 0.01 to 5 mg/kg, or 0.01 to 1 mg/kg.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered on about 1 day (eg, -3 days, -2 days, -1 days) of each dosing cycle. , day 1, 2, or 3).

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in a step-by-step dosing regimen (eg, dosing based on the subject's body weight (BW) or body surface area (BSA)). ) (eg, every 3 weeks). The dosing regimen may be utilized to treat subjects with relatively low body weight (eg, 40 kg or less (eg, 5 kg to 40 kg, 15 kg to 40 kg, or 5 kg to 15 kg)), and in adult data It was developed through in vivo simulation studies based on extrapolation of estimated pharmacokinetic parameters.

In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) for treating a subject having cancer is a dose in steps based on the subject's body weight. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 250 mg to about 350 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 350 mg to about 450 mg every 3 weeks (eg, about 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of about 550 mg to about 650 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks; (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or (c) greater than 40 kg, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 15 kg and no more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 250 mg to 350 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of 350 mg to 450 mg every 3 weeks (eg, 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of 550 mg to 650 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 300 mg every 3 weeks; (b) greater than 15 kg and not more than 40 kg, wherein said anti-TIGIT antagonist antibody is administered at a dose of 400 mg every 3 weeks; or (c) greater than 40 kg, wherein said anti-TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject weighing more than 40 kg (eg, 40.5 kg, 41 kg, 42 kg, 43 kg, 44 kg, 45 kg, 46 kg, 47 kg, 48 kg, 49 kg, 50 kg, 51 kg, 52 kg, 53 kg, 54 kg, 55 kg, 56 kg, 57 kg, 58 kg , 59 kg, 60 kg, 61 kg, 62 kg, 63 kg, 64 kg, 65 kg, 66 kg, 67 kg, 68 kg, 69 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 110 kg, 120 kg, 130 kg, 140 kg, 150 kg or more) every 3 weeks (Q3W) about 30 mg to about 1200 mg (eg, about 30 mg to about 1100 mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 600 mg every 3 weeks for a subject weighing more than 40 kg . In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject weighing more than 40 kg (eg, 40.5 kg, 41 kg, 42 kg, 43 kg, 44 kg, 45 kg, 46 kg, 47 kg, 48 kg, 49 kg, 50 kg, 51 kg, 52 kg, 53 kg, 54 kg, 55 kg, 56 kg, 57 kg, 58 kg , 59 kg, 60 kg, 61 kg, 62 kg, 63 kg, 64 kg, 65 kg, 66 kg, 67 kg, 68 kg, 69 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 110 kg, 120 kg, 130 kg, 140 kg, 150 kg or more) every 3 weeks (Q3W) 30 mg to 1200 mg (eg 30 mg to 1100 mg, eg 60 mg to 1000 mg) , such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as , 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg , eg 600±0.5 mg, eg 600 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg every 3 weeks for a subject weighing more than 40 kg.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject weighing more than 15 kg and no more than 40 kg (eg, 15.1 kg, 15.2 kg). , 15.3 kg, 15.4 kg, 15.5 kg, 16 kg, 17 kg, 18 kg, 19 kg, 20 kg, 21 kg, 22 kg, 23 kg, 24 kg, 25 kg, 26 kg, 27 kg, 28 kg, 29 kg, 30 kg, 31 kg, 32 kg, 33 kg, 34 kg, 35 kg, 36 kg, 37 kg, 38 kg, 39 kg, or 39.5 kg) every 3 weeks (Q3W) from about 10 mg to about 1000 mg ( For example, about 20 mg to about 1000 mg, such as about 50 mg to about 900 mg, such as about 100 mg to about 850 mg, such as about 200 mg to about 700 mg, such as about 250 mg to about 600 mg, eg, from about 300 mg to about 500 mg, such as from about 350 mg to about 450 mg, such as from about 390 mg to about 410 mg, such as about 400 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (e.g., an anti TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is about 400 mg every 3 weeks for a subject weighing more than 15 kg and no more than 40 kg ( For example, every 3 weeks 400 mg ± 10 mg, such as 400 ± 6 mg, such as 400 ± 5 mg, such as 400 ± 3 mg, such as 400 ± 1 mg, such as 400 ± 0.5 mg, such as 400 mg ) is the capacity of In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject weighing more than 15 kg and no more than 40 kg (eg, 15.1 kg, 15.2 kg). , 15.3 kg, 15.4 kg, 15.5 kg, 16 kg, 17 kg, 18 kg, 19 kg, 20 kg, 21 kg, 22 kg, 23 kg, 24 kg, 25 kg, 26 kg, 27 kg, 28 kg, 29 kg, 30 kg, 31 kg, 32 kg, 33 kg, 34 kg, 35 kg, 36 kg, 37 kg, 38 kg, 39 kg, or 39.5 kg) every 3 weeks (Q3W) 10 mg to 1000 mg (eg, 20 mg to 1000 mg, such as 50 mg to 900 mg, such as 100 mg to 850 mg, such as 200 mg to 700 mg, such as 250 mg to 600 mg, such as 300 mg to 500 mg, such as 350 mg to 450 mg, such as 390 mg to 410 mg, such as 400 mg). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 400 mg (eg, every 3 weeks) for a subject weighing more than 15 kg and not more than 40 kg. , 400 mg ± 10 mg, such as 400 ± 6 mg, such as 400 ± 5 mg, such as 400 ± 3 mg, such as 400 ± 1 mg, such as 400 ± 0.5 mg, such as 400 mg, every 3 weeks) is the capacity of

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject weighing 15 kg or less (eg, 0.5 kg, 1 kg, 1.5 kg). , 2.0 kg, 2.5 kg, 3.0 kg, 3.5 kg, 4.0 kg, 4.5 kg, 5.0 kg, 5.5 kg, 6.0 kg, 6.5 kg, 7.0 kg, 7.5 kg, 8.0 kg, 8.5 kg, 9.0 kg, 9.5 kg, 10.0 kg, 10.5 kg, 11.0 kg, 11.5 kg, 12.0 kg, 12.5 kg, 13.0 kg, 13.5 kg, 14.0 kg, 14.5 kg, or 15.0 kg) about 10 mg to about 1000 mg (e.g., about 10 mg to about 900 mg, such as about 50 mg to about 900 mg, such as about 100 mg to about 750 mg, such as about 100 mg to about 600 mg, such as about 150 mg to about 500 mg, such as about 200 mg to about 400 mg, such as about 250 mg to about 350 mg, such as about 290 mg to about 310 mg, such as about 300 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about 300 mg (eg, 3 weeks) for a subject weighing 15 kg or less. a dose of 300 mg ± 10 mg, such as 300 ± 6 mg, such as 300 ± 5 mg, such as 300 ± 3 mg, such as 300 ± 1 mg, such as 300 ± 0.5 mg, such as 300 mg, weekly to be. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject weighing 15 kg or less (eg, 0.5 kg, 1 kg, 1.5 kg). , 2.0 kg, 2.5 kg, 3.0 kg, 3.5 kg, 4.0 kg, 4.5 kg, 10 mg, 5.5 kg, 6.0 kg, 6.5 kg, 7.0 kg, 7.5 kg, 8.0 kg, 8.5 kg, 9.0 kg, 9.5 kg, 10.0 kg, 10.5 kg, 11.0 kg, 11.5 kg, 12.0 kg, 12.5 kg, 13.0 kg, 13.5 kg, 14.0 kg, 14.5 kg, or 15.0 kg) every 3 weeks (Q3W) 10 mg to 1000 mg (e.g., 10 mg to 900 mg, such as 50 mg to 900 mg, such as 100 mg to 750 mg, such as 100 mg to 600 mg, such as 150 mg to 500 mg, such as 200 mg to 400 mg, such as 250 mg to 350 mg , such as 290 mg to 310 mg, such as 300 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 300 mg every 3 weeks (eg, 3 weeks) for a subject weighing 15 kg or less. 300 mg ± 10 mg, such as 300 ± 6 mg, such as 300 ± 5 mg, such as 300 ± 3 mg, such as 300 ± 1 mg, such as 300 ± 0.5 mg, such as 300 mg) .

In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) for treating a subject having cancer is a dose in steps based on the subject's body surface area. In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 350 mg every 3 weeks); (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 250 mg to about 350 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg to about 400 mg every 3 weeks (eg, about 350 mg every 3 weeks); or (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg to about 500 mg every 3 weeks (eg, about 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein the anti TIGIT antagonist antibody is administered at a dose of about 550 mg to about 650 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks; (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or (c) greater than 0.75 m2 and less than or equal to 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 450 mg every 3 weeks; or (d) greater than 1.25 m 2 , wherein said anti TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks. In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) for treating a subject having cancer is a dose in steps based on the subject's body surface area. In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 350 mg every 3 weeks); (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein the anti TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 250 mg to 350 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 300 mg to 400 mg every 3 weeks (eg, 350 mg every 3 weeks); (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of 400 mg to 500 mg every 3 weeks (eg, 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein said anti TIGIT antagonist antibody is administered at a dose of 550 mg to 650 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of 300 mg every 3 weeks; (b) greater than 0.5 m ² and not more than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 400 mg every 3 weeks; or (c) greater than 0.75 m2 and less than or equal to 1.25 m2, wherein said anti-TIGIT antagonist antibody is administered at a dose of 450 mg every 3 weeks; or (d) greater than 1.25 m 2 , wherein said anti TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject with a body surface area greater than 1.25 m ² (eg, 1.25 m ² , 1.35 m ² , 1.45 m ² , 1.50 m ² , 1.55 m ² , 1.60 m ² , 1.65 m ² , 1.70 m ² , 1.75 m ² , 1.80 m ² , 1.85 m ² , 1.90 m ² , 1.95 m ² , 2.0 m ² , 2.1 m ² , 2.2 m ² , 2.3 m ² , 2.4 m ² , 2.5 m ² , 2.6 m ² , 2.7 m ² , 2.8 m ² , 2.9 m ² , 3.0 m ² or more every 3 weeks (Q3W) ) about 30 mg to about 1200 mg (e.g., about 30 mg to about 1100 mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as , about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as , from about 550 mg to about 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is about 600 mg every 3 weeks for a subject with a body surface area greater than 1.25 m ² is the capacity. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject with a body surface area greater than 1.25 m ² (eg, 1.25 m ² , 1.35 m ² , 1.45 m ² , 1.50 m ² , 1.55 m ² , 1.60 m ² , 1.65 m ² , 1.70 m ² , 1.75 m ² , 1.80 m ² , 1.85 m ² , 1.90 m ² , 1.95 m ² , 2.0 m ² , 2.1 m ² , 2.2 m ² , 2.3 m ² , 2.4 m ² , 2.5 m ² , 2.6 m ² , 2.7 m ² , 2.8 m ² , 2.9 m ² , 3.0 m ² or more every 3 weeks (Q3W) ) 30 mg to 1200 mg (eg 30 mg to 1100 mg, such as 60 mg to 1000 mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg every 3 weeks for a subject with a body surface area greater than 1.25 m ² to be.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject having a body surface area greater than 0.75 m ² and less than or equal to 1.25 m ² (eg, 0.76 m 2 ). ² , 0.77 m ² , 0.78 m ² , 0.79 m ² , 0.80 m ² , 0.82 m ² , 0.84 m ² , 0.86 m ² , 0.88 m ² , 0.90 m ² , 0.95 m ² , 1.0 m ² , 1.05 m ² , 1.10 m ² , 1.15 m ² , 1.20 m ² , or 1.25 m ² ) every 3 weeks (Q3W) about 10 mg to 1000 mg (eg, about 20 mg to about 1000 mg, such as about 50 mg to about 900 mg, For example, about 100 mg to about 850 mg, such as about 200 mg to about 700 mg, such as about 250 mg to about 600 mg, such as about 300 mg to about 500 mg, such as about 400 mg to about 500 mg, eg, from about 440 mg to about 460 mg, such as about 450 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about every 3 weeks for a subject having a body surface area greater than 0.75 m ² and less than or equal to 1.25 m ² . 450 mg (e.g., every 3 weeks 450 mg ± 10 mg, such as 450 ± 6 mg, such as 450 ± 5 mg, such as 450 ± 3 mg, such as 450 ± 1 mg, such as 450 ± 0.5 mg, such as , 450 mg).

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is for a subject having a body surface area greater than 0.5 m ² and no greater than 0.75 m ² (eg, 0.51 m 2 ). ² , 0.52 m ² , 0.53 m ² , 0.54 m ² , 0.55 m ² , 0.56 m ² , 0.57 m ² , 0.58 m ² , 0.59 m ² , 0.60 m ² , 0.61 m ² , 0.62 m ² , 0.63 m ² , 0.64 m ² , 0.65 m ² , 0.66 m ² , 0.67 m ² , 0.68 m ² , 0.69 m ² , 0.70 m ² , 0.71 m ² , 0.72 m ² , 0.73 m ² , 0.74 m ² , or 0.75 m ² ) 3 weekly (Q3W) about 10 mg to 1000 mg (eg, about 20 mg to about 1000 mg, such as about 50 mg to about 900 mg, such as about 100 mg to about 850 mg, such as about 200 mg to about 700 mg, such as about 250 mg to about 600 mg, such as about 300 mg to about 500 mg, such as about 300 mg to about 400 mg, such as about 340 mg to about 360 mg, such as about 350 mg). to be. In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about every 3 weeks for a subject with a body surface area greater than 0.5 m ² and no greater than 0.75 m ² . 350 mg (eg, every 3 weeks 350 mg ± 10 mg, such as 350 ± 6 mg, such as 350 ± 5 mg, such as 350 ± 3 mg, such as 350 ± 1 mg, such as 350 ± 0.5 mg, such as , 350 mg).

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) has a body surface area of 0.5 m ² or less (eg, 0.02 m ² , 0.04 m ² , 0.06 ). m ² , 0.08 m ² , 0.1 m ² , 0.15 m ² , 0.20 m ² , 0.25 m ² , 0.30 m ² , 0.35 m ² , 0.40 m ² , 0.45 m ² , or 0.50 m ² ) about 10 mg to about 1000 mg (e.g., about 10 mg to about 900 mg, such as about 50 mg to about 900 mg, such as about 100 mg to about 750 mg, such as about 100 mg to about 600 mg, such as about 150 mg to about 500 mg, such as about 200 mg to about 400 mg, such as about 250 mg to about 350 mg, such as about 290 mg to about 310 mg, such as about 300 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about 300 mg (eg, every 3 weeks) for a subject having a body surface area of 0.5 m ² or less. , 300 mg ± 10 mg, such as 300 ± 6 mg, such as 300 ± 5 mg, such as 300 ± 3 mg, such as 300 ± 1 mg, such as 300 ± 0.5 mg, such as 300 mg, every 3 weeks) is the capacity of

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is from about 10 mg to about 1000 mg (eg, about 20) every two weeks (Q2W). mg to about 1000 mg, such as about 50 mg to about 900 mg, such as about 100 mg to about 850 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 600 mg, such as about 400 mg to about 500 mg, such as about 405 mg to about 450 mg, such as about 410 mg to about 430 mg, such as about 420 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about 420 mg every 2 weeks (eg, 420 mg ± 10 mg every 2 weeks, For example, a dose of 420 ± 6 mg, such as 420 ± 5 mg, such as 420 ± 3 mg, such as 420 ± 1 mg, such as 420 ± 0.5 mg, such as 420 mg). In some cases, the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of about 300 mg to about 600 mg every two weeks. In some cases, the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of 300 mg to 600 mg every two weeks. In some cases, the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of about 420 mg every two weeks. In some cases, the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of 420 mg every two weeks. In some cases, the dose of the anti-TIGIT antagonist antibody is a fixed dose.

In some embodiments, an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is from about 30 mg to about 1200 mg (eg, from about 30 mg to about) every 3 weeks (Q3W). 1100 mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is a dose of about 600 mg every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 200 mg to about 2000 mg (eg, about 200 mg) every 3 weeks (Q3W). to about 2000 mg, such as about 400 mg to about 1900 mg, such as about 500 mg to about 1800 mg, such as about 600 mg to about 1700 mg, such as about 700 mg to about 1400 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg, such as 1200 mg ± 10 mg, such as 1200 ± 6 mg, such as 1200 ± 5 mg, eg, 1200±3 mg, eg, 1200±1 mg, eg, 1200±0.5 mg, eg, 1200 mg) (eg, a fixed dose). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 1200 mg every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 1200 mg every 3 weeks.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 200 mg to about 2000 mg (eg, from about 200 to about 2000 mg every 4 weeks (Q4W) 300 mg, about 300-400 mg, about 400-500 mg, about 500-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg, about 900-1000 mg, about 1000-1100 mg , about 1100 to 1200 mg, about 1200 to 1300 mg, about 1300 to 1400 mg, about 1400 to 1500 mg, about 1500 to 1600 mg, about 1600 to 1700 mg, about 1700 to 1800 mg, about 1800 to 1900 mg, or about 1900-2000 mg, such as about 200 mg to about 1600 mg, such as about 250 mg to about 1600 mg, such as about 300 mg to about 1600 mg, such as about 400 mg to about 1500 mg, such as about 500 mg to about 1400 mg, such as about 600 mg to about 1200 mg, such as about 700 mg to about 1100 mg, such as about 800 mg to about 1000 mg, such as about 800 mg to about 900 mg, such as about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg, such as about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890, or about 900 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 700 mg to about 1000 mg every 4 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is 700 mg to 1000 mg every 4 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is about 840 mg every 4 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is 840 mg every 4 weeks. The 840 mg Q4W dosing regimen is supported by the results of PK modeling and simulation and exposure safety analysis. Briefly, the mean concentrations after the 840 mg Q4W dosing regimen are similar to those of the 600 mg every 3 weeks dosing regimen evaluated in previous studies. The Cmax of the 840 mg Q4W dosing regimen was simulated to be 28% higher at steady state compared to the Cmax of the 600 mg dosing regimen every 3 weeks, but falls within the observed exposure range of the highest dosing dose in the hospital (1200 mg every 3 weeks). . A preliminary analysis of the tiragoluumab exposure-safety relationship based on previous observations (a dose of 2-1200 mg tiragoluumab administered as monotherapy every 3 weeks or in combination with atezolizumab 1200 mg every 3 weeks) was suggesting that golumab exhibits a uniform exposure-safety relationship. In summary, the 840 mg Q4W dosing regimen was similar in safety and efficacy to the 600 mg every 3 weeks dosing regimen given that the predicted exposure was within the observed effective exposure range and that tiragoluumab exhibited a uniform exposure-safety relationship. can provide

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is about 840 mg every 4 weeks (eg, 840 mg ± 10 mg every 4 weeks, For example, a dose of 840 ± 6 mg, such as 840 ± 5 mg, such as 840 ± 3 mg, such as 840 ± 1 mg, such as 840 ± 0.5 mg, such as 840 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 200 mg to about 2000 mg (eg, from about 200 mg to about 2000) every 4 weeks. mg, such as about 400 mg to about 1900 mg, such as about 500 mg to about 1800 mg, such as about 600 mg to about 1700 mg, such as about 700 mg to about 1400 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg (eg, 200 mg to 2000 mg mg, such as 400 mg to 1900 mg, such as 500 mg to 1800 mg, such as 600 mg to 1700 mg, such as 700 mg to 1400 mg, such as 800 mg to 1600 mg, 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg , such as 1150 mg to 1250 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg), such as about 1200 mg, such as 1200 mg ± 10 mg, such as 1200 ± 6 mg, such as 1200 ± 5 mg, such as 1200 ± 3 mg, such as 1200 ± 3 mg, such as 1200 ± 1 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 1200 mg every 4 weeks.

In some cases, combination therapy (eg, combination therapy with a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab))) The dose of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tiragolumab as disclosed herein) administered as a monotherapy may be reduced compared to a standard dose of the anti-TIGIT antagonist antibody administered as monotherapy.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered intravenously. Alternatively, in some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered subcutaneously. In some cases, tiragolumab is administered to the patient intravenously at a dose of about 420 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1200 mg every 4 weeks. In some cases, tiragolumab is administered to the patient intravenously at a dose of 420 mg every 2 weeks, 1200 mg every 3 weeks, or 1200 mg every 4 weeks.

In some cases, the subject administers a total of 1 to 20 doses of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, tiragolumab), eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses is administered In some cases, the subject has a total of 1 to 50 doses, such as 1 to 50 doses, 1 to 45 doses, of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, tiragolumab). dose, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 20 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 doses to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses Dose, 4 to 10 doses, 4 to 5 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 50 doses, 15 to 45 doses, 15 40 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 50 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 50 doses, 25 doses to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 30 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 50 doses, 40 to 45 doses, or 45 to 50 doses are administered. In certain instances, the dose may be administered intravenously.

ii. Dosing of PD-1 axis binding antagonists

As a general suggestion, a therapeutically effective amount of a PD-1 axis binding antagonist antibody (eg, atezolizumab) administered to a human is in the range of about 0.01 to about 50 mg/kg of body weight of the patient by one or more administrations. would.

In some exemplary embodiments, the PD-1 axis binding antagonist antibody is, for example, from about 0.01 to about 45 mg/kg, from about 0.01 to about every day, weekly, every 2 weeks, every 3 weeks, or every 4 weeks. 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, It is administered at a dose of about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg. In some exemplary embodiments, the PD-1 axis binding antagonist antibody is, for example, 0.01 to 45 mg/kg, 0.01 to 40 mg/kg every day, weekly, every 2 weeks, every 3 weeks, or every 4 weeks. , 0.01 to 35 mg/kg, 0.01 to 30 mg/kg, 0.01 to 25 mg/kg, 0.01 to 20 mg/kg, 0.01 to 15 mg/kg, 0.01 to 10 mg/kg, 0.01 to 5 mg/kg, or 0.01 to 1 mg/kg.

In some cases, the PD-1 axis binding antagonist antibody is administered on about day 1 (eg, day -3, day -2, day -1, day 1, day 2, or day 3) of a dosing cycle.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered every two weeks ( Q2W) about 20 mg to about 1600 mg (e.g., about 40 mg to about 1500 mg, such as about 200 mg to about 1400 mg, such as about 300 mg to about 1400 mg, such as about 400 mg to about 1400 mg, For example, about 500 mg to about 1300 mg, such as about 600 mg to about 1200 mg, such as about 700 mg to about 1100 mg, such as about 800 mg to about 1000 mg, such as about 800 mg to about 900 mg, For example, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg) For example, fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered every two weeks ( Q2W) 20 mg to 1600 mg (eg 40 mg to 1500 mg, such as 200 mg to 1400 mg, such as 300 mg to 1400 mg, such as 400 mg to 1400 mg, such as 500 mg to 1300 mg, such as, 600 mg to 1200 mg, such as 700 mg to 1100 mg, such as 800 mg to 1000 mg, such as 800 mg to 900 mg, such as 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, or 900 mg) (eg, a fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is about every two weeks. A dose of 840 mg (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, every two weeks , eg, 840 mg). In some cases, the effective amount of atezolizumab is a dose of about 840 mg every two weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, pembrolizumab) or an anti-PD-1 antagonist antibody (eg, atezolizumab)) is about 0.01 mg/kg to about 50 mg/kg (eg, about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg, of the subject's body weight) kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 5 mg/kg to about 15 mg/kg, For example, about 7.5 mg/kg to about 12.5 mg/kg, such as about 10 ± 2 mg/kg, about 10 ± 1 mg/kg, about 10 ± 0.5 mg/kg, about 10 ± 0.2 mg/kg, or about 10 ± 0.1 mg/kg, such as about 10 mg/kg). In some cases, an effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, pembrolizumab) or an anti-PD-1 antagonist antibody (eg, atezolizumab)) is administered to the subject every two weeks. about 0.01 mg/kg to about 10 mg/kg of body weight (eg, about 0.1 mg/kg to about 10 mg/kg, such as about 0.5 mg/kg to about 10 mg/kg, such as about 1 mg/kg to about 10 mg/kg, such as about 2.5 mg/kg to about 10 mg/kg, such as about 5 mg/kg to about 10 mg/kg, such as about 7.5 mg/kg to about 10 mg/kg, such as , about 8 mg/kg to about 10 mg/kg, such as about 9 mg/kg to about 10 mg/kg, such as about 9.5 mg/kg to about 10 mg/kg, such as about 10 ± 1 mg/kg , such as about 10 ± 0.5 mg/kg, such as about 10 ± 0.2 mg/kg, such as about 10 ± 0.1 mg/kg, such as about 10 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, pembrolizumab) or an anti-PD-1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 50 mg/kg (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, per body weight of the subject; For example, 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 5 mg/kg to 15 mg/kg, such as 7.5 mg/kg to 12.5 mg/kg, such as, 10 ± 2 mg/kg, 10 ± 1 mg/kg, 10 ± 0.5 mg/kg, 10 ± 0.2 mg/kg, or 10 ± 0.1 mg/kg, such as 10 mg/kg). In some embodiments, an effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, pembrolizumab) or an anti-PD-1 antagonist antibody (eg, atezolizumab)) is administered to the subject every two weeks. 0.01 mg/kg to 10 mg/kg of body weight (eg, 0.1 mg/kg to 10 mg/kg, such as 0.5 mg/kg to 10 mg/kg, such as 1 mg/kg to 10 mg/kg, such as , 2.5 mg/kg to 10 mg/kg, such as 5 mg/kg to 10 mg/kg, such as 7.5 mg/kg to 10 mg/kg, such as 8 mg/kg to 10 mg/kg, such as 9 mg/kg to 10 mg/kg, such as 9.5 mg/kg to 10 mg/kg, such as 10 ± 1 mg/kg, such as 10 ± 0.5 mg/kg, such as 10 ± 0.2 mg/kg, such as, 10 ± 0.1 mg/kg, such as 10 mg/kg). In some cases, the effective amount of pembrolizumab is a dose of about 10 mg/kg every two weeks. In some cases, the effective amount of pembrolizumab is a dose of 10 mg/kg every two weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) for treating a subject having cancer is about 0.01 per body weight of the subject every 3 weeks mg/kg to about 50 mg/kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg , eg, about 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 0.01 mg/kg to about 15 mg/kg of the subject's body weight every 3 weeks. (e.g., about 0.1 mg/kg to about 15 mg/kg, such as about 0.5 mg/kg to about 15 mg/kg, such as about 1 mg/kg to about 15 mg/kg, such as about 2.5 mg/kg to about 15 mg/kg, such as about 5 mg/kg to about 15 mg/kg, such as about 7.5 mg/kg to about 15 mg/kg, such as about 10 mg/kg to about 15 mg/kg, such as , about 12.5 mg/kg to about 15 mg/kg, such as about 14 mg/kg to about 15 mg/kg, such as about 15 ± 1 mg/kg, such as about 15 ± 0.5 mg/kg, such as about 15 ± 0.2 mg/kg, such as about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) for treating a subject having cancer is 0.01 mg per body weight of the subject every 3 weeks /kg to 50 mg/kg (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg , 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some embodiments, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 0.01 mg/kg to 15 mg/kg (eg, from 0.01 mg/kg to 15 mg/kg of body weight of the subject every 3 weeks) , 0.1 mg/kg to 15 mg/kg, such as 0.5 mg/kg to 15 mg/kg, such as 1 mg/kg to 15 mg/kg, such as 2.5 mg/kg to 15 mg/kg, such as 5 mg/kg to 15 mg/kg, such as 7.5 mg/kg to 15 mg/kg, such as 10 mg/kg to 15 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 14 mg/kg kg to 15 mg/kg, such as 15 ± 1 mg/kg, such as 15 ± 0.5 mg/kg, such as 15 ± 0.2 mg/kg, such as 15 ± 0.1 mg/kg, such as 15 mg/kg) is the capacity of In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 15 mg/kg administered every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is about 15 mg/administered every 3 weeks with a maximum dose of 1200 mg every 3 weeks. capacity in kg. In some cases, a PD-1 axis binding antagonist (eg, anti-PD-) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of the L1 antagonist antibody (eg, atezolizumab) may be reduced compared to a standard dose of the PD-1 axis binding antagonist administered as monotherapy. In some embodiments, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a maximum dose of 1200 mg every 3 weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered every 3 weeks ( Q3W) about 80 mg to about 2000 mg (e.g., about 100 mg to about 1600 mg, such as about 200 mg to about 1600 mg, such as about 300 mg to about 1600 mg, such as about 400 mg to about 1600 mg, For example, about 500 mg to about 1600 mg, such as about 600 mg to about 1600 mg, such as about 700 mg to about 1600 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, For example, about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, For example, a dose of about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is about every 3 weeks. A dose of 1200 mg (e.g., 1200 mg ± 10 mg, e.g., 1200 ± 6 mg, e.g., 1200 ± 5 mg, e.g., 1200 ± 3 mg, e.g., 1200 ± 1 mg, e.g., 1200 ± 0.5 mg, every 3 weeks) , eg, 1200 mg). In some cases, the effective amount of atezolizumab is a dose of about 1200 mg every 3 weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered every 3 weeks ( Q3W) about 10 mg to about 800 mg (e.g., about 10 mg to about 800 mg, such as about 20 mg to about 700 mg, such as about 50 mg to about 600 mg, such as about 75 mg to about 500 mg, For example, about 100 mg to about 400 mg, such as about 100 mg to about 300 mg, such as about 125 mg to about 275 mg, such as about 150 mg to about 250 mg, such as about 175 mg to about 225 mg, For example, from about 190 mg to about 210 mg, such as about 200 mg ± 10 mg, such as 200 mg ± 7.5 mg, such as 200 mg ± 5 mg, such as 200 ± 2.5, such as 200 ± 1.0 mg, such as, 200 ± 0.5 mg, such as 200 mg) (eg, a fixed dose). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is about every 3 weeks. A dose of 200 mg (e.g., 200 mg ± 10 mg, e.g., 200 ± 6 mg, e.g., 200 ± 5 mg, e.g., 200 ± 3 mg, e.g., 200 ± 1 mg, e.g., 200 ± 0.5 mg, every 3 weeks) , eg 200 mg). In some cases, the effective amount of the anti-PD-L1 antagonist antibody (eg, pembrolizumab) is a dose of about 200 mg every 3 weeks (eg, 200 mg ± 10 mg, eg, 200 ± 6 mg, every 3 weeks, such as , 200 ± 5 mg, such as 200 ± 3 mg, such as 200 ± 1 mg, such as 200 ± 0.5 mg, such as 200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered every 3 weeks ( Q3W) 10 mg to 800 mg (eg, 10 mg to 800 mg, such as 20 mg to 700 mg, such as 50 mg to 600 mg, such as 75 mg to 500 mg, such as 100 mg to 400 mg, such as, 100 mg to 300 mg, such as 125 mg to 275 mg, such as 150 mg to 250 mg, such as 175 mg to 225 mg, such as 190 mg to 210 mg, such as 200 mg ± 10 mg, such as 200 mg A dose (eg, a fixed dose) of ± 7.5 mg, such as 200 mg ± 5 mg, such as 200 ± 2.5 , such as 200 ± 1.0 mg, such as 200 ± 0.5 mg, such as 200 mg. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is 200 every 3 weeks. a dose of mg (e.g., 200 mg ± 10 mg, e.g., 200 ± 6 mg, e.g., 200 ± 5 mg, e.g., 200 ± 3 mg, e.g., 200 ± 1 mg, e.g., 200 ± 0.5 mg, every 3 weeks; eg 200 mg). In some cases, the effective amount of the anti-PD-L1 antagonist antibody (eg, pembrolizumab) is a dose of 200 mg every 3 weeks (eg, 200 mg±10 mg every 3 weeks, eg 200±6 mg, eg, 200 ± 5 mg, such as 200 ± 3 mg, such as 200 ± 1 mg, such as 200 ± 0.5 mg, such as 200 mg). In some cases, the effective amount of pembrolizumab is a dose of about 200 mg every 3 weeks. In some cases, the effective amount of pembrolizumab is a dose of about 200 mg every 3 weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered every 4 weeks ( Q4W) about 80 mg to about 3000 mg (eg, about 80-200 mg, about 200-400 mg, about 400-600 mg, about 600-800 mg, about 800-1000 mg, about 1000-1200 mg, about 1200) ~1400 mg, about 1400-1600 mg, about 1600-1800 mg, about 1800-2000 mg, about 2200-2400 mg, about 2400-2600 mg, about 2600-2800 mg, or about 2800-3000 mg, such as about 100 mg to about 3000 mg, such as about 200 mg to about 2900 mg, such as about 500 mg to about 2800 mg, such as about 600 mg to about 2700 mg, such as about 650 mg to about 2600 mg, such as about 700 mg to about 2500 mg, such as about 1000 mg to about 2400 mg, such as about 1100 mg to about 2300 mg, such as about 1200 mg to about 2200 mg, such as about 1300 mg to about 2100 mg, such as about 1400 mg to about 2000 mg, such as about 1500 mg to about 1900 mg, such as about 1600 mg to about 1800 mg, such as about 1620 mg to about 1700 mg, such as about 1640 mg to about 1690 mg, such as about 1660 mg to about 1680 mg, about 1680 mg, such as about 80 mg, about 200 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2200 mg, about 2400 mg, about 2600 mg, about 2800 mg, or about 3000 mg, such as about 1600 mg, about 1610 mg, about 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, or about 1700 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) or anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered every 4 weeks. (Q4W) 500 mg to 3000 mg (such as 500 mg to 2800 mg, such as 600 mg to 2700 mg, such as 650 mg to 2600 mg, such as 700 mg to 2500 mg, such as 1000 mg to 2400 mg, such as 1100 mg to 2300 mg, such as 1200 mg to 2200 mg, such as 1300 mg to 2100 mg, such as 1400 mg to 2000 mg, such as 1500 mg to 1900 mg, such as 1600 mg to 1800 mg, such as 1620 mg to 1700 mg, such as 1640 mg to 1690 mg, such as 1660 mg to 1680 mg, 1680 mg, such as 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, 1660 mg, 1670 mg, 1680 mg, 1690 mg, or 1700 mg ) is the capacity of In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is 1680 every 4 weeks. a dose of mg (e.g., 1680 mg ± 10 mg, e.g., 1680 ± 6 mg, e.g., 1680 ± 5 mg, e.g., 1680 ± 3 mg, e.g., 1680 ± 1 mg, e.g., 1680 ± 0.5 mg, every 4 weeks; eg 1680 mg). In some cases, the effective amount of atezolizumab is a dose of about 1680 mg every 4 weeks. In some cases, the effective amount of atezolizumab is a dose of 1680 mg every 4 weeks.

In some cases, an effective amount of an anti-PD-1 antagonist antibody (eg, pembrolizumab) is about 50 mg to about 2000 mg (eg, about 50-100 mg, about 100-250 mg, about every 6 weeks (Q6W) 250-500 mg, about 500-750 mg, about 750-1000 mg, about 1000-1250 mg, about 1250-1500 mg, about 1500-1750 mg, or about 1750-2000 mg, such as about 100 mg to about 1000 mg, about 120 mg to about 900 mg, about 150 mg to about 800 mg, about 200 mg to about 700 mg, about 250 mg to about 600 mg, about 300 mg to about 500 mg, or about 350 mg to about 450 mg , e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg , about 600 mg to about 700 mg, about 700 mg to about 800 mg, or about 800 mg to about 1000 mg, such as about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg, or about 2000 mg, such as about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg , or about 500 mg, such as 400 mg). In some cases, an effective amount of an anti-PD-1 antagonist antibody (eg, pembrolizumab) is 50 mg to 2000 mg (eg, 100 mg to 1000 mg, 120 mg to 900 mg, 150 mg to 800 mg) every 6 weeks (Q6W). mg, 200 mg to 700 mg, 250 mg to 600 mg, 300 mg to 500 mg, or 350 mg to 450 mg, such as 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, or 800 mg to 1000 mg, such as 300 mg, 310 mg, 320 mg, 330 mg, 340 mg , 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg, eg 400 mg). In some cases, the effective amount of the anti-PD-L1 antagonist antibody (eg, pembrolizumab) is a dose of about 400 mg every 6 weeks (eg, 400 mg ± 10 mg, eg, 400 ± 6 mg, every 6 weeks, such as , 400 ± 5 mg, such as 400 ± 3 mg, such as 400 ± 1 mg, such as 400 ± 0.5 mg, such as 400 mg). In some cases, the dose of the PD-1 axis binding antagonist is a fixed dose. In some cases, an effective amount of pembrolizumab is a dose (eg, a fixed dose) of about 400 mg every 6 weeks. In some cases, the effective amount of pembrolizumab is a dose of 400 mg (eg, a fixed dose) every 6 weeks.

In some cases, a PD-1 axis binding antagonist (eg, anti-PD-) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab). The dose of an L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) may be reduced compared to a standard dose of a PD-1 axis binding antagonist administered as monotherapy.

In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered intravenously. Alternatively, in some embodiments, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is administered subcutaneously. is administered In some cases, atezolizumab is administered to the patient intravenously at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks. In some cases, atezolizumab is administered to the patient intravenously at a dose of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.

In some cases, the subject receives a total of 1 to 20 doses of the PD-1 axis binding antagonist, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses are administered. In some cases, the subject has a total of 1 to 50 doses of the PD-1 axis binding antagonist, such as 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses of the PD-1 axis binding antagonist. , 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 From 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 doses to 10 doses, 2 to 5 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses Dose, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses dose, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 25 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 doses to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 30 to 30 doses, 30 to 30 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 50 doses, 35 to 45 doses, 35 doses 40 to 40 doses, 40 to 50 doses, 40 to 45 doses, or 45 to 50 doses are administered. In certain instances, the dose may be administered intravenously.

i. Effective dose of anti-TIGIT antagonist antibody and PD-1 axis binding antagonist

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 30 mg to about 600 mg (eg, from about 50 mg to about 600) every two weeks. mg, such as about 60 mg to about 600 mg, such as about 100 mg to about 600 mg, such as about 200 mg to about 600 mg, such as about 200 mg to about 550 mg, such as about 250 mg to about 600 mg, such as about 300 mg to about 500 mg, such as about 350 mg to about 450 mg, such as about 400 mg to about 440 mg, such as about 410 mg to about 430 mg, such as about 420 ± 10 mg, For example, a dose (eg, a fixed dose) of 420 ± 6 mg, such as 420 ± 5 mg, such as 420 ± 3 mg, such as 420 ± 1 mg, such as 420 ± 0.5 mg, such as 420 mg. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is 30 mg to 600 mg (eg, 50 mg to 600 mg, eg, 60 mg to 600 mg, such as 100 mg to 600 mg, such as 200 mg to 600 mg, such as 200 mg to 550 mg, such as 250 mg to 600 mg, such as 300 mg to 500 mg, such as 350 mg to 450 mg, such as 400 mg to 440 mg, such as 410 mg to 430 mg, such as 420 mg ± 10 mg, such as 420 ± 6 mg, such as 420 ± 5 mg, such as 420 ± 3 mg, such as , 420 ± 1 mg, such as 420 ± 0.5 mg, such as 420 mg) (eg, a fixed dose). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 420 mg every two weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 420 mg every two weeks.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is from about 30 mg to about 1200 mg (eg, from about 30 mg to about 1100) every 3 weeks. mg, such as about 60 mg to about 1000 mg, such as about 100 mg to about 900 mg, such as about 200 mg to about 800 mg, such as about 300 mg to about 800 mg, such as about 400 mg to about 800 mg, such as about 400 mg to about 750 mg, such as about 450 mg to about 750 mg, such as about 500 mg to about 700 mg, such as about 550 mg to about 650 mg, such as 600 mg ± 10 mg, For example, a dose of 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is 30 mg to 1200 mg (eg, 30 mg to 1100 mg, eg, 60 mg to 1000 mg, such as 100 mg to 900 mg, such as 200 mg to 800 mg, such as 300 mg to 800 mg, such as 400 mg to 800 mg, such as 400 mg to 750 mg, such as 450 mg to 750 mg, such as 500 mg to 700 mg, such as 550 mg to 650 mg, such as 600 mg ± 10 mg, such as 600 ± 6 mg, such as 600 ± 5 mg, such as 600 ± 3 mg, such as , 600 ± 1 mg, such as 600 ± 0.5 mg, such as 600 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 600 mg every 3 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg every 3 weeks.

In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is from about 600 mg to about 1200 mg (eg, from about 600 mg to about) every 4 weeks. 1100 mg, such as about 600 mg to about 1000 mg, such as about 700 mg to about 950 mg, such as about 800 mg to about 900 mg, such as about 820 mg to about 860 mg, such as about 840 ± 10 mg , such as 840 ± 6 mg, such as 840 ± 5 mg, such as 840 ± 3 mg, such as 840 ± 1 mg, such as 840 ± 0.5 mg, such as 840 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is 600 mg to 1200 mg (eg, 600 mg to 1100 mg, eg, every 4 weeks) , 600 mg to 1000 mg, such as 700 mg to 950 mg, such as 800 mg to 900 mg, such as 820 mg to 860 mg, such as 840 ± 10 mg, such as 840 ± 6 mg, such as 840 ± 5 mg, such as 840 ± 3 mg, such as 840 ± 1 mg, such as 840 ± 0.5 mg, such as 840 mg). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 840 mg every 4 weeks. In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 840 mg every 4 weeks.

In some cases, combination therapy (eg, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab)) or Dose of said anti TIGIT antagonist antibody (eg, anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) administered in combination therapy with MK-3475 (pembrolizumab, formerly known as lambrolizumab) can be reduced compared to the standard dose of the anti-TIGIT antagonist antibody administered as monotherapy In some cases, one or more chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and / or non-platinum-based chemotherapeutic agents (eg, alkylating agents (eg, cyclophosphamide), taxanes (eg, paclitaxel, such as nap-paclitaxel) and/or topoisomerase II inhibitors (eg, doxorubicin)) and/or G -CSF or GM-CSF, said anti-TIGIT antagonist administered in combination therapy (eg, combination therapy with a PD-1 axis binding antagonist (eg, combination therapy with an anti-PD-L1 antagonist antibody (eg, atezolizumab)) with or without -CSF The dose of an antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) may be reduced compared to a standard dose of said anti TIGIT antagonist antibody administered as monotherapy.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is about 20 mg to about 1600 mg (eg, about 20-100 mg) every two weeks. , about 100-200 mg, about 200-400 mg, about 400-600 mg, about 600-800 mg, about 800-1000 mg, about 1000-1200 mg, about 1200-1400 mg, or about 1400-1600 mg, For example, about 80 mg to about 1200 mg, such as about 100 mg to about 1200 mg, such as about 200 mg to about 1200 mg, such as about 300 mg to about 1200 mg, such as about 400 mg to about 1200 mg, For example, about 500 mg to about 1200 mg, such as about 600 mg to about 1100 mg, such as about 700 mg to about 1000 mg, such as about 740 mg to about 940 mg, such as about 790 mg to about 890 mg, For example, about 815 mg to about 865 mg, such as about 830 mg to about 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as , 840 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 1200 mg (eg, 80 mg to 1200 mg, eg, every 2 weeks) , 100 mg to 1200 mg, such as 200 mg to 1200 mg, such as 300 mg to 1200 mg, such as 400 mg to 1200 mg, such as 500 mg to 1200 mg, such as 600, mg to 1100 mg, such as 700 mg to 1000 mg, such as 740 mg to 940 mg, such as 790 mg to 890 mg, such as 815 mg to 865 mg, such as 830 mg to 850 mg, such as 840 mg ± 5 mg, such as 840 ± 2.5 mg, such as 840 ± 1.0 mg, such as 840 ± 0.5 mg, such as 840 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is about 20 mg, 100 mg, 200 mg, 300 mg, 400 mg every two weeks. , 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, 1400 mg, or 1600 mg. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 840 mg every two weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 840 mg every two weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 80 mg to about 2000 mg (eg, from about 100 mg to about) every 3 weeks. 2000 mg, such as about 200 mg to about 1900 mg, such as about 300 mg to about 1700 mg, such as about 400 mg to about 1600 mg, such as about 500 mg to about 1600 mg, such as about 600 mg to about 1600 mg, such as about 700 mg to about 1600 mg, such as about 800 mg to about 1600 mg, such as about 900 mg to about 1500 mg, such as about 1000 mg to about 1400 mg, such as about 1050 mg to about 1350 mg, such as about 1100 mg to about 1300 mg, such as about 1150 mg to about 1250 mg, such as about 1175 mg to about 1225 mg, such as about 1190 mg to about 1210 mg, such as 1200 mg ± 5 mg , such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 80 mg to 2000 mg (eg, 100 mg to 2000 mg, such as every 3 weeks) , 200 mg to 1900 mg, such as 300 mg to 1700 mg, such as 400 mg to 1600 mg, such as 500 mg to 1600 mg, such as 600 mg to 1600 mg, such as 700 mg to 1600 mg, such as 800 mg to 1600 mg, such as 900 mg to 1500 mg, such as 1000 mg to 1400 mg, such as 1050 mg to 1350 mg, such as 1100 mg to 1300 mg, such as 1150 mg to 1250 mg, such as 1175 mg to 1225 mg, such as 1190 mg to 1210 mg, such as 1200 mg ± 5 mg, such as 1200 ± 2.5 mg, such as 1200 ± 1.0 mg, such as 1200 ± 0.5 mg, such as 1200 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1200 mg every 3 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1200 mg every 3 weeks.

In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is from about 1200 mg to about 2000 mg (eg, from about 1200 mg to about) every 4 weeks. 1900 mg, such as about 1200 mg to about 1800 mg, such as about 1300 mg to about 1800 mg, such as about 1400 mg to about 1800 mg, such as about 1500 mg to about 1800 mg, such as about 1580 mg to about 1780 mg, such as about 1630 mg to about 1730 mg, such as about 1655 mg to about 1705 mg, such as about 1670 mg to about 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). In some cases, the effective amount of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is 1200 mg to 2000 mg (eg, 1200 mg to 1900 mg, such as every 4 weeks) , 1200 mg to 1800 mg, such as 1300 mg to 1800 mg, such as 1400 mg to 1800 mg, such as 1500 mg to 1800 mg, such as 1580 mg to 1780 mg, such as 1630 mg to 1730 mg, such as 1655 mg to 1705 mg, such as 1670 mg to 1690 mg, such as 1680 mg ± 5 mg, such as 1680 ± 2.5 mg, such as 1680 ± 1.0 mg, such as 1680 ± 0.5 mg, such as 1680 mg). . In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of about 1680 mg every 4 weeks. In some cases, the effective amount of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose of 1680 mg every 4 weeks.

In some cases, a PD-1 axis binding antagonist (eg, anti-PD) administered in combination therapy (eg, combination therapy with an anti TIGIT antagonist antibody, eg, an anti TIGIT antagonist antibody (eg, tyragolumab) disclosed herein). The dose of the -L1 antagonist antibody (eg, atezolizumab) may be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as monotherapy. In some cases, one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (eg, an alkylating agent (eg, cyclophosphamide), a taxane) Combination therapy (eg, anti-TIGIT antagonist antibody, eg, with or without paclitaxel, eg, nap-paclitaxel), and/or a topoisomerase II inhibitor (eg, doxorubicin) and/or G-CSF or GM-CSF For example, the dose of said PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered with an anti-TIGIT antagonist antibody disclosed herein, e.g., in combination treatment with tiragolumab, is compared to the standard dose of the PD-1 axis binding antagonist administered as monotherapy.

ii. Dosing Cycles of Anti-TIGIT Antagonist Antibodies and PD-1 Axis Binding Antagonists

In any of the methods and uses of the invention, said anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tiragolumab) and/or said PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist) The antibody (eg, atezolizumab) may be administered in one or more dosing cycles (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). , 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, ate Zolizumab)), the dosing cycle is continued until clinical benefit is lost (eg, disease progression, drug resistance, death, or unacceptable toxicity is identified). In some cases, the length of each dosing cycle is between about 7 and 42 days (eg, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days). work) is Days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 41 days, 42 days). In some cases, the length of each dosing cycle is about 14 days. In some cases, the length of each dosing cycle is about 21 days. In some cases, the length of each dosing cycle is about 28 days. In some cases, the length of each dosing cycle is about 42 days. In some cases, the length of each dosing cycle is about 7 days. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered on about day 1 (eg, day 1 ± 3 days) of each dosing cycle. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered on about 15 days (eg, 15 days ± 3 days) of each dosing cycle. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered on about 22 days (eg, 22 days ± 3 days) of each dosing cycle. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered on about 29 days (eg, 29 days ± 3 days) of each dosing cycle. For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of about 600 mg (eg, a fixed dose) on Day 1 of each 21 day cycle (eg, a fixed dose) ( i.e., at a dose of about 600 mg every 3 weeks). For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) may be administered at a dose of about 600 mg (eg, a fixed dose) on days 1 and 15 of each 28-day cycle. ) (ie, at a dose of about 420 mg every 2 weeks). For example, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) may be administered at a dose of about 600 mg on days 1, 15, and 29 of each 42-day cycle ( eg, as a fixed dose) (ie, at a dose of about 420 mg every two weeks). For example, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tyragolumab) may be administered at a dose of about 600 mg (eg, a fixed dose) on days 1 and 22 of each 42 day cycle. ) (ie, at a dose of about 600 mg every 3 weeks). In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 ( Pembrolizumab (previously known as lambrolizumab)) is administered on about day 1 of each dosing cycle (e.g., day 1 ± 3 days) In some cases, the PD-1 axis binding antagonist (e.g., An anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) Administer on about 15 days (eg, 15 days ± 3 days) of each dosing cycle.For example, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered on each Administer intravenously at a dose of about 1200 mg (ie, at a dose of about 1200 mg every 3 weeks) on Day 1 of a 21-day cycle, For example, the PD-1 axis binding antagonist (eg, anti-PD-L1 The antagonist antibody (eg, atezolizumab)) is administered intravenously at a dose of about 1200 mg (ie, at a dose of about 840 mg every two weeks) on days 1 and 15 of each 28-day cycle. , the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) is administered at a dose of 600 mg (eg, a fixed dose) on Day 1 of each 21-day cycle (ie, 3 weeks). In some cases, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD-1 antagonist antibody (eg, MDX-1106 (nivolumab) or MK-3475 (pembrolizumab, formerly known as lambrolizumab)) is administered on Day 1 (e.g., Day 1 ± 3) of each dosing cycle. , wherein the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) It is administered intravenously at a dose of 1200 mg per day (ie at a dose of 1200 mg every 3 weeks).

In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) and the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli Zumab)) is administered on about day 1 (eg, day 1 ± 3 days) of each dosing cycle.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 600 mg on Day 1 of each 21-day cycle (ie, every 3 weeks). at a dose of about 600 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at about 1200 mg on Day 1 of each 21-day cycle. It is administered intravenously as a dose (ie, at a dose of about 1200 mg every 3 weeks). In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 600 mg on Day 1 of each 21-day cycle (ie, 600 every 3 weeks). mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of 1200 mg on Day 1 of each 21-day cycle ( i.e., administered intravenously (in a dose of 1200 mg every 3 weeks).

In other instances, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 420 mg (ie, every two weeks) on Day 1 of each 14-day cycle. at a dose of about 420 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at about 840 mg on Day 1 of each 14-day cycle. It is administered intravenously as a dose (ie, at a dose of about 840 mg every two weeks). In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 420 mg on Day 1 of each 14-day cycle (ie, about every two weeks). 420 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of 840 mg on Day 1 of each 14-day cycle. It is administered intravenously (ie, at a dose of 840 mg every 2 weeks).

In other cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of about 840 mg on Day 1 of each 28-day cycle (ie, every 4 weeks). at a dose of about 840 mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at about 1680 mg on Day 1 of each 28-day cycle. It is administered intravenously as a dose (ie, at a dose of about 1680 mg every 4 weeks). In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered at a dose of 840 mg on Day 1 of each 28-day cycle (ie, 840 every 4 weeks). mg), and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a dose of 1680 mg on Day 1 of each 28-day cycle ( i.e., at a dose of 1680 mg every 4 weeks) intravenously.

iii. Intravenous infusion and subcutaneous administration of anti-TIGIT antagonist antibody and PD-1 axis binding antagonist

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered intravenously. Alternatively, in some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered subcutaneously. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered intravenously. Alternatively, in some embodiments, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered subcutaneously.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is administered in about 60 ± 15 minutes (eg, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes). minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, About 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered in about 60 ± 10 minutes (eg, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes , about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes) by intravenous infusion to the subject or population of subjects. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) is administered in about 60±15 minutes (eg, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes , about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes) by intravenous infusion to the subject.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is administered in about 30±10 minutes (eg, about 20 minutes, about 21 minutes, about 22 minutes, About 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) by intravenous infusion. In some cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered in about 30 ± 10 minutes (eg, about 20 minutes, about 21 minutes, about 22 minutes, About 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes) by intravenous infusion.

iv. Dosing sequence and observation period

In some cases where both an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist are administered to a subject or population of subjects, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) ) is administered to the subject prior to the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)).

In some cases, for example, after administration of the anti-TIGIT antagonist antibody and prior to administration of the PD-1 axis binding antagonist, the method comprises an intermediate first observation period. In some cases, eg, following administration of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered to the subject. In some cases, the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is first administered to the subject, and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist) The antibody (eg, atezolizumab)) is administered to the subject following administration of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab).

In some cases, the method further comprises a second observation period following administration of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)).

In some cases, the method comprises a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation after administration of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) includes all periods. In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. In instances where the first and second observation periods are each about 60 minutes in length, the method comprises the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist (eg, anti-PD) during the first or second observation period. - recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) about 30 ± 10 minutes after administration of the -L1 antagonist antibody (eg, atezolizumab). In instances where the first and second observation periods are each about 30 minutes in length, the method comprises the anti-TIGIT antagonist antibody or the PD-1 axis binding antagonist (eg, anti-PD) during the first or second observation period. - recording the subject's vital signs (eg, pulse rate, respiration rate, blood pressure and temperature) about 15±10 minutes after administration of the -L1 antagonist antibody (eg, atezolizumab).

In general cases, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is the anti-TIGIT antagonist antibody ( eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is administered to said subject or population of subjects prior to. In some cases, e.g., after administration of said PD-1 axis binding antagonist (eg, anti PD-L1 antagonist antibody (eg, atezolizumab)) and said anti TIGIT antagonist antibody (eg, as disclosed herein) Prior to administration of an anti-TIGIT antagonist antibody (eg, tyragolumab), the method includes an interim first observation period.

In some cases, the method further comprises a second observation period following administration of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab).

In some cases, the method comprises a first observation period following administration of the PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)), and the anti TIGIT antagonist antibody (eg, herein a second observation period all after administration of an anti-TIGIT antagonist antibody, such as tyragolumab, as disclosed in In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. In instances where the first and second observation periods are each about 60 minutes, the method comprises, during the first or second observation period, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, artezoli). Zumab)) or the subject's vital signs (e.g., pulse, respiratory rate, blood pressure) at about 30±10 minutes after administration of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tiragolumab as disclosed herein). , body temperature). In cases where the first and second observation periods are each about 30 minutes, the method comprises, during the first or second observation period, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezoli zumab)), the subject's vital signs (eg, pulse, respiratory rate, blood pressure , body temperature).

In some cases, the method further comprises administration of a VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)). In some cases, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab) or anti-PD- 1 antagonist antibody (eg, pembrolizumab)) and the anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody as disclosed herein, eg, tiragolumab). In some cases, the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) is the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) or the PD- Administration of the uniaxial binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is followed by the second observation period.

In some cases, the method further comprises a third observation period following administration of the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)). In some cases, the third observation period is between about 30 minutes and about 120 minutes in length. In some cases, the first observation period, the second observation period, and the third observation period are each between about 30 minutes and about 120 minutes in length.

Co-administration of anti-TIGIT antagonist antibody and PD-1 axis binding antagonist

In some cases, the dose of an effective amount of an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab) is

Combination therapy (eg, a PD-1 axis binding antagonist (eg, an anti PD-L1 antagonist antibody (eg, atezolizumab)) and an anti TIGIT antagonist antibody (eg, as disclosed herein) for the treatment of a subject having cancer combination therapy with an anti-TIGIT antagonist antibody, such as tyragolumab), with a dose of an effective amount of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody, such as atezolizumab). In these cases, the anti-TIGIT antagonist antibody is administered every two weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered 2 weeks as described in Section III(K)(ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every two weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered in Section III(K)(i) herein ( ii) is administered every 3 weeks as described in. In some cases, the anti-TIGIT antagonist antibody is administered every two weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered herein is administered every 4 weeks as described in Section III(K)(ii) of the In some cases, the anti-TIGIT antagonist antibody is administered every 2 weeks, as described in Section III(K)(i) herein, and The -1 axis binding antagonist is administered every 6 weeks as described in Section III(K)(ii) herein In some cases, the anti-TIGIT antagonist antibody is administered as described in Section III(K)(i) herein Administer every 3 weeks, and the PD-1 axis binding antagonist is administered every 2 weeks as described in Section III(K)(ii) herein In some cases, the anti-TIGIT antagonist antibody is administered in Section III(K) herein Administer every 3 weeks as described in (i), and the PD-1 axis binding antagonist is administered every 3 weeks as described in Section III(K)(ii) herein In some cases, the anti-TIGIT antagonist antibody is As described in Section III(K)(i) herein This is administered every 3 weeks, and the PD-1 axis binding antagonist is administered every 4 weeks as described in Section III(K)(ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every 3 weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered as described in Section III(K)(ii) herein. administered together every 6 weeks. In some cases, the anti TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered as described in Section III(K)(ii) herein. administered together every 2 weeks. In some cases, the anti TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered as described in Section III(K)(ii) herein. administered every 3 weeks. In some cases, the anti TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered as described in Section III(K)(ii) herein. administered together every 4 weeks. In some cases, the anti TIGIT antagonist antibody is administered every 4 weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered as described in Section III(K)(ii) herein. administered together every 6 weeks. In some cases, the anti-TIGIT antagonist antibody is administered every 2 weeks, 3 weeks, or 4 weeks as described in Section III(K)(i) herein, and the PD-1 axis binding antagonist is administered in Section III (K)(K) herein. ) every 2 weeks, 3 weeks, 4 weeks, or 6 weeks as described in (ii).

In some cases, the dose of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of about 600 mg every 3 weeks. In some cases, the dose of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose of 600 mg every 3 weeks. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is administered on a step-by-step dosing regimen (eg, based on the subject's body weight (BW) or body surface area (BSA)). dosing) and a PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody) at a dose of from about 0.01 mg/kg to about 50 mg/kg (eg, about 15 mg/kg) to up to 1200 mg, eg, every 3 weeks , such as atezolizumab), such as every 3 weeks. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) is administered on a step-by-step dosing regimen (eg, based on the subject's body weight (BW) or body surface area (BSA)). dosing) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab). The dosing regimen can be utilized to treat subjects with relatively low body weight (eg, 40 kg or less (eg, 5 kg to 40 kg, 15 kg to 40 kg, or 5 kg to 15 kg)), and in adult data It was developed through in vivo simulation studies based on extrapolation of estimated pharmacokinetic parameters. In some cases, the dose of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a subject's body weight (eg, body weight (BW) > 40 kg: 600 mg, BW > 15 kg and ≤ 40 kg: 400 mg, and BW ≤ 15 kg: 300 mg))). In some cases, the dose of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a dose based on the subject's body weight (eg, 15 mg/kg). In some cases, the dose of the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) is a body surface area (eg, body surface area (BSA) > 1.25 m ² :600 of the subject) mg, BSA > 0.75 m ² and ≤ 1.25 m ² : 450 mg, BSA > 0.5 m ² and ≤ 0.75 m ² : 350 mg, and BSA ≤ 0.5 m ² : 300 mg). In some cases, the dose (eg, about 600 mg) of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab) is administered at a dose (eg, about 600 mg) of the subject's body weight (eg, 15 mg/kg) every 3 weeks. ) in combination with a dose of the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)). In some cases, step-wise doses (eg, body weight (BW) > 40 kg: 600 mg, BW > 15 kg) of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and ≤ 40 kg: 400 mg, and BW ≤ 15 kg: 300 mg) of the anti-PD-1 axis binding antagonist (eg, anti-PD-) based on the subject's body weight (eg, 15 mg/kg) every 3 weeks. It is administered in combination with a dose of an L1 antagonist antibody (eg, atezolizumab). In some cases, step-wise doses (eg, body weight (BW) > 40 kg: 600 mg, BW > 15 kg) of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) and ≤ 40 kg: 400 mg, and BW ≤ 15 kg: 300 mg) is the subject's body surface area (eg, BSA > 1.25 m ² 600 mg, BSA > 0.75 m ² and ≤ 1.25 m ² : 450 mg, The anti-PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, artezoli) based on BSA > 0.5 m ² and ≤ 0.75 m ² :350 mg, and BSA ≤ 0.5 m ² :300 mg). It is administered in combination with a dose of Zumab)). In some embodiments, the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) is administered at a maximum dose of 1200 mg every 3 weeks. In some cases, the combination therapy comprises one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (eg, an antimetabolites (eg, pemetrec)). Syd or gemcitabine).

In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tyragolumab as disclosed herein) for treating a subject having cancer is a tiered dose based on the subject's body weight, wherein said the subject's body weight is (a) 15 kg or less, and the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 250 mg to about 350 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 350 mg to about 450 mg every 3 weeks (eg, about 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of about 550 mg to about 650 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks; (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or (c) greater than 40 kg, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks. In some cases, about 0.01 mg/kg to about 50 mg/kg of the subject's body weight (eg, about 0.01 mg/kg of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, For example, about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg) Administered in combination with step-dose doses of said anti-TIGIT antagonist antibody (eg, anti-TIGIT antagonist antibody, eg, tiragolumab as disclosed herein) as a reference, wherein said subject weighs (a) no more than 15 kg; the anti TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 15 kg and no more than 40 kg, wherein the anti TIGIT antagonist antibody is administered every 3 weeks administered at a dose of about 10 mg to about 1000 mg (eg, about 400 mg every 3 weeks); or (c) greater than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks. (e.g., about 600 mg every 3 weeks) In some cases, the subject weighing 15 kg or less is administered with the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tyragolumab). a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks) and every 3 weeks for the PD - about 0.01 mg/kg to about 50 mg/kg of the subject's body weight (eg, about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, a subject weighing more than 15 kg and no more than 40 kg has from about 10 mg to about 1000 every 3 weeks for said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). about 0.01 of the subject's body weight for a dose of mg (eg, about 400 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) mg/kg to about 50 mg/kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg , eg, about 15 mg/kg). In some cases, the subject weighing more than 40 kg receives from about 30 mg to about 1200 mg every 3 weeks for said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). About 0.01 mg/m of the subject's body weight for a dose (eg, about 600 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) kg to about 50 mg/kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, For example, from about 2.5 mg/kg to about 30 mg/kg, such as from about 5 mg/kg to about 25 mg/kg, such as from about 10 mg/kg to about 20 mg/kg, such as from about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as , about 15 mg/kg).

In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tyragolumab as disclosed herein) for treating a subject having cancer is a tiered dose based on the subject's body weight, wherein said the subject's body weight is (a) 15 kg or less and the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 15 kg and no more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 250 mg to 350 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 15 kg and not more than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of 350 mg to 450 mg every 3 weeks (eg, 400 mg every 3 weeks); or (c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is administered at a dose of 550 mg to 650 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on a subject's body weight, wherein the subject's body weight is (a) 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 300 mg every 3 weeks; (b) greater than 15 kg and not more than 40 kg, wherein said anti-TIGIT antagonist antibody is administered at a dose of 400 mg every 3 weeks; or (c) greater than 40 kg, wherein said anti-TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks. In some cases, 0.01 mg/kg to 50 mg/kg of the subject's body weight (eg, 0.01 mg/kg to 45 mg/kg of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 A dose of ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, e.g., 15 mg/kg) of said anti TIGIT antagonist antibody (e.g., an anti TIGIT antagonist antibody as disclosed herein, e.g., tyragolumab), wherein the subject's body weight is (a) 15 kg or less, and wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 300 mg every 3 weeks). (b) greater than 15 kg and up to 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg 400 mg every 3 weeks); or (c) 40 kg and the anti-TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg every 3 weeks (e.g., 600 mg every 3 weeks) In some cases, the subject weighing 15 kg or less is administered with the anti-TIGIT antagonist antibody ( For example, a dose of 10 mg to 1000 mg every 3 weeks (eg 300 mg every 3 weeks) and every 3 weeks for an anti TIGIT antagonist antibody, such as tiragolumab, as disclosed herein and the PD-1 axis binding antagonist every 3 weeks 0.01 of the subject's body weight for (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) mg/kg to 50 mg/kg (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, a subject weighing more than 15 kg and no more than 40 kg is administered 10 mg to 1000 mg every 3 weeks for said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). 0.01 mg/kg to the subject's body weight for a dose (eg, 400 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) 50 mg/kg (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg /kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, the subject weighing more than 40 kg is administered at a dose of 30 mg to 1200 mg every 3 weeks for said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab) ( 0.01 mg/kg to 50 mg of the subject's body weight for the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 3 weeks) and every 3 weeks /kg (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg , such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg /kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg).

In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tyragolumab) for treating a subject having cancer is a dose in steps based on the subject's body surface area. In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 350 mg every 3 weeks); (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 250 mg to about 350 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg to about 400 mg every 3 weeks (eg, about 350 mg every 3 weeks); or (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg to about 500 mg every 3 weeks (eg, about 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein the anti TIGIT antagonist antibody is administered at a dose of about 550 mg to about 650 mg every 3 weeks (eg, about 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks; (b) greater than 0.5 m ² and less than or equal to 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or (c) greater than 0.75 m2 and less than or equal to 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 450 mg every 3 weeks; or (d) greater than 1.25 m 2 , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks.

In some cases, about 0.01 mg/kg to about 50 mg/kg of the subject's body weight (eg, about 0.01 mg/kg of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, For example, about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg) of the body surface area of the subject is administered in combination with a step-by-step dose of said anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody, such as tiragolumab as disclosed herein) on the basis of, wherein the subject's body surface area is (a) 0.5 m ² or less wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks); (b) greater than 0.5 m ² and not more than 0.75 m ² , wherein the anti-TIGIT antagonist the antibody is administered at a dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 350 mg every 3 weeks); (c) greater than 0.75 m ² and no more than 1.25 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg per week (eg, about 450 mg every 3 weeks); or (d) greater than 1.25 m ² , wherein the anti-TIGIT antagonist antibody is from about 30 mg to about 1200 mg every 3 weeks. (e.g., about 600 mg every 3 weeks) In some cases, a subject having a body surface area of 0.5 m ² or less A dose of about 10 mg to about 1000 mg every 3 weeks (eg, about 300 mg every 3 weeks) and every 3 weeks for a TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tiragolumab) about 0.01 mg/kg to about 50 mg/kg (eg, about 0.01 mg/kg) of the subject's body weight for the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as , about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg , about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, a subject having a body surface area greater than 0.5 m ² and less than or equal to 0.75 m ² receives about 10 mg every 3 weeks for said anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). body weight of the subject for a dose of from about 1000 mg (eg, about 350 mg every 3 weeks) and every 3 weeks to the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) from about 0.01 mg/kg to about 50 mg/kg (e.g., from about 0.01 mg/kg to about 45 mg/kg, such as from about 0.1 mg/kg to about 40 mg/kg, such as from about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, a subject having a body surface area greater than 0.75 m ² and less than or equal to 1.25 m ² receives about 10 mg every 3 weeks for said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). body weight of the subject for a dose of from to about 1000 mg (eg, about 450 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) from about 0.01 mg/kg to about 50 mg/kg (e.g., from about 0.01 mg/kg to about 45 mg/kg, such as from about 0.1 mg/kg to about 40 mg/kg, such as from about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the subject having a body surface area greater than 1.25 m ² has a dose of from about 30 mg to about 1200 every 3 weeks for said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). about 0.01 of the subject's body weight for a dose of mg (eg, about 600 mg every 3 weeks) and the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) every 3 weeks mg/kg to about 50 mg/kg (e.g., about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg, such as about 12.5 mg/kg kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg , eg, about 15 mg/kg).

In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 350 mg every 3 weeks); (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein the anti TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of 250 mg to 350 mg every 3 weeks (eg, 300 mg every 3 weeks); (b) greater than 0.5 m ² and no greater than 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 300 mg to 400 mg every 3 weeks (eg, 350 mg every 3 weeks); (c) greater than 0.75 m2 and no greater than 1.25 m2, wherein the anti-TIGIT antagonist antibody is administered at a dose of 400 mg to 500 mg every 3 weeks (eg, 450 mg every 3 weeks); or (d) greater than 1.25 m 2 , wherein said anti TIGIT antagonist antibody is administered at a dose of 550 mg to 650 mg every 3 weeks (eg, 600 mg every 3 weeks). In some cases, the effective amount of the anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, such as tiragolumab) is a dose in steps based on the subject's body surface area, wherein the subject's body surface area is (a ) 0.5 m ² or less, and the anti-TIGIT antagonist antibody is administered at a dose of 300 mg every 3 weeks; (b) greater than 0.5 m ² and less than or equal to 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 400 mg every 3 weeks; or (c) greater than 0.75 m2 and less than or equal to 1.25 m2, wherein said anti-TIGIT antagonist antibody is administered at a dose of 450 mg every 3 weeks; or (d) greater than 1.25 m 2 , wherein said anti TIGIT antagonist antibody is administered at a dose of 600 mg every 3 weeks.

In some cases, 0.01 mg/kg to 50 mg/kg of the subject's body weight (eg, 0.01 mg/kg to 45 mg/kg of a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 A dose of ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, e.g., 15 mg/kg) of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, such as , tiragolumab), wherein the subject's body surface area is (a) 0.5 m ² or less, and wherein the anti-TIGIT antagonist antibody is 10 mg to 1000 mg every 3 weeks (eg, 300 every 3 weeks). mg), (b) greater than 0.5 m ² and up to 0.75 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 350 mg every 3 weeks); (c) greater than 0.75 m ² and less than or equal to 1.25 m ² , wherein the anti-TIGIT antagonist antibody is administered at a dose of 10 mg to 1000 mg every 3 weeks (eg, 450 mg every 3 weeks); or (d) greater than 1.25 m ² and the anti TIGIT antagonist antibody is administered at a dose of 30 mg to 1200 mg every 3 weeks (eg, 600 mg every 3 weeks) In some cases, the subject with a body surface area of 0.5 m ² or less is the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, such as tiragolumab) every 3 weeks body weight of the subject at a dose of 10 mg to 1000 mg (eg, 300 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) 0.01 mg/kg to 50 mg/kg of (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, a subject having a body surface area greater than 0.5 m ² and less than or equal to 0.75 m ² is administered from 10 mg to every 3 weeks for said anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). 0.01 mg of the subject's body weight for a dose of 1000 mg (eg, 350 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) /kg to 50 mg/kg (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg , 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, a subject having a body surface area greater than 0.75 m ² and less than or equal to 1.25 m ² is administered from 10 mg every 3 weeks to 0.01 mg of the subject's body weight for a dose of 1000 mg (eg, 450 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) /kg to 50 mg/kg (eg 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg , 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some cases, a subject with a body surface area greater than 1.25 m ² is administered 30 mg to 1000 mg every 3 weeks for said anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody as disclosed herein, eg, tyragolumab). 0.01 mg/kg to the subject's body weight for a dose (eg, 600 mg every 3 weeks) and every 3 weeks for the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) 50 mg/kg (eg, 0.01 mg/kg to 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg /kg, such as 5 mg/kg to 25 mg/kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg).

administration of chemotherapeutic agents

Therapeutically effective amounts of various chemotherapeutic agents are known in the art and are contemplated herein. In certain instances, one or more chemotherapeutic agents (eg, a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (eg, an alkylating agent (eg, cyclophosphamide)); The taxane (eg, paclitaxel, eg, nap-paclitaxel) and/or topoisomerase II inhibitor (eg, doxorubicin)) is administered according to the doses recited herein.

Platinum-based chemotherapeutic agents

In some cases, an effective amount of a platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 1-50 mg/ml/min (eg, 2-25 mg/ml/min, 3-15 mg/ml/min) , 4-10 mg/ml/min, or 5 mg/ml/min, such as 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/min ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml /min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/ min, 45 mg/ml/min, 50 mg/ml/min). In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is a dose sufficient to achieve AUC=5 mg/ml/min. In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is a dose sufficient to achieve AUC=6 mg/ml/min. In some cases, an effective amount of carboplatin is a dose sufficient to achieve AUC=5 mg/ml/min. In some cases, an effective amount of carboplatin is a dose sufficient to achieve AUC=6 mg/ml/min. In some cases, the effective amount of carboplatin is a dose sufficient to achieve AUC=5 mg/ml/min on Day 1 of a 21-day dosing cycle. In some cases, the effective amount of carboplatin is a dose sufficient to achieve AUC=6 mg/ml/min on Day 1 of a 21-day dosing cycle. In some cases, the effective amount of carboplatin is a dose sufficient to achieve AUC=5 mg/ml/min when administered after pemetrexed or gemcitabine. In some cases, the effective amount of carboplatin is a dose sufficient to achieve AUC=6 mg/ml/min when administered after paclitaxel.

AUC can be calculated using the Calvert formula (Calvert et al., J. Clin. Oncol . 1989, 7:1748-56):

Total dose (mg)　(target AUC)　(glomerular filtration rate [GFR]　25)

In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 200 mg to 1500 mg (eg, 300 mg to 1200 mg, 400 mg to 1100 mg, or 500 mg to 1000 mg, For example 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-750 mg, 750 mg-800 mg, 800 mg-900 mg, 900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg, such as about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg). In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is between about 500 mg and 1000 mg (eg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg). mg, or about 1000 mg).

In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is from about 20 mg/m ² to about 200 mg/m ² (eg, from about 20 mg/m ² to about 150 mg/m 2 ) m ² , such as from about 30 mg/m ² to about 125 mg/m ² , such as from about 40 mg/m ² to about 110 mg/m ² , such as from about 50 mg/m ² to about 100 mg/m ^{2 .} , such as about 60 mg/m ² to about 90 mg/m ² , such as about 70 mg/m ² to about 80 mg/m ² , such as about 75 mg/m ² , such as 75 mg/m ² ) to be. In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is about 75 mg/m ² . In some cases, the effective amount of cisplatin is about 75 mg/m ² . In some cases, the effective amount of cisplatin is about 75 mg/m ² every 3 weeks. In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 20 mg/m ² to 200 mg/m ² (eg, 20 mg/m ² to 150 mg/m ² , such as , 30 mg/m ² to 125 mg/m ² , such as 40 mg/m ² to 110 mg/m ² , such as 50 mg/m ² to 100 mg/m ² , such as 60 mg/m ² to 90 mg/m ² , such as 70 mg/m ² to 80 mg/m ² , such as 75 mg/m ² , such as 75 mg/m ² ). In some cases, the effective amount of the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is 75 mg/m ² . In some cases, the effective amount of cisplatin is 75 mg/m ² . In some cases, the effective amount of cisplatin is 75 mg/m ² every 3 weeks.

In some cases, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is administered to the subject or population of subjects intravenously (eg, over a 30-120 minute infusion). In some cases, carboplatin is administered intravenously over a 30-60 minute infusion. In some cases, cisplatin is administered intravenously over a 60-120 minute infusion. In some cases, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is administered to the subject or population of subjects every three weeks. In some cases, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) is administered on about 1 day (eg, -3 days, -2 days, -1 days, 1 day, 2 days, or day 3) to said subject or population of subjects.

taxane

A therapeutically effective amount of a taxane (eg, paclitaxel or nap-paclitaxel (ABRAXANE®)) administered to a human is from about 25 to about 300 mg/m ² (eg, about 25 mg/m ² , in one or more administrations). about 50 mg/m ² , about 75 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg/m ² , about 110 mg/m ² , about 120 mg/m ² , about 125 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/m ² , about 175 mg/m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 225 mg/m ² , about 250 mg/m ² , about 275 mg/m ² , or about 300 mg/m ² (eg, 25 mg/m ² , 50 mg/m ² , 75 mg/m ² , 80 mg/m ² , 90 mg/m ² , 100 mg/m ² , 110 mg/m ² , 120 mg/m ² , 125 mg /m ² , 130 mg/m ² , 140 mg/m ² , 150 mg/m ² , 160 mg/m ² , 170 mg/m ² , 175 mg/m ² , 180 mg/m ² , 190 mg/m ² , 200 mg/m ² , 225 mg/m ² , 250 mg/m ² , 275 mg/m ² , or 300 mg/m ² )). For example, in some embodiments, about 175 mg/m ² of paclitaxel is administered. In some embodiments, about 175 mg/m ² of paclitaxel is administered. In some embodiments, paclitaxel is administered at a dose of about 175 mg/m ² to about 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of about 175 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of about 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of 175 mg/m ² to 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of 175 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at a dose of 200 mg/m ² every 3 weeks. In some embodiments, paclitaxel is administered at 175 mg/m ² IV every 3 weeks. In some embodiments, paclitaxel is administered to a subject of Asian race/ethnicity at 175 mg/m ² IV every 3 weeks. In some embodiments, paclitaxel is administered at 200 mg/m ² IV every 3 weeks. In some embodiments, paclitaxel is administered to a subject of non-Asian race/ethnicity at 200 mg/m ² IV every 3 weeks. In some embodiments, about 100 mg/m ² of nap-paclitaxel (ABRAXANE®) is administered. In some embodiments, 100 mg/m ² of nap-paclitaxel (ABRAXANE®) is administered. In some embodiments, nap-paclitaxel (ABRAXANE®) is administered at 100 mg/m ² IV weekly. In some embodiments, nap-paclitaxel (ABRAXANE®) is administered at 100 mg/m ² IV three times every 4 weeks (eg, on days 1, 8, and 15 of each 28-day dosing cycle). In some embodiments, the taxane (eg, paclitaxel or nap-paclitaxel (ABRAXANE®)) is administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, days 1, 8 and 15 of each 21 day cycle. , or on days 1, 8 and 15 of each 28-day cycle.

In some embodiments, the taxane (eg, paclitaxel or nap-paclitaxel (ABRAXANE®)) is administered to the subject or population of subjects intravenously (eg, over a 3-hour infusion). In some embodiments, the taxane is administered to the subject or population of subjects every three weeks. In some embodiments, the taxane is administered to the subject or population of subjects on about day 1 (eg, day -3, day -2, day -1, day 1, day 2, or day 3) of a 21 day dosing cycle. is administered In some embodiments, paclitaxel is administered to the subject every 3 weeks. In some embodiments, paclitaxel is administered to the subject or population of subjects on about day 1 of a 21 day dosing cycle. In some embodiments, nap-paclitaxel (ABRAXANE®) is administered to the subject or population of subjects every 3 weeks. In some embodiments, nap-paclitaxel (ABRAXANE®) is administered to the subject or population of subjects on about day 1 of a daily dosing cycle.

antimetabolites

In some cases, the effective amount of an antimetabolite (eg, pemetrexed or gemcitabine) administered as part of a method described herein is 10-0000 mg/m ² (eg, 20-8000 mg/m ² , 30- 5000 mg/m ² , 40-2500 mg/m ² , 50-2000 mg/m ² , 100-1500 mg/m ² , or 400-1200 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m ² , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg /m ² , about 110 mg/m ² , about 120 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/ m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 250 mg/m ² , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , about 1000 mg/m ² , about 1100 mg/m ² , about 1200 mg/m ² , about 1250 mg/m ² , about 1300 mg/m ² , about 1400 mg/m ² , about 1500 mg/m ² , about 1750 mg/m ² , about 2000 mg/m ² , about 3000 mg/m ² , about 4000 mg/m ² , about 5000 mg/m ² , about 6000 mg/m ² , about 7000 mg/m ² , about 8000 mg/m ² , about 9000 mg/m ² , or about 10000 mg/m ² ) to be. In some cases, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is from about 500 mg/m ² to about 1250 mg/m ² (eg, 20 mg/m ² , 30 mg/m ² , 40 mg/m ² , 50 mg/m ² , 60 mg/m ² , 70 mg/m ² , 80 mg/m ² , 90 mg/m ² , 100 mg/m ² , 110 mg/m ² , 120 mg /m ² , 130 mg/m ² , 140 mg/m ² , 150 mg/m ² , 160 mg/m ² , 170 mg/m ² , 180 mg/m ² , 190 mg/m ² , 200 mg/m ² , 250 mg/m ² , 300 mg/m ² , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , 1000 mg/m ² , 1100 mg/m ² , 1200 mg/m ² , 1250 mg/m ² , 1300 mg/m ² , 1400 mg/m ² , 1500 mg/m ² , 1750 mg/m ² , 2000 mg /m ² , 3000 mg/m ² , 4000 mg/m ² , 5000 mg/m ² , 6000 mg/m ² , 7000 mg/m ² , 8000 mg/m ² , 9000 mg/m ² , or 10000 mg/ m ² ). In some cases, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is about 500 mg/m ² . In some cases, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is about 1000 mg/m ² . In some cases, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is about 1250 mg/m ² . In some cases, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is 500 mg/m ² . In some cases, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is 1000 mg/m ² . In some cases, the effective amount of the antimetabolite (eg, pemetrexed or gemcitabine) is 1250 mg/m ² .

In some cases, an effective amount of pemetrexed administered as part of a method described herein is 10-1000 mg/m ² (eg, 20-900 mg/m ² , 30-800 mg/m ² , 40-700 mg /m ² , 50-650 mg/m ² , 100-600 mg/m ² , or 200-550 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m ² , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg/m ² , about 110 mg/m ² , about 120 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 250 mg/m ² , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , or about 1000 mg/m ² ). In some cases, the effective amount of pemetrexed is about 500 mg/m ² . In some cases, the effective amount of pemetrexed is about 500 mg/m ² every 3 weeks. In some cases, the effective amount of pemetrexed is 500 mg/m ² . In some cases, the effective amount of pemetrexed is 500 mg/m ² every 3 weeks.

In some embodiments, the pemetrexed is administered to the subject or population of subjects intravenously (eg, over a 10-minute infusion). In some embodiments, the pemetrexed is administered to the subject or population of subjects every 3 weeks. In some embodiments, the pemetrexed is administered to the subject or population of subjects on about 1 day (eg, -3 days, -2 days, -1 days, 1 day, 2 days, or 3 days) of a 21 day dosing cycle. is administered to

In some cases, the effective amount of gemcitabine administered as part of the methods described herein is 10-10000 mg/m ² (eg, 20-8000 mg/m ² , 30-5000 mg/m ² , 40-2500 mg/m 2 ) m ² , 50-2000 mg/m ² , 100-1500 mg/m ² , or 400-1250 mg/m ² , for example, about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m ² , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg/m ² , about 110 mg/m ² , about 120 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 250 mg/m ² , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , about 1000 mg/m ² , about 1100 mg/m ² , about 1200 mg/m ² , about 1250 mg/m ² , about 1300 mg/m ² , about 1400 mg/m ² , about 1500 mg/m ² , about 1750 mg/m ² , about 2000 mg/m ² , about 3000 mg/m ² , about 4000 mg/m ² , about 5000 mg /m ² , about 6000 mg/m ² , about 7000 mg/m ² , about 8000 mg/m ² , about 9000 mg/m ² , or about 10000 mg/m ² (eg, 20 mg/m ² , 30 mg /m ² , 40 mg/m ² , 50 mg/m ² , 60 mg/m ² , 70 mg/m ² , 80 mg/m ² , 90 mg/m ² , 100 mg/m ² , 110 mg/m ² , 120 mg/m ² , 130 mg/m ² , 140 mg/m ² , 150 mg/m ² , 160 mg/m ² , 170 mg/m ² , 180 mg/m ² , 190 mg/m ² , 200 mg/m ² , 250 mg/m ² , 300 mg/m ² , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , 1000 mg/m ² , 1100 mg/ m ² , 1200 mg/m ² , 1250 mg/m ² , 1300 mg/m ² , 1400 mg/m ² , 1500 mg/m ² , 1750 mg/m ² , 2000 mg/m ² , 3000 mg/m ² , 4000 mg/m ² , 5000 mg/m ² , 6000 mg/m ² , 7000 mg/m ² , 8000 mg/m ² , 9000 mg/m ² , or 10000 mg/m ² )). In some cases, the effective amount of gemcitabine is from about 500 mg/m ² to about 1250 mg/m ² . In some cases, the effective amount of gemcitabine is about 500 mg/m ² . In some cases, the effective amount of gemcitabine is about 1000 mg/m ² . In some cases, the effective amount of gemcitabine when administered prior to carboplatin is about 1000 mg/m ² . In some cases, the effective amount of gemcitabine is about 1250 mg/m ² . In some cases, the effective amount of gemcitabine is about 1250 mg/m ² when administered prior to cisplatin. In some cases, the effective amount of gemcitabine is about 1000 mg/m ² on days 1 and 8 of a 21 day dosing cycle. In some cases, the effective amount of gemcitabine is about 1250 mg/m ² on days 1 and 8 of a 21 day dosing cycle. In some cases, the effective amount of gemcitabine is 1000 mg/m ² . In some cases, the effective amount of gemcitabine is 1000 mg/m ² when administered prior to carboplatin. In some cases, the effective amount of gemcitabine is 1250 mg/m ² . In some cases, the effective amount of gemcitabine is 1250 mg/m ² when administered prior to cisplatin. In some cases, the effective amount of gemcitabine is 1000 mg/m ² on days 1 and 8 of a 21 day dosing cycle. In some cases, the effective amount of gemcitabine is 1250 mg/m ² on days 1 and 8 of a 21 day dosing cycle.

In some embodiments, the gemcitabine is administered to the subject or population of subjects intravenously (eg, over a 30 minute infusion). In some cases, the gemcitabine is administered to the subject or population of subjects on about day 1 (eg, day -3, day -2, day -1, day 1, day 2, or day 3) of a 21 day dosing cycle. is administered In some cases, the gemcitabine is administered to the subject or on about days 1 and about 8 (eg, 5, 6, 7, 8, 9, 10, or 11 days) of a 21 day dosing cycle. administered to a population of subjects.

Topoisomerase II inhibitors

In some cases, an effective amount of a topoisomerase II inhibitor (eg, etoposide) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40-500 mg/m ² , 50-300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m 2 , m ² , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg/m ² , about 110 mg/m ² , about 120 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 250 mg/m ² , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , or about 1000 mg/m ² (eg, 20 mg/m ² , 30 mg/m ² , 40 mg/m ² , 50 mg/m ² , 60 mg/m ² , 70 mg/m ² , 80 mg/m ² , 90 mg/m ² , 100 mg/m ² , 110 mg/m ² , 120 mg/m ² , 130 mg/ m ² , 140 mg/m ² , 150 mg/m ² , 160 mg/m ² , 170 mg/m ² , 180 mg/m ² , 190 mg/m ² , 200 mg/m ² , 250 mg/m ² , 300 mg/m ² , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , or 1000 mg/m ² ) )to be. In some cases, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is about 100 mg/m ² . In some cases, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is about 100 mg/m ² on days 1 to 3 every 3 weeks. In some cases, the effective amount of the topoisomerase II inhibitor (eg, etoposide) is 100 mg/m ² on days 1 to 3 every 3 weeks.

In some embodiments, the topoisomerase II inhibitor (eg, etoposide) is administered to the subject intravenously (eg, over a 60 minute infusion).

In some cases, an effective amount of a topoisomerase II inhibitor (eg, doxorubicin) is 10-1000 mg/m ² (eg, 20-800 mg/m ² , 30-700 mg/m ² , 40-500 mg/m 2 ) m ² , 50-300 mg/m ² , 75-200 mg/m ² , or 80-150 mg/m ² , such as about 20 mg/m ² , about 30 mg/m ² , about 40 mg/m ² . , about 50 mg/m ² , about 60 mg/m ² , about 70 mg/m ² , about 80 mg/m ² , about 90 mg/m ² , about 100 mg/m ² , about 110 mg/m ² , about 120 mg/m ² , about 130 mg/m ² , about 140 mg/m ² , about 150 mg/m ² , about 160 mg/m ² , about 170 mg/m ² , about 180 mg/m ² , about 190 mg/m ² , about 200 mg/m ² , about 250 mg/m ² , about 300 mg/m ² , about 400 mg/m ² , about 500 mg/m ² , about 600 mg/m ² , about 700 mg/m ² , about 800 mg/m ² , about 900 mg/m ² , or about 1000 mg/m ² (eg, 20 mg/m ² , 30 mg/m ² , 40 mg/m ² , 50 mg/m 2 ) m ² , 60 mg/m ² , 70 mg/m ² , 80 mg/m ² , 90 mg/m ² , 100 mg/m ² , 110 mg/m ² , 120 mg/m ² , 130 mg/m ² , 140 mg/m ² , 150 mg/m ² , 160 mg/m ² , 170 mg/m ² , 180 mg/m ² , 190 mg/m ² , 200 mg/m ² , 250 mg/m ² , 300 mg/m ² , 400 mg/m ² , 500 mg/m ² , 600 mg/m ² , 700 mg/m ² , 800 mg/m ² , 900 mg/m ² , or 1000 mg/m ² )) . In some cases, the effective amount of the topoisomerase II inhibitor (eg, doxorubicin) is about 60 mg/m ² . In some cases, the effective amount of the topoisomerase II inhibitor (eg, doxorubicin) is 60 mg/m ² . In some cases, the effective amount of the topoisomerase II inhibitor (eg, doxorubicin) is about 100 mg/m ² . In some cases, the effective amount of the topoisomerase II inhibitor (eg, doxorubicin) is 100 mg/m ² . In some cases, the dose of the topoisomerase II inhibitor (eg, doxorubicin) is reduced or delayed to avoid toxicity.

In some embodiments, the topoisomerase II inhibitor (eg, doxorubicin) is administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, on days 1, 8 and 15 of each 21 day cycle, or It may be administered on days 1, 8 and 15 of each 28-day cycle. In some embodiments, the platinum-based chemotherapeutic agent (eg, carboplatin or cisplatin) may be administered every two weeks.

In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered to the subject as an IV bolus over 3-5 minutes. In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered to the subject by IV infusion over 15-30 minutes. In some embodiments, the topoisomerase II inhibitor (eg, doxorubicin) is administered to the subject intravenously (eg, over a 60 minute infusion).

alkylating agent

A therapeutically effective amount of an alkylating agent (eg, cyclophosphamide) administered to a human can be from about 400 to about 800 mg/m ² (eg, about 400 mg/m ² , about 425 mg/m 2 , in one or more administrations). ² , about 450 mg/m ² , about 475 mg/m ² , about 500 mg/m ² , about 525 mg/m ² , about 550 mg/m ² , about 575 mg/m ² , about 600 mg/m ² , about 625 mg/m ² , about 650 mg/m ² , about 675 mg/m ² , about 700 mg/m ² , about 725 mg/m ² , about 750 mg/m ² , about 775 mg/m ² , or about 800 mg/m ² (eg, 400 mg/m ² , 425 mg/m ² , 450 mg/m ² , 475 mg/m ² , 500 mg/m ² , 525 mg/m ² , 550 mg/m ² , 575 mg/m ² , 600 mg/m ² , 625 mg/m ² , 650 mg/m ² , 675 mg/m ² , 700 mg/m ² , 725 mg/m ² , 750 mg/m ² , 775 mg/m ² , or 800 mg/m ² ) For example, in some embodiments, about 600 mg/m ² of an alkylating agent (eg, cyclophosphamide) is administered. In embodiments, about 600 mg/m ² of alkylating agent (eg, cyclophosphamide) is administered every two weeks.In some embodiments, about 600 mg/m ² of cyclophosphamide is administered. In some cases, about 600 mg/m ² of cyclophosphamide is administered every two weeks, in some embodiments, 600 mg/m ² of an alkylating agent (eg, cyclophosphamide) is administered every two weeks. In embodiments, the alkylating agent (eg, cyclophosphamide) is administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, on days 1, 8 and 15 of each 21 day cycle, each 28 day cycle on days 1 and 22, or on days 1, 8 and 15 of each 28-day cycle.

In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered to the subject as an IV bolus over 3-5 minutes. In some embodiments, the alkylating agent (eg, cyclophosphamide) is administered to the subject by IV infusion.

Dosing of colony stimulating factors

A therapeutically effective amount of a colony stimulating factor (CSF (eg, G-CSF (eg, pegfilgrastim or filgrastim) and GM-CSF (eg, sagramostim)) administered to a human is from about 1 to about 100 mg. (e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg , about 25 mg, about 30 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg).For example, in some embodiments In the field, about 6 mg is administered Colony stimulating factor (CSF) administered to humans (eg G-CSF (eg pegfilgrastim or filgrastim) and GM-CSF (eg sagramostim)) A therapeutically effective amount of about 1 to about 100 mg (eg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg) In some embodiments, 6 mg of pegfilgrastim is administered. In some embodiments, the colony stimulating factor is pegfilgrastim.In some embodiments, the colony stimulating factor is filgrastim.In some embodiments, about 6 mg of pegfilgrastim is administered. .

A therapeutically effective amount of a colony stimulating factor (eg, G-CSF (eg, pegfilgrastim or filgrastim) and GM-CSF (eg, sagrammostim)) administered to a human is from about 1 to about 400 mcg/kg per day (eg, about 1 mcg/kg/day, about 2 mcg/kg/day, about 3 mcg/kg/day, about 4 mcg/kg/day, about 5 mcg/kg/day, about 6 mcg/kg /day, about 7 mcg/kg/day, about 8 mcg/kg/day, about 9 mcg/kg/day, about 10 mcg/kg/day, about 15 mcg/kg/day, about 20 mcg/kg/day , about 25 mcg/kg/day, about 50 mcg/kg/day, about 75 mcg/kg/day, about 100 mcg/kg/day, about 125 mcg/kg/day, about 150 mcg/kg/day, about 175 mcg/kg/day, about 200 mcg/kg/day, about 225 mcg/kg/day, about 250 mcg/kg/day, about 275 mcg/kg/day, about 300 mcg/kg/day, about 325 mcg /kg/day, about 350 mcg/kg/day, about 375 mcg/kg/day, or about 400 mcg/kg/day). For example, in some embodiments, about 250 mcg/m ² /day is administered. In some embodiments, a therapeutically effective amount of a colony stimulating factor (eg, G-CSF (eg, pegfilgrastim or filgrastim) and GM-CSF (eg, sagramostim)) administered to a human is 1 to 400 mcg/kg/day (eg, 1 mcg/kg/day, 2 mcg/kg/day, 3 mcg/kg/day, 4 mcg/kg/day, 5 mcg/kg/day, 6 mcg/kg/day , 7 mcg/kg/day, 8 mcg/kg/day, 9 mcg/kg/day, 10 mcg/kg/day, 15 mcg/kg/day, 20 mcg/kg/day, 25 mcg/kg/day, 50 mcg/kg/day, 75 mcg/kg/day, 100 mcg/kg/day, 125 mcg/kg/day, 150 mcg/kg/day, 175 mcg/kg/day, 200 mcg/kg/day, 225 mcg/kg/day, 250 mcg/kg/day, 275 mcg/kg/day, 300 mcg/kg/day, 325 mcg/kg/day, about 350 mcg/kg/day, 375 mcg/kg/day, or 400 mcg/kg/day). For example, in some embodiments, about 250 mcg/m ² /day is administered. In some embodiments, the colony stimulating factor (eg, G-CSF (eg, pegfilgrastim or filgrastim) and GM-CSF (eg, sagramostim)) is administered by subcutaneous injection. In some embodiments, the colony stimulating factor is sagramostim. In some embodiments, sagramostim is administered to the human at a dose of about 250 mcg/m2/day. In some embodiments, sagramostim is administered to the human at a dose of 250 mcg/m2/day.

Dosing of VEGF antagonists

In some cases, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered every 3 weeks (eg, on Day 1 (eg, 1 day ± 3 days) of each 21-day dosing cycle)) about 0.01 mg/kg to about 50 mg/kg (eg, about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg, of the subject's body weight) /kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 10 mg/kg to about 20 mg/kg , such as from about 12.5 mg/kg to about 15 mg/kg, such as about 15 ± 2 mg/kg, about 15 ± 1 mg/kg, about 15 ± 0.5 mg/kg, about 15 ± 0.2 mg/kg, or about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the effective amount of the VEGF antagonist (eg, an anti VEGF antibody (eg, bevacizumab)) is from about 0.01 mg/kg to about 15 mg/kg (eg, about 0.1 mg/kg) of the subject's body weight every 3 weeks. kg to about 15 mg/kg, such as about 0.5 mg/kg to about 15 mg/kg, such as about 1 mg/kg to about 15 mg/kg, such as about 2.5 mg/kg to about 15 mg/kg, For example, from about 5 mg/kg to about 15 mg/kg, such as from about 7.5 mg/kg to about 15 mg/kg, such as from about 10 mg/kg to about 15 mg/kg, such as from about 12.5 mg/kg to about 15 mg/kg, such as about 14 mg/kg to about 15 mg/kg, such as about 15 ± 1 mg/kg, such as about 15 ± 0.5 mg/kg, such as about 15 ± 0.2 mg/kg, For example, a dose of about 15 ± 0.1 mg/kg, such as about 15 mg/kg). In some cases, the effective amount of the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) is a dose of about 15 mg/kg administered every 3 weeks. In some cases, the effective amount of the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) is administered every 2 weeks (eg, on Day 1 (eg, 1 day±3 days) of each 14-day dosing cycle) or from about 0.01 mg/kg to about 50 mg/kg (eg, from about 0.01 mg/kg to about 50 mg/kg of body weight of the subject on days 1 (eg, day 1±3) and day 15 (eg, day 15±3)) of each 28-day dosing cycle about 0.01 mg/kg to about 45 mg/kg, such as about 0.1 mg/kg to about 40 mg/kg, such as about 1 mg/kg to about 35 mg/kg, such as about 2.5 mg/kg to about 30 mg/kg, such as about 5 mg/kg to about 25 mg/kg, such as about 7.5 mg/kg to about 20 mg/kg, such as about 7.5 mg/kg to about 15 mg/kg, such as about 7.5 mg/kg to about 12.5 mg/kg, such as about 10 ± 2 mg/kg, about 10 ± 1 mg/kg, about 10 ± 0.5 mg/kg, about 10 ± 0.2 mg/kg, or about 10 ± 0.1 mg /kg, such as about 10 mg/kg). In some cases, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is from about 0.01 mg/kg to about 15 mg/kg (eg, about 0.1 mg/kg) of the subject's body weight every two weeks. kg to about 15 mg/kg, such as about 0.5 mg/kg to about 15 mg/kg, such as about 1 mg/kg to about 15 mg/kg, such as about 2.5 mg/kg to about 15 mg/kg, For example, about 5 mg/kg to about 15 mg/kg, such as about 7.5 mg/kg to about 12.5 mg/kg, such as about 8 mg/kg to about 12

mg/kg, such as about 9 mg/kg to about 11 mg/kg, such as about 9.5 mg/kg to about 10.5 mg/kg, such as about 10 ± 1 mg/kg, such as about 10 ± 0.5 mg/kg kg, such as about 10 ± 0.2 mg/kg, such as about 10 ± 0.1 mg/kg, such as about 10 mg/kg). In some cases, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of about 10 mg/kg administered every two weeks. In some cases, the effective amount of the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) is a dose of about 5 mg/kg administered every two weeks. In some cases, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of about 7.5 mg/kg administered every two weeks.

In some cases, the effective amount of the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is 0.01 mg/kg to 50 mg/kg (eg, 0.01 mg/kg to) of the subject's body weight every 3 weeks. 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg /kg, such as 10 mg/kg to 20 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 15 ± 2 mg/kg, 15 ± 1 mg/kg, 15 ± 0.5 mg/kg, 15 ± 0.2 mg/kg, or 15 ± 0.1 mg/kg, such as 15 mg/kg). In some embodiments, the effective amount of the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is 0.01 mg/kg to 15 mg/kg (eg, 0.1 mg/kg to 15) of the subject's body weight every 3 weeks. mg/kg, such as 0.5 mg/kg to 15 mg/kg, such as 1 mg/kg to 15 mg/kg, such as 2.5 mg/kg to 15 mg/kg, such as 5 mg/kg to 15 mg/kg kg, such as 7.5 mg/kg to 15 mg/kg, such as 10 mg/kg to 15 mg/kg, such as 12.5 mg/kg to 15 mg/kg, such as 14 mg/kg to 15 mg/kg, eg 15±1 mg/kg, eg 15±0.5 mg/kg, eg 15±0.2 mg/kg, eg 15±0.1 mg/kg, eg 15 mg/kg). In some cases, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of 15 mg/kg administered every 3 weeks. In some cases, the effective amount of the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is 0.01 mg/kg to 50 mg/kg (eg, 0.01 mg/kg to) of the subject's body weight every two weeks. 45 mg/kg, such as 0.1 mg/kg to 40 mg/kg, such as 1 mg/kg to 35 mg/kg, such as 2.5 mg/kg to 30 mg/kg, such as 5 mg/kg to 25 mg /kg, such as 7.5 mg/kg to 20 mg/kg, such as 7.5 mg/kg to 15 mg/kg, such as 7.5 mg/kg to 12.5 mg/kg, such as 10 ± 2 mg/kg, 10 ± 1 mg/kg, 10±0.5 mg/kg, 10±0.2 mg/kg, or 10±0.1 mg/kg, such as 10 mg/kg). In some embodiments, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is 0.01 mg/kg to 15 mg/kg (eg, 0.1 mg/kg to 15) of the subject's body weight every two weeks. mg/kg, such as 0.5 mg/kg to 15 mg/kg, such as 1 mg/kg to 15 mg/kg, such as 2.5 mg/kg to 15 mg/kg, such as 5 mg/kg to 15 mg/kg kg, such as 7.5 mg/kg to 12.5 mg/kg, such as 8 mg/kg to 12 mg/kg, such as 9 mg/kg to 11 mg/kg, such as 9.5 mg/kg to 10.5 mg/kg, For example, a dose of 10 ± 1 mg/kg, such as 10 ± 0.5 mg/kg, such as 10 ± 0.2 mg/kg, such as 10 ± 0.1 mg/kg, such as 10 mg/kg). In some cases, the effective amount of the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) is a dose of 10 mg/kg administered every two weeks. In some cases, the effective amount of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is a dose of 5 mg/kg administered every two weeks. In some cases, the effective amount of the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) is a dose of 7.5 mg/kg administered every two weeks.

In some cases, combination therapy (eg, an anti TIGIT antagonist antibody, such as an anti TIGIT antagonist antibody disclosed herein (eg, tiragolumab) and/or a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody) The dose of the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) administered as an anti-PD-1 antagonist antibody (eg, pembrolizumab)) is the PD administered as a monotherapy. -1 may be reduced compared to the standard dose of an axis binding antagonist.

In some cases, the VEGF antagonist (eg, an anti-VEGF antibody (eg, bevacizumab)) is administered intravenously. In some cases, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered in 90±15 minutes (eg, about 75 minutes, about 76 minutes, about 77 minutes, about 78 minutes, about 79 minutes, About 80 minutes, about 81 minutes, about 82 minutes, about 83 minutes, about 84 minutes, about 85 minutes, about 86 minutes, about 87 minutes, about 88 minutes, about 89 minutes, about 90 minutes, about 91 minutes, about 92 minutes, about 93 minutes, about 94 minutes, about 95 minutes, about 96 minutes, about 97 minutes, about 98 minutes, about 99 minutes, about 100 minutes, about 101 minutes, about 102 minutes, about 103 minutes, about 104 minutes, or about 105 minutes). Alternatively, in some embodiments, the VEGF antagonist (eg, anti-VEGF antibody (eg, bevacizumab)) is administered subcutaneously.

J. Assessment of PD-L1 expression

Expression of PD-L1 can be assessed in a subject being treated according to any of the methods, uses, and compositions for use described herein. The methods, uses, and compositions for use may comprise determining the expression level of PD-L1 in a biological sample (eg, a tumor sample) obtained from the subject. In some cases, the patient has bladder cancer, and the sample is a transurethral resection (TURBT) sample of a bladder tumor. In some cases, the sample is a cystectomy or nephrectomy sample. In some cases, the sample is a lobectomy, lobectomy, bilobectomy, or pneumonectomy sample. In some cases, the sample is a cystectomy or lymphadenectomy sample. In other instances, the expression level of PD-L1 in a biological sample obtained from the subject (eg, a tumor sample) is determined prior to or after initiation of treatment. PD-L1 expression can be determined using any suitable approach. For example, PD-L1 expression can be determined as described in US Patent Application Nos. US20180030138A1 and US20180037655A1. Any suitable tumor sample may be a formalin-fixed and paraffin-embedded (FFPE) tumor sample, a storage tumor sample, a refrigerated tumor sample, or a frozen tumor sample.

For example, PD-L1 expression is dependent on tumor invasiveness in a tumor sample expressing a detectable expression level of PD-L1 in terms of the percentage of tumor infiltrating immune cells expressing a detectable expression level of PD-L1 in the tumor sample. as a percentage of immune cells and/or as a percentage of tumor cells in a tumor sample that express a detectable expression level of PD-L1. In any of the preceding examples, the percentage of tumor-infiltrating immune cells in the tumor sample is, for example, as assessed by IHC with an anti-PD-L1 antibody (eg, SP142 antibody), tumor in a section of a sample obtained from the subject. It should be understood that it may be in terms of the percentage of tumor area covered by infiltrating immune cells. Any suitable anti-PD-L1 antibody is, for example, SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics) and 9A11. In some embodiments, the anti-PD-L1 antibody is SP142. In some embodiments, The anti-PD-L1 antibody is SP263 In some embodiments, the anti-PD-L1 antibody is 22C3 In some embodiments, the anti-PD-L1 antibody is 28-8.

In some embodiments, the tumor sample obtained from the subject has a detectable expression level of PD-L1 of less than 1% of tumor cells in the tumor sample, greater than or equal to 1% of tumor cells in the tumor sample, of tumor cells in the tumor sample. between 1% and less than 5%, at least 5% of the tumor cells in the tumor sample, between 5% and less than 50% of the tumor cells in the tumor sample, or at least 50% of the tumor cells in the tumor sample.

In some embodiments, the tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor infiltrating immune cells of less than 1% of the tumor sample, greater than 1% of the tumor sample, between 1% and 5% of the tumor sample. %, greater than 5% of the tumor sample, between 5% and less than 10% of the tumor sample, or greater than 10% of the tumor sample.

In some aspects, the tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor infiltrating immune cells of 5%-19% (eg, 5%-19% TIC) of the tumor sample; For example, PD-L1 has a low PD-L1 expression level. In some aspects, the tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor infiltrating immune cells of at least 20% (eg, at least 20% TIC) of the tumor sample; For example, PD-L1 has a high level of PD-L1 expression. In some embodiments, a tumor sample determined to have a TIC of at least 5% is comparable to at least 1 CPS.

In some examples, the tumor sample may be scored for PD-L1 positivity in tumor infiltrating immune cells and/or tumor cells according to the diagnostic evaluation criteria set forth in Table 1 and/or Table 2, respectively.

PD-L1 Diagnostic Assessment IC score No discernable PD-L1 staining OR
Presence of identifiable PD-L1 staining of any intensity in tumor-infiltrating immune cells occupying <1% of the tumor area occupied by tumor cells, associated intratumoral stroma, and adjacent peritumoral connective tissue forming stroma IC0 Presence of identifiable PD-L1 staining of any intensity in tumor-infiltrating immune cells occupying ≥1% to <5% of the tumor area occupied by tumor cells, associated intratumoral stroma, and adjacent peritumoral connective tissue forming stroma IC1 Presence of identifiable PD-L1 staining of any intensity in tumor-infiltrating immune cells occupying ≥5% to <10% of the tumor area occupied by tumor cells, associated intratumoral stroma and adjacent peritumoral connective tissue forming stroma IC2 Presence of identifiable PD-L1 staining of any intensity in tumor-infiltrating immune cells occupying >10% of the tumor area occupied by tumor cells, associated intratumoral stroma and adjacent peritumoral connective tissue forming stroma IC3

IHC Diagnostic Criteria for Tumor Infiltrating Immune Cells (IC)

PD-L1 Diagnostic Assessment TC score No discernable PD-L1 staining OR
Presence of identifiable PD-L1 staining of any intensity in <1% of tumor cells TC0 Presence of identifiable PD-L1 staining of any intensity in >1% to <5% of tumor cells TC1 Presence of identifiable PD-L1 staining of any intensity in >5% to <50% of tumor cells TC2 Presence of identifiable PD-L1 staining of any intensity in ≥50% of tumor cells TC3

IHC diagnostic criteria for tumor cells (TC)

In some cases, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1-selected tumor (eg, the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC)) ratio is greater than or equal to 5% in the tumor sample as determined by IHC with SP142 antibody). In some cases, the PD-L1-selected tumor is a tumor in which the proportion of tumor area occupied by PD-L1-expressing immune cells (IC) is determined to be greater than or equal to 5% by immunohistochemical (IHC) analysis. In some cases, the IHC assay uses anti-PD-L1 antibodies SP142, SP263, 22C3, or 28-8. In some cases, the IHC assay uses anti-PD-L1 antibody SP142. In some cases, the IHC IHC assay uses the anti-PD-L1 antibody SP263. In some cases, the IHC assay uses anti-PD-L1 antibody 22C3. In some cases, the IHC assay uses anti-PD-L1 antibody 22C3. In some cases, the IHC assay uses anti-PD-L1 antibody 28-8.

In some cases, the IC was determined to be greater than or equal to 5% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC score was determined to be 2 or 3 (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 1% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 10% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 1% and less than 50% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay). In some cases, the IC was determined to be greater than or equal to 1% and less than 30% (eg, as determined using a Ventana (SP142) PD-L1 IHC assay).

In some cases, in a method, use, or composition for use described herein, a tumor sample obtained from an individual has a detectable protein expression level of PD-L1. In some cases, detectable protein expression levels of PD-L1 were determined by IHC analysis. In some cases, the IHC assay uses anti-PD-L1 antibody SP142. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor infiltrating immune cells comprising at least 5% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 1% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor infiltrating immune cells comprising at least 1% and less than 5% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 5% and less than 10% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells comprising at least 10% of the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 1% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 1% and less than 5% of tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 5% and less than 50% of the tumor cells in the tumor sample. In some cases, the tumor sample has been determined to have a detectable expression level of PD-L1 in at least 50% of the tumor cells in the tumor sample.

In some cases, in any method, use, or composition for use described herein, the subject has a PD-L1 selected tumor (eg, as determined by IHC with PD-L1 high (eg, IHC with SP263 antibody). (PD-L1 tumor rate score (TPS) greater than 50% in the same tumor sample. In some cases, the PD-L1 selected tumor is the selected PD-L1 high. In some cases, the PD-L1 selected tumor is the tumor determined by immunohistochemical (IHC) analysis to be greater than or equal to 50% TPS.In some cases, the IHC analysis uses anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some cases, said IHC assay uses anti-PD-L1 antibody SP263.In some cases, said IHC assay uses anti-PD-L1 antibody SP142.In some cases, said IHC assay uses anti-PD-L1 antibody 22C3 is used.In some cases, the TPS is determined to be greater than or equal to 50% (eg, as determined using Ventana (SP263) PD-L1 IHC analysis).In some cases, the TPS is determined to be greater than 50%. was determined to be less than (eg, as determined using Ventana (SP263) PD-L1 IHC analysis) In some cases, the TPS was determined to be greater than or equal to 1% (eg, Ventana (SP263) PD-L1). As determined using an IHC assay) In some cases, the TPS was determined to be greater than or equal to 1% and less than 50% (eg, as determined using a Ventana (SP263) PD-L1 IHC assay).

In some cases, in a method, use, or composition for use described herein, a tumor sample obtained from an individual has a detectable protein expression level of PD-L1. In some cases, detectable protein expression levels of PD-L1 were determined by IHC analysis. In some cases, the IHC assay uses the anti-PD-L1 antibody SP263. In some cases, the tumor sample has been determined to have a fraction of PD-L1 positive tumor cells greater than or equal to 50% of the tumor sample. In some cases, the tumor sample has been determined to have a fraction of PD-L1 positive tumor cells less than 50% of the tumor sample. In some cases, the tumor sample has been determined to have a fraction of PD-L1 positive tumor cells that is greater than or equal to 1% and less than 50% of the tumor sample.

In some cases, the IHC assay uses the anti-PD-L1 antibody 22C3. In some cases, the IHC assay is a pharmDx 22C3 IHC assay. In some cases, the PD-L1 positive tumor cell fraction is greater than or equal to 50% as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the tumor sample has a composite positive score (CPS) of at least 10 and a tumor rate score in the tumor sample, e.g., as determined using anti-PD-L1 antibody 22C3 as part of a PalmDx 22C3 IHC assay TPS) was determined to be greater than or equal to 1%. In some embodiments, the tumor sample has a CPS of 10 or greater and a TPS of greater than or equal to 1% and less than 50% in the tumor sample, e.g., as determined using anti-PD-L1 antibody 22C3 as part of a PalmDx 22C3 IHC assay. It was decided. In some embodiments, the tumor sample has a CPS of 20 or greater and a TPS of 50% or greater in the tumor sample, eg, as determined using anti-PD-L1 antibody 22C3 as part of a PalmDx 22C3 IHC assay. In some embodiments, a tumor sample determined to have a CPS of 1 or greater is similar to a CPS of 5% or greater.

In some cases, the IHC assay uses the anti-PD-L1 antibody 28-8. In some cases, the IHC assay is a PalmDx 28-8 IHC assay. In some cases, the PD-L1 positive tumor cell fraction is greater than or equal to 50% as determined by positive staining with anti-PD-L1 antibody 28-8.

In some cases, in a method, use, or composition for use described herein, a tumor sample obtained from an individual has a detectable nucleic acid expression level of PD-L1. In some cases, the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. became In some cases, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some cases, the tissue sample is a tumor sample. In some cases, the tumor sample comprises tumor infiltrating immune cells, tumor cells, stromal cells, and any combination thereof.

K. Assessment of TIGIT expression

Expression of TIGIT can be assessed in a subject being treated according to any of the methods, uses, and compositions for use described herein. The methods, uses, and compositions for use may comprise determining the expression level of TIGIT in a biological sample (eg, a tumor sample) obtained from the subject. In other examples, the expression level of TIGIT in a biological sample obtained from the subject (eg, a tumor sample) is determined prior to or after initiation of treatment. TIGIT expression can be determined using any suitable approach. Any suitable tumor sample may be a formalin-fixed and paraffin-embedded (FFPE) tumor sample, a storage tumor sample, a refrigerated tumor sample, or a frozen tumor sample.

For example, TIGIT expression is defined as the percentage of tumor infiltrating immune cells in a tumor sample expressing a detectable expression level of TIGIT in terms of the percentage of tumor infiltrating immune cells expressing a detectable expression level of TIGIT in the tumor sample, and/or as the percentage of tumor cells in the tumor sample that express a detectable expression level of TIGIT. In any of the preceding examples, the percentage of tumor-infiltrating immune cells in the tumor sample that is covered by tumor-infiltrating immune cells in a section of the sample obtained from the subject, e.g., as assessed by IHC using an anti-TIGIT antagonist antibody. It should be understood that it may be in terms of a percentage of tumor area. Any suitable anti-TIGIT antagonist antibody may be used. In some embodiments, the anti-TIGIT antagonist antibody is 10A7 (WO 2009/126688A3; US Pat. No. 9,499,596).

L. Assessment of EGFR and ALK or higher

In some cases, in a method, use, or compositions for use described herein, the subject does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormality. In some cases, in a method, use, or compositions for use described herein, the subject has an EGFR gene mutation (eg, a sensitizing or activating EGFR gene mutation) or an ALK gene rearrangement (eg, an ALK fusion oncogene) do not have In some cases, the subject has an Eastern Corporate Oncology Group (ECOG) systemic activity (PS) of 0 or 1.

Methods for detecting the mutant state EGFR and ALK are generally known in the art, and DNA from a clinical sample (e.g., a tumor biopsy or a blood sample (e.g., circulating tumor DNA in blood)) can be analyzed using next-generation sequencing methods; including, but not limited to, sequencing using, for example, targeted gene pulldown and sequencing methods described in Frampton et al. ( Nature Biotechnology . 31(11): 1023-1033, 2013), which is incorporated herein in its entirety. This sequencing method can be used in conjunction with any of the methods disclosed herein to detect a variety of mutations (eg, insertions, deletions, base substitutions, local gene amplifications and/or homozygous gene deletions), while simultaneously extracting small samples. (e.g. small core needle biopsy, fine needle aspiration and/or cell blocks) or fixed samples (e.g., formalin fixed and paraffin embedded (FFPE) samples).Detect mutation status of EGFR and ALK Other methods include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods.Exemplary methods for detection of mutant state of ALK are disclosed in US Pat. No. 9,651,555, which is herein incorporated by reference in its entirety. In some cases, the VENTANA® anti- ALK (D5F3) IHC assay is used to determine the mutation status of the ALK gene.

In some cases of any of the methods described herein, the mutation is a sensitizing EGFR mutation. Sensitizing EGFR mutations are generally known in the art and described in US Patent Publication Nos. US 2018/0235968 and in Juan et al. ( Therapeutic Advances in Medical Oncology. 9(3): 201-216, 2017), which is incorporated herein by reference in its entirety. In some cases, the sensitizing EGFR mutation is a mutation in any one of exon 18-21 (eg, a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some cases, the sensitizing EGFR mutation is a deletion in exon 19 (del19). In other examples, the sensitizing EGFR mutation is an L858R point mutation in exon 21. In some cases, the sensitizing EGFR mutation is a G719X point mutation of exon 18, wherein "X" is most commonly C, A, or S. In some cases, the sensitizing EGFR mutation is a G719S point mutation of exon 18. In some cases, the sensitizing EGFR mutation is a G719A point mutation in exon 18. In some cases, the sensitizing EGFR mutation is an S720F point mutation in exon 18. In some cases, the sensitizing EGFR mutation is an L861Q point mutation in exon 21. In some cases, the sensitizing EGFR mutation is an L861R point mutation in exon 21. In other cases, the sensitizing EGFR mutation is the T790M point mutation. In some cases, the sensitizing EGFR mutation is an E709X point mutation, wherein “X” is most commonly K, A, or H. In some cases, the sensitizing EGFR mutation is an S768I point mutation.

In some cases of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are generally known in the art and described in US Pat. Nos. 9,651,555 and in Du et al. ( Thoracic Cancer. 9: 423-430, 2018), which is incorporated herein by reference in its entirety. In some cases, ALK gene rearrangement results in the production of oncogenic ALK tyrosine kinases that activate downstream signaling pathways to increase cell proliferation and survival. In some cases, the ALK gene rearrangement is a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A , BIRC6, RANBP2, ATIC, CLTC, TMP4, and MSN . ALK rearrangement with and forms a fusion oncogene. In some cases, the ALK gene rearrangement is an EML4 rearrangement with ALK and forms the fusion oncogene EML4-ALK .

IV. Exemplary Anti-TIGIT Antagonist Antibodies, PD-1 Axis Binding Antagonists, and Other Agents

Exemplary anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, chemotherapeutic agents, colony stimulating factors, and VEGF antagonists are described herein.

A. Exemplary Anti-TIGIT Antagonist Antibodies

The present invention provides anti-TIGIT antagonist antibodies useful for treating cancer in a subject (eg, a human).

In some cases, the anti-TIGIT antagonist antibody is tiragolumab (CAS Accession Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A.

In certain instances, the anti-TIGIT antagonist antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and/or (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6), or at least about 90% sequence identity to one or more of said HVRs and any one of SEQ ID NO: 1 to SEQ ID NO: 6 (e.g., 90% %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). , 4, 5 or 6 HVRs.

In some cases, the anti-TIGIT antagonist antibody comprises HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and/or (f) an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some cases, the anti-TIGIT antagonist antibody is EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS, such as at least 90%, 91%, 94%, (such as at least 90%, 91%, 94%, SEQ ID NO: %, 98% or 99% sequence identity) or QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (at least 95% sequence identity), such as at least 95% sequence identity, or 92% identity, such as at least 90% sequence identity a VH domain comprising an amino acid sequence having 96%, 97%, 98% or 99% sequence identity; and/or DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO:19) or a sequence thereof with at least 90% sequence identity (such as at least 90% 99%, 91% 91%, such as a VL domain comprising an amino acid sequence with the same identity). In some cases, the anti-TIGIT antagonist antibody has at least 90% sequence identity to SEQ ID NO:17 or a sequence thereof (eg, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 A VH domain comprising an amino acid sequence having % or 99% sequence identity, and/or at least 90% sequence identity (eg, at least 91%, 92%, 93%, 94%, 95 %, 96%, 97%, 98% or 99% sequence identity). In some cases, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, the anti-TIGIT antagonist antibody has at least 90% sequence identity to SEQ ID NO:18 or a sequence thereof (eg, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 A VH domain comprising an amino acid sequence having % or 99% sequence identity, and/or at least 90% sequence identity (eg, at least 91%, 92%, 93%, 94%, 95 %, 96%, 97%, 98% or 99% sequence identity). In some cases, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

일부 경우들에서, 상기 항 TIGIT 길항제 항체는 중쇄 및 경쇄 서열을 포함하고, 여기서: (a) 상기 중쇄는 하기의 아미노산 서열: EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(서열번호 33)를 포함하고; (b) 상기 경쇄는 하기의 아미노산 서열: DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(서열번호 34)를 포함한다.

In some cases, the anti-TIGIT antagonist antibody comprises a light chain variable region framework region (FR): FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and/or a FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), or at least about 90% sequence identity (e.g., 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). more dogs. In some cases, for example, the antibody comprises FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

In some cases, the anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs: FR-H1 comprising the amino acid sequence of X ₁ VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X ₁ is E or Q; FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or at least about 90% sequence identity (e.g., 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). more dogs. The anti-TIGIT antagonist antibody comprises FR-H1 comprising the amino acid sequence of the following heavy chain variable region FRs: EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or at least about 90% sequence identity (e.g., 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). more dogs. In some cases, the anti-TIGIT antagonist antibody comprises FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In other instances, for example, the anti-TIGIT antagonist antibody comprises FR-H1 comprising the amino acid sequence of the following heavy chain variable region FRs: QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or at least about 90% sequence identity with one or more of said FRs and any one of SEQ ID NO: 12 to SEQ ID NO: 14 and SEQ ID NO: 16 (e.g., at least 1, 2, 3 selected from combinations of one or more variants thereof having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). dogs, or 4 more. In some cases, the anti-TIGIT antagonist antibody comprises FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

In another aspect, an anti TIGIT antagonist antibody is provided, wherein said antibody comprises a VH as in any of the instances provided above and a VL as in any of the instances provided above, wherein one or both of said variable domain sequences are provided. All include post-translational modifications.

In some cases, any of the anti-TIGIT antagonist antibodies are capable of binding rabbit TIGIT in addition to human TIGIT. In some cases, any of the anti-TIGIT antagonist antibodies described above can bind to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some cases, any of the anti-TIGIT antagonist antibodies described above are capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some cases, any of the anti-TIGIT antagonist antibodies described above can bind human TIGIT, cyno TIGIT, and rabbit TIGIT, but not murine TIGIT.

In some cases, the anti TIGIT antagonist antibody binds human TIGIT with a K _{D of about 10 nM or less and cyno TIGIT with a K D of} about 10 nM or less (eg, between about 0.1 nM and about 1 nM of human TIGIT). binds to cyno TIGIT with a K _D of about 0.5 nM to about 1 nM, such as to human TIGIT with a K _D of about 0.1 nM or less and to cyno _TIGIT with a K _D of about 0.5 nM or less).

In some cases, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with a poliovirus receptor (PVR) (eg, the antagonist antibody binds to a cell mediated by TIGIT binding to PVR). inhibit my signaling). In some cases, the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or less (eg, 1 nM to about 10 nM). In some cases, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with PVR without affecting PVR-CD226 interaction. In some cases, the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or less (eg, 1 nM to about 50 nM, eg, 1 nM to about 5 nM). In some cases, the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 with TIGIT. In some cases, the anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to interfere with CD226 homodimerization.

In some cases, a method or use described herein may comprise using or administering an isolated anti TIGIT antagonist antibody that competes with any of the anti TIGIT antagonist antibodies described above for binding to TIGIT. For example, the method comprises the following six HVRs for binding to TIGIT: (a) HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and/or (f) administering an isolated anti-TIGIT antagonist antibody that competes with the anti-TIGIT antagonist antibody having HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO:6). The methods described herein may also comprise administering an isolated anti TIGIT antagonist antibody that binds to the same epitope as the anti TIGIT antagonist antibody described above.

In some aspects, the anti-TIGIT antagonist antibody is a prototypical Fc mediated effector function (eg, tiragolumab, bivostolimab, ethigilumab, EOS084448 or TJ-T6) or enhanced effector function (eg, SGN-TGT). an antibody with

In other aspects, the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector function (eg, dombanalimab, BMS-986207, ASP8374, or COM902).

In some aspects, the anti-TIGIT antagonist antibody is an IgG1 class antibody, such as tiragolumab, bivostolimab, dombanalimab, BMS-986207, ethigilumab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448) , TJ-T6, or AB308.

In some aspects, the anti-TIGIT antagonist antibody is an IgG class antibody, such as ASP8374 or COM902.

Anti-TIGIT antagonist antibodies (eg, tyragolumab) useful in the present invention, including compositions containing such antibodies, include PD-1 axis binding antagonists (eg, PD-L1 binding antagonists (eg, anti-PD-L1 antagonist antibodies, such as , atezolizumab), a PD-1 binding antagonist (eg, an anti-PD-1 antagonist antibody, such as pembrolizumab), and a PD-L2 binding antagonist (eg, an anti-PD-L2 antagonist antibody)). have.

In some embodiments, the anti-TIGIT antagonist antibody functions to inhibit TIGIT signaling. In some embodiments, the anti TIGIT antagonist antibody inhibits binding of TIGIT to its binding partners. Exemplary TIGIT binding partners include CD155 (PVR), CD112 (PVRL2 or Nectin-2), and CD113 (PVRL3 or Nectin-3). In some embodiments, the anti-TIGIT antagonist antibody is capable of inhibiting binding between TIGIT and CD155. In some embodiments, the anti-TIGIT antagonist antibody is capable of inhibiting binding between TIGIT and CD112. In some embodiments, the anti-TIGIT antagonist antibody is capable of inhibiting binding between TIGIT and CD113. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT-mediated cellular signaling in immune cells. In some embodiments, the anti TIGIT antagonist antibody inhibits TIGIT by depleting regulatory T cells (eg, when engaged with FcγRs).

In some embodiments, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT 1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv and (Fab') ₂ fragments. In some embodiments, the anti-TIGIT antibody is a humanized antibody. In some embodiments, the anti-TIGIT antibody is a human antibody. In some embodiments, an anti-PD-L1 antibody described herein binds to human TIGIT. In some embodiments, the anti-TIGIT antibody is an Fc fusion protein.

In some embodiments, the anti-TIGIT antibody is tyragolumab (MTIG7192A, RG6058 or RO7092284), vivostolimab (MK-7684), ASP8374 (PTZ-201), EOS884448 (EOS-448), SEA-TGT (SGN) -TGT)), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), IBI939, dombanalimab (AB154), M6223, AB308, AB154, TJ-T6, MG1131, NB6253, HLX301, HLX53, SL-9258 (TIGIT-Fc-LIGHT), STW264, and YBL-012. In some embodiments, the anti-TIGIT antibody is tyragolumab (MTIG7192A, RG6058 or RO7092284), vivostolimab (MK-7684), ASP8374 (PTZ-201), EOS-448, and SEA-TGT (SGN-TGT). ) is selected from the group consisting of The anti-TIGIT antibody may be tiragolumab (MTIG7192A, RG6058 or RO7092284).

Non-limiting examples of anti-TIGIT antibodies useful in the methods disclosed herein and methods of making them include PCT Publication Nos. WO2018183889A1, WO2019129261A1, WO2016106302A9, WO2018033798A1, WO2020020281A1, WO2019023504A1, WO2017152088A1, WO2018405030856A1, WO2016402860823A , WO2019152574A1, and WO2020041541A2; US Pat. Nos. 10,189,902, US 10,213,505, US 10,124,061, US 10,537,633, and US 10,618,958; and US Patent Publication Nos. 2020/0095324, 2019/0112375, 2018/0371083, and 2020/0062859, which are incorporated herein by reference in their entirety. Additional non-limiting examples of anti-TIGIT antibodies useful in the methods disclosed herein and methods of making them are described in PCT Publication Nos. WO2018204363A1, WO2018047139A1, WO2019175799A2, WO2018022946A1, WO2015143343A2, WO2018218056A1, WO2019232484A1, WO2019079777 WO2017196867A1, WO2019154415A1, WO2019062832A1, WO2018234793A3, WO2018102536A1, WO2019137548A1, WO2019129221A1, WO2018102746A1, WO2018160704A9, WO2020041541A2, WO1824A No. , WO2019032619A9, WO2018157162A1, WO2020176718A1, WO2020047329A1, WO2020047329A1, WO2018220446A9; US Pat. Nos. 9,617,338, US 9,567,399, US 10,604,576, and US 9,994,637; and Patent Publication Nos. US 2018/0355040, US 2019/0175654, US 2019/0040154, US 2019/0382477, US 2019/0010246, US 2020/0164071, US 2020/0131267, US 2019/0338032 Nos., US 2019/0330351, US 2019/0202917, US 2019/0284269, US 2018/0155422, US 2020/0040082, US 2019/0263909, US 2018/0185480, US 2019/0375843, US 2017/0037133, US 2019/0077869, US 2019/0367579, US 2020/0222503, US 2020/0283496, CN109734806A, and CN110818795A, which are incorporated herein by reference in their entirety.

Anti-TIGIT antibodies useful in the methods disclosed herein include ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS-448, dombanalimab (AB154). ), vivostolimab (MK-7684), and SEA-TGT (SGN-TGT). Additional anti-TIGIT antibodies useful in the methods disclosed herein include: AGEN1307; AGEN1777; antibody clones pab2197 and pab2196 (Agenus Inc.); Antibody clones TBB8, TDC8, 3TB3, 5TB10, and D1Y1A (Anhui Anke Biotechnology Group Co. Ltd.), antibody clones MAB1, MAB2, MAB3, MAB4, MAB5, MAB6, MAB 7, MAB8, MAB9 , MAB 10, MAB 11, MAB 12, MAB13, MAB 14, MAB 15, MAB 16, MAB 17, MAB 18, MAB19, MAB20, MAB21 (Astellas Pharma/Potenza Therapeutics )), antibody clones hu1217-1-1 and hu1217-2-2 (BeiGene), antibody clones 4D4 and 19G (Brigham & Women's Hospital), antibody clones 11G11, 10D7, 15A6, 22G2, TIGIT G2a, and TIGIT G1 D265A—including these antibodies with modified heavy chain constant regions (Bristol-Myers Squibb); Antibody clones 10A7, CPA.9.086, CPA.9.083.H4 (S241P), CPA.9.086.H4 (S241P), CHA.9.547.7.H4 (S241P) and CHA.9.547.13.H4 (S241P) (Compugen (Compugen)); anti PVRIG/anti TIGIT bispecific antibody (Compugen), antibody clones 315293, 328189, 350426, 326504, and 331672 (Fred Hutchinson Cancer Research Center); Antibody clones T-01, T-02, T-03, T-04, T-05, T-06, T-07, T-08, T-09, and T-10 (Gensun BioPharma Inc.) .)); Antibody clones 1H6, 2B11, 3A10, 4A5, 4A9, 4H5, 6A2, 6B7, 7F4, 8E1, 8G3, 9F4, 9G6, 10C1, 10F10, 11G4, 12B7, 12C8, 15E9, 16C11, 16D6, and 16E10 (Hefei Ruida) Hefei Ruida Immunological Drugs Research Institute Co. Ltd.); antibody clones h3C5H1, h3C5H2, h3C5H3, h3C5H4, h3C5H3-1, h3C5H3-2, h3C5H3-3, h3C5L1, and h3C5L2 (IGM Biosciences Inc.); antibody clones 90D9, 101E1, 116H8, 118A12, 131A12, 143B6, 167F7, 221F11, 222H4, 327C9, 342A9, 344F2, 349H6, and 350D10 (I-Mab Biopharma); Antibody clones ADI-27238, ADI-30263, ADI-30267, ADI-30268, ADI-27243, ADI-30302, ADI-30336, ADI-27278, ADI-30193, ADI-30296, ADI-27291, ADI-30283, ADI-30286, ADI-30288, ADI27297, ADI-30272, ADI-30278, ADI-27301, ADI-30306, and ADI-30311 (Innovent Biologics, Inc.); Antibody clones 26518, 29478, 26452, 29487, 29489, 31282, 26486, 29494, 29499, 26521, 29513, 26493, 29520, 29523, 29527, 31288, 32919, 32931, 26432, and 32959 (Aiteos Therapeutics ( iTeos Therapeutics)); antibody clones m1707, m1708, m1709, m1710, m1711, h1707, h1708, h1709, h1710, and h1711 (Jiangsu Hengrui Medicine Co. Ltd.); antibody clones TIG1, TIG2, and TIG3 (JN Biosciences LLC); Antibody clones (eg, KY01, KY02, KY03, KY04, KY05, KY06, KY07, KY08, KY09, KY10, K11, K12, K13, K14, K15, K16, K17, K18, K19, K20, K21, K22, K23 Kymab TIGIT (antibody 2), and Tool TIGIT (antibody 4) (Kymab Limited); bispecific antibody 1D05/in-house anti TIGIT + 1D05 (anti-PD-L1) native variable domain and kymab TIGIT Antigen binding site (ABS) domain (bispecific 1), in house anti TIGIT/1D05 + chimap TIGIT native variable domain and 1D05 ABS domain (bispecific 2), tool anti TIGIT/tool anti PD-L1 + tool anti TIGIT Native variable domain and tool anti PD-L1 ABS domain (bispecific 3), tool anti PD-L1/tool anti TIGIT + tool anti PD-L1 native variable domain and tool anti TIGIT ABS domain (bispecific 4) (Kimab) Ltd): antibody clones and antibody variants 14D7, 26B10, Hu14D7, Hu26B10, 14A6, Hu14A6, 28H5, 31C6, Hu31C6, 25G10, MBS43, 37D10, 18G10, 11A11, c18G10, and LB155.14A6.G2.A8 (Merck (Merck) )); Etigilimab (OMP-313M32) (Mereo BioPharma); Antibody clones 64G1E9B4, 100C4E7D11, 83G5H11C12, 92E9D4B4, 104G12E12G2, 121C2F102F2, 82D2, 121C2F10B5, 16F2, 703F11A, 48G1E9B4, 100C4E7D11F3 128E3G7F5, AS19584, AS19852, AS19858, AS19886, AS19887, AS19888, AS20160, AS19584VH26, AS19584VH29, AS19584VH30, AS19584VH31, AS19886VH 5, AS19886VH8, AS19886VH9, AS19886VH10, AS19886VH19, AS19886VH20, AS19584VH28-Fc, AS19886VH5-Fc, AS19886VH8-Fc, AS19584-Fc, and AS19886-Fc (Nanjing Legend Biotechnology Co. Ltd.)); Antibody clones ARE clones: Ab58, Ab69, Ab75, Ab133, Ab177, Ab122, Ab86, Ab180, Ab83, Ab26, Ab20, Ab147, Ab12, Ab66, Ab176, Ab96, Ab123, Ab109, Ab149, Ab34, Ab61, Ab64, Ab105 , Ab108, Ab178, Ab166, Ab29, Ab135, Ab171, Ab194, Ab184, Ab164, Ab183, Ab158, Ab55, Ab136, Ab39, Ab159, Ab151, Ab139, Ab107, Ab36, Ab193, Ab115, Ab106, Ab13f8, Ab127, Ab165 , Ab155, Ab19, Ab6, Ab187, Ab179, Ab65, Ab114, Ab102, Ab94, Ab163, Ab110, Ab80, Ab92, Ab117, Ab162, Ab121, Ab195, Ab84, Ab161, Ab198, Ab24, Ab98, Ab116, Ab174, Ab196 , Ab51, Ab91, Ab185, Ab23, Ab7, Ab95, Ab100, Ab140, Ab145, Ab150, Ab168, Ab54, Ab77, Ab43, Ab160, Ab82, Ab189, Ab17, Ab103, Ab18, Ab130, Ab132, Ab134, Ab144; ARG clones: Ab2, Ab47, Ab49, Ab31, Ab53, Ab40, Ab5, Ab9, Ab48, Ab4, Ab10, Ab37, Ab33, Ab42, Ab45; ARV clones: Ab44, Ab97, Ab81, Ab188, Ab186, Ab62, Ab57, Ab192, Ab73, Ab60, Ab28, Ab32, Ab78, Ab14, Ab152, Ab72, Ab137, Ab128, Ab169, Ab87, Ab74, Ab172, Ab153, Ab120 , Ab13, Ab113, Ab16, Ab56, Ab129, Ab50, Ab90, Ab99, Ab3, Ab148, Ab124, Ab22, Ab41, Ab119, Ab157, Ab27, Ab15, Ab191, Ab190, Ab79, Ab181, Ab146, Ab167, Ab88, Ab199 , Ab71, Ab85, Ab59, Ab141, Ab68, Ab143, Ab46, Ab197, Ab175, Ab156, Ab63, Ab11, Ab182, Ab89, Ab8, Ab101, Ab25, Ab154, Ab21, Ab111, Ab118, Ab173, Ab38, Ab76, Ab131 , Ab1, Ab67, Ab70, Ab170, Ab30, Ab93, Ab142, Ab104, Ab112, Ab35, Ab126, and Ab125 (Rigel Pharmaceuticals, Inc.); CASC-674 (Seattle Genetics); Antibody clones 2, 2C, 3, 5, 13, 13A, 13B, 13C, 13D, 14, 16, 16C, 16D, 16E, 18, 21, 22, 25, 25A, 25B, 25C, 25D, 25E, 27, 54, 13 IgG2a fucosylation, 13 hIgG1 wild-type, and 13 LALA-PG (Seattle Genetics); JS006 (Shanghai Junshi Biosciences Ltd.); Anti-TIGIT Fc antibody and bispecific antibody PD1 x TIGIT (Xencor), antibody clones VSIG9#1 (Vsig9.01) and 258-CS1#4 (#4) (Yissum Research, Hebrew University, Jerusalem) Development Company of The Hebrew University Of Jerusalem Ltd.)); YH29143 (Yuhan Co, Ltd.); antibody clones S02, S03, S04, S05, S06, S11, S12, S14, S19, S32, S39, S43, S62, S64, F01, F02, F03, F04, 32D7, 101H3, 10A7, and 1F4 (limited); Anti zB7R1 clones 318.4.1.1 (E9310), 318.28.2.1 (E9296), 318.39.1.1 (E9311), 318.59.3.1 (E9400), and 318.77.1.10 (ZymoGenetics, Inc).

In some embodiments, the anti-TIGIT antibody is tyragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS- 448), dombanalimab (AB154), bivostolimab (MK-7684), and SEA-TGT (SGN-TGT). ASP874 (PTZ-201) is an anti-TIGIT monoclonal antibody described in PCT Publication No. WO2018183889A1 and US Patent Publication No. 2020/0095324. BGB-A1217 is an anti-TIGIT monoclonal antibody as described in PCT Publication No. WO2019129261A1. BMS-986207 (ONO-4686) is an anti-TIGIT monoclonal antibody as described in PCT Publication No. WO2016106302A9, U.S. Patent No. 10,189,902, and U.S. Patent Publication No. 2019/0112375. COM902 (CGEN-15137) is an anti-TIGIT monoclonal antibody as described in PCT Publication No. WO2018033798A1 and US Patent Nos. 10,213,505 and 10,124,061. IBI939 is an anti-TIGIT monoclonal antibody as described in PCT Publication No. WO2020020281A1. EOS884448 (EOS-448) is an anti-TIGIT monoclonal antibody as described in PCT Publication No. WO2019023504A1. Dombanalimab (AB154) is an anti-TIGIT monoclonal antibody as described in PCT Publication No. WO2017152088A1 and US Patent No. 10,537,633. Vivostolimab (MK-7684) is an anti-TIGIT monoclonal antibody as described in PCT Publication Nos. WO2016028656A1, WO2017030823A2, WO2018204405A1, and/or WO2019152574A1, U.S. Patent No. 10,618,958, and U.S. Patent Publication No. 2018/0371083 to be. SEA-TGT (SGN-TGT) is an anti-TIGIT monoclonal antibody as described in PCT Publication No. WO2020041541A2 and US Patent Publication No. 2020/0062859.

In some embodiments, the anti-TIGIT antagonist antibody is tiragolumab (CAS Accession Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A, RG6058 or RO7092284. Tiragolumab is disclosed in PCT Publication Nos. WO2003072305A8, WO2004024068A3, WO2004024072A3, WO2009126688A2, WO2015009856A2, WO2016011264A1, WO2016109546A2, WO2017053748A2, and WO2019165434A1, and US Patent Publication Nos. 2017/0044 2017/0145093, 2017/260594, 2017/0088613, 2018/0186875, 2019/0119376 and US Patents US9873740B2, US10626174B2, US10611836B2, US9499596B2, US8431350B2, US10047158B2, and US10017572B2 Anti-TIGIT monoclonal antibody as described.

In some embodiments, the anti-TIGIT antibody comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) of any of the anti-TIGIT antibodies disclosed herein. . In some embodiments, the anti-TIGIT antibody comprises 6 CDRs of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody is tyragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS- 448), dombanalimab (AB154), bivostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) sequence of any one of the anti-TIGIT antibodies disclosed herein and the light chain is a light chain of the same antibody. variable region (VL). In some embodiments, the anti-TIGIT antibody is tyragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS- 448), dombanalimab (AB154), vivostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises the heavy and light chains of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody is tyragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS- 448), dombanalimab (AB154), bivostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, an anti TIGIT antagonist antibody according to any of the embodiments described herein may carry any of the above features, alone or in combination, as described in Section C below.

B. PD-1 axis binding antagonists

Provided herein are methods of treating cancer in a subject (eg, a human) comprising administering to the subject an effective amount of a PD-1 axis binding antagonist. The PD-1 axis binding antagonist may include a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. Any suitable PD-1 axis binding antagonist may be used.

1. PD-L1 Binding Antagonists

In some cases, the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other cases, the PD-L1 binding antagonist inhibits PD-L1 binding to PD-1. In still other cases, the PD-L1 binding antagonist inhibits PD-L1 binding to B7-1. In some cases, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. The PD-L1 binding antagonist may be, without limitation, an antibody, antigen-binding fragment thereof, immunoconjugate, fusion protein, oligopeptide, or small molecule. In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (eg, GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041). In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some cases, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some cases, the small molecule is a compound described in WO 2015/033301 and/or WO 2015/033299.

In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD-L1 antibodies are contemplated and described herein. In any of the cases herein, the isolated anti-PD-L1 antibody is human PD-L1, eg, as shown in UniProt KB/Swiss-Prot Accession No. Q9NZQ7-1. It is capable of binding to human PD-L1, or a variant thereof. In some cases, the anti-PD-L1 antibody may inhibit binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1. In some cases, the anti-PD-L1 antibody is a monoclonal antibody. In some cases, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and F(ab') ₂ fragments. In some cases, the anti-PD-L1 antibody is a humanized antibody. In some cases, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies are atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072 , IMC-001, KL-A167, APL-502, Cosibelimab, Rhodapoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL -GEX, KD036, KY1003, YBL-007, and Hs-636. Examples of anti-PD-L1 antibodies useful in the methods of the present invention and methods of making them are described in International Patent Application Publication No. WO 2010/077634 and US Patent No. 8,217,149, which are incorporated herein by reference in their entirety.

In some cases, the anti-PD-L1 antibody (eg, atezolizumab) comprises: (a) the HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO: 20); (b) the HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21); (c) the HVR-H3 sequence of RHWPGGFDY (SEQ ID NO: 22); (d) the HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO: 23); (e) the HVR-L2 sequence of SASFLYS (SEQ ID NO: 24); and (f) at least 1, 2, 3, 4, 5, or 6 HVRs selected from the HVR-L3 sequence of QQYLYHPAT (SEQ ID NO: 25).

In some cases, the anti-PD-L1 antibody comprises:

(a) comprising the sequences HVR-H1, HVR-H2, and HVR-H3 of SEQ ID NO: 20, SEQ ID NO: 21 and SEQ ID NO: 22, respectively;

(b) HVR-L1, HVR-L2, and HVR-L3 sequences of SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, respectively.

In some cases, the anti-PD-L1 antibody (eg, atezolizumab) comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain variable (VH) region sequence has the following amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGTGAVYYWVAWISPYGGSTYYADSVKGRFTMSLRGTFDYSKNTAYCARWISPYGGSTISADTWGGTAYCARWISPYGGSTISADT. ); (b) the light chain variable (VL) region sequence comprises the following amino acid sequence: DIQMTQSPSSLSSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 27).

일부 경우들에서, 상기 항 PD-L1 항체(예컨대, 아테졸리주맙)는 중쇄 및 경쇄 서열을 포함하고, 여기서: (a) 상기 중쇄는 다음 아미노산 서열: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(서열번호 28)를 포함하고; (b) 상기 경쇄는 하기의 아미노산 서열: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(서열번호 29)를 포함한다.

In some cases, the anti-PD-L1 antibody comprises (a) (SEQ ID NO: 26) or a sequence thereof with at least 95% sequence identity (eg, at least 95%, 96%, 97%, 98%, or 99% sequence identity). a VH domain comprising an amino acid sequence comprising identity); (b) a VL domain comprising an amino acid sequence comprising (SEQ ID NO: 27) or a sequence thereof and at least 95% sequence identity (eg, at least 95%, 96%, 97%, 98%, or 99% sequence identity); or (c) a VH domain as in (a) and a VL domain as in (b). In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, comprising (a) a heavy chain amino acid sequence of SEQ ID NO: 28, and (b) a light chain amino acid sequence of SEQ ID NO: 29.

In some cases, the anti-PD-L1 antibody is avelumab (CAS Accession Number: 1537032-82-8). Abelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

In some cases, the anti-PD-L1 antibody is durvalumab (CAS Accession Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc optimized human monoclonal IgG1 kappa anti PD-L1 antibody (MedImmune, AstraZeneca) described in WO2011/066389 and US2013/034559.

In some cases, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007/005874.

In some cases, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

In some cases, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody.

In some cases, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camel phage display library.

In some cases, the anti-PD-L1 antibody is cleaved such that when cleaved (eg, by a protease in the tumor microenvironment) the antibody antigen binding domain is activated to bind its antigen, eg, by removing a non-binding steric moiety. sex moieties or linkers. In some cases, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

In some cases, the anti-PD-L1 antibody comprises six HVR sequences from an anti-PD-L1 antibody described in US 20160108123, WO 9,205,148, WO 2013/181634, or WO 2016/061142 (eg 3 two heavy chain HVRs and three light chain HVRs) and/or a heavy chain variable domain and a light chain variable domain.

In yet further specific embodiments, said anti-PD-L1 antibody has reduced or minimal effector function. In yet further specific embodiments, said minimal effector function results from an “effector-free Fc mutation” or aglycosylation mutation. In still further cases, said effector-free Fc mutation is N297A or D265A/N297A in the constant region. Substitution.In yet further cases, the Fc mutation without effector is N297A substitution in the constant region.In some cases, the isolated anti-PD-L1 antibody is deglycosylated.The glycosylation of antibodies is typically N-linked or O linkage.N linkage means that the carbohydrate moiety is attached to the side chain of the asparagine residue.The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline Recognition sequence for enzymatic attachment of carbohydrate moiety to asparagine side chain.Therefore, the presence of any of the above tripeptide sequences in the polypeptide creates a possible glycosylation site.O-linked glycosylation is hydroxyamino acid, most commonly refers to the attachment of the sugar N acetylgalactosamine, galactose or xylose to serine or threonine, but 5-hydroxyproline or 5-hydroxylysine can also be used. This is easily accomplished by altering the amino acid sequence so that one of the peptide sequences (for N-linked glycosylation sites) is removed.The alteration is to replace an asparagine, serine or threonine residue in the glycosylation site with another amino acid residue (e.g., glycine, alanine) or conservative substitution).

2. PD-1 binding antagonists

In some cases, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, the PD-1 binding antagonist inhibits the binding of PD-1 to one or more ligand binding partners thereof. In some cases, the PD-1 binding antagonist inhibits PD-1 binding to PD-L1. In other instances, the PD-1 binding antagonist inhibits PD-1 binding to PD-L2. In still other cases, the PD-1 binding antagonist inhibits PD-1 from binding to both PD-L1 and PD-L2. The PD-1 binding antagonist may be, without limitation, an antibody, antigen-binding fragment thereof, immunoconjugate, fusion protein, oligopeptide, or small molecule. In some cases, the PD-1 binding antagonist comprises an extracellular or PD-1 binding site of PD-L1 or PD-L2 fused to an immunoconjugate (eg, a constant region (eg, an Fc region of an immunoglobulin sequence)). immunoconjugate). For example, in some cases, the PD-1 binding antagonist is an Fc-fusion protein. In some cases, the PD-1 binding antagonist is AMP-224. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO 2010/027827 and WO 2011/066342. In some cases, the PD-1 binding antagonist is a peptide or small molecule compound. In some cases, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, eg, WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317, and WO 2011/161699. In some cases, the PD-1 binding antagonist is a small molecule that inhibits PD-1.

In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the cases herein, the PD-1 antibody is capable of binding to human PD-1 or a variant thereof. In some cases, the anti-PD-1 antibody is a monoclonal antibody. In some cases, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and F(ab') ₂ fragments. In some cases, the anti-PD-1 antibody is a humanized antibody. In other instances, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-L1 antagonist antibodies are nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (semipliumab), BGB-108, prolgolimab, camrelizumab, scintilimab , tislelizumab, torifalimab, dostalimab, retipanrimab, sasanrimab, fenpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab , YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21.

In some cases, the anti-PD-1 antibody is nivolumab (CAS Accession Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and ^OPDIVO® , is disclosed in WO2006/121168. described anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is pembrolizumab (CAS Accession Number: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, SCH-900475 and KEYTRUDA®, is an anti-PD-1 antibody described in WO2009/114335.

In some cases, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is PDR001 (CAS Accession No. 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

In some cases, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is BGB-108 (BeiGene).

In some cases, the anti-PD-1 antibody is BGB-A317 (BeiGene).

In some cases, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is PF-06801591 (Pfizer).

In some cases, the anti-PD-1 antibody is TSR-042 (ANB011; also known as Tesaro/AnaptysBio).

In some cases, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

In some cases, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking the binding of PD-L1 to PD-1.

In some cases, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

In some cases, the anti-PD-L1 antibody is WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769, WO2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 6 HVR sequences from anti-PD-1 antibodies described in 2012/145493, US 9,205,148, WO 2015/119930, WO 2015/119923, WO 2016/032927, WO 2014/179664, WO 2016/106160, and WO 2014/194302 (eg, three heavy chain HVRs and three light chain HVRs) and/or a heavy chain variable domain and a light chain variable domain.

In still further specific embodiments, said anti-PD-1 antibody has reduced or minimal Fc-mediated effector function. In yet further specific embodiments, said minimal Fc mediated effector function results from an "effector-free Fc mutation" or aglycosylation mutation. In still further specific cases, said effector-free Fc mutation is N297A or D265A in the constant region. /N297A substitution In some cases, the isolated anti-PD-1 antibody is deglycosylated.

3. PD-L2 binding antagonists

In some cases, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some cases, the PD-L2 binding antagonist is a molecule that inhibits PD-L2 binding to its ligand binding partner. In certain embodiments, the PD-L2 binding ligand partner is PD-1. The PD-L2 binding antagonist may be, without limitation, an antibody, antigen-binding fragment thereof, immunoconjugate, fusion protein, oligopeptide, or small molecule.

In some cases, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any of the cases herein, the anti-PD-L2 antibody is capable of binding to human PD-L2 or a variant thereof. In some cases, the anti-PD-L2 antibody is a monoclonal antibody. In some cases, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and F(ab') ₂ fragments. In some cases, the anti-PD-L2 antibody is a humanized antibody. In other instances, the anti-PD-L2 antibody is a human antibody. In still further specific embodiments, said anti-PD-L2 antibody has reduced or minimal effector function. In yet further specific embodiments, said minimal effector function results from an “effector-free Fc mutation” or aglycosylation mutation. In yet further cases, said effector-free Fc mutation is N297A or D265A/N297A in the constant region. In some cases, the isolated anti-PD-L2 antibody is deglycosylated.

PD-1 axis binding antagonists (eg, atezolizumab) useful in the present invention, including compositions containing such molecules, may be used in combination with anti-TIGIT antagonist antibodies.

In a further aspect, the PD-1 axis binding antagonist is a PD-1 axis binding antagonist antibody according to any of the preceding instances, wherein any of the above features, alone or in combination, are described in Section C below. can be integrated

C. Antibody Format and Properties

1. Antibody Affinity

In certain instances, an anti TIGIT antagonist antibody, a PD-1 axis binding antagonist antibody (eg, an anti PD-L1 antagonist antibody or an anti PD-1 antagonist antibody), an anti VEGF antibody, and/or an anti IL-6R antibody provided herein ) is ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 ^-8 M or less, such as 10 ^-8 M to 10 ^-13 M, For example, it has a dissociation constant (K _D ) of 10 ^-9 M to 10 ^-13 M).

In one case, K _D is determined by radiolabeled antigen binding assay (RIA). In one case, RIA is performed using the Fab form of the antibody of interest and its antigen. For example, the lytic binding affinity of a Fab for antigen is determined by equilibrating the Fab with a minimal concentration of ( ¹²⁵ I) labeled antigen in the presence of a titer sequencing of unlabeled antigen, and then transferring the bound antigen to an anti Fab antibody coated plate. (see, eg, Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish the conditions for the assay, MICROTITER ^® multiwell plates (Thermo Scientific) were coated overnight with 5 μg/ml of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate, pH 9.6, and subsequently, at room temperature. Blocked with 2% (w/v) bovine serum albumin in PBS for 2-5 hours at (approx. 23° C.). In non-adsorbent plates (Nunc #269620), 100 pM or 26 pM [ ¹²⁵ I] antigens are mixed in serial dilutions of the Fab of interest (e.g., Presta et al., Cancer Res. 57:4593-4599). (1997) Fab-12 anti-VEGF antibody). The Fabs of interest are then incubated overnight; However, the incubation may be continued for a longer period (eg, about 65 hours) to ensure equilibrium is reached. Thereafter, the mixture is transferred to the capture plate for room temperature incubation (eg, for 1 hour). The solution is then removed and the plate washed 8 times with 0.1% polysorbate 20 (TWEEN-20 ^® ) in PBS. When the plates are dry, 150 μl/well of a scintillator (MICROSCINT-20™; Packard) is added and the plates are counted on a TOPCOUNT™ gamma counter (Packard) for 10 minutes. Each Fab concentration that provides 20% or less of maximal binding is selected for use in competitive binding assays.

According to another case, K _D is determined using BIACORE® surface plasmon resonance analysis. For example, assays using Biacore ^® -2000 or Biacore ^® -3000 (BIAcore, Inc., Piscataway, NJ) can be performed with immobilized antigen CM5 chips at ~10 response units (RU). carried out at 25°C. In one case, a carboxymethylated dextran biosensor chip (CM5, Biacore) was prepared with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N -Activated with hydroxysuccinimide (NHS). Antigen is diluted to 5 μg/ml (~0.2 μM) with 10 mM sodium acetate, pH 4.8 and then injected at a flow rate of 5 μl/min to yield approximately 10 response units (RU) of bound protein. After antigen injection, 1 M ethanolamine is injected to block the unreacted group. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) were mixed with 0.05% polysorbate 20 (Tween-20™) surfactant (PBST) at 25° C. at a flow rate of about 25 μl/min. Inject into PBS. Association rates (k _on ) and dissociation rates (k _off ) are calculated using a simple one-to-one Langmuir binding model ( ^BIACORE® evaluation software version 3.2) by simultaneously fitting association and dissociation sensorgrams. The equilibrium dissociation constant (K _D ) is calculated as the ratio k _off /k _on . See, eg, Chen et al., Biol. 293:865-881 (1999). If the on-rate exceeds 10 ⁶ M ¹ s ¹ by the surface plasmon resonance analysis, the on-rate is measured by a spectrometer, such as a spectrophotometer equipped with a stationary-flow (Aviv Instruments) or an 8000-series SLM-AMINCO ^™ with stirring cuvette. Fluorescence emission intensity at 25° C. of 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2 in the presence of increasing concentrations of antigen as measured on a spectrophotometer (ThermoSpectronic) (excitation = 295 nm; emission = 340 nm, 16 nm band) can be determined by using a fluorescence quenching technique that measures the increase or decrease.

2. Antibody fragments

n, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); WO 93/16185; 및 미국 특허 제5,571,894호 및 5,587,458호를 또한 참조한다. 구제 수용체 결합 에피토프 잔기를 포함하고 증가된 생체내 반감기를 갖는 Fab 및 F(ab')₂ 단편에 관한 논의를 위해, 미국 특허 제5,869,046호를 참조한다. In certain instances, an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody) provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv, and scFv fragments, and other fragments described below. For a review of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). A review of scFv fragments can be found, for example, in Pluckth

n, in The Pharmacology of Monoclonal Antibodies , vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); WO 93/16185; and US Pat. Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab′) ₂ fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see US Pat. No. 5,869,046.

A duplex is an antibody fragment having two antigen binding sites, which may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triplets and quadrules are also described by Hudson et al. Nat. Med. 9:129-134 (2003).

Single domain antibodies are antibody fragments comprising all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain instances, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, MA; see, eg, US Pat. No. 6,248,516 B1).

Antibody fragments can be prepared by a variety of techniques, including proteolytic cleavage of the original antibody, as well as antibodies produced by recombinant host cells (eg, E. coli or phage), as described herein. including, but not limited to.

3. Chimeric and Humanized Antibodies

In certain instances, an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody) provided herein is a chimeric antibody. Certain chimeric antibodies are described, eg, in US Pat. Nos. 4,816,567; and Morrison et al., Proc. Proc. Natl. Acad. Sci. USA , 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (eg, a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, eg, monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. A chimeric antibody comprises an antigen-binding fragment thereof.

In certain embodiments, the chimeric antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity to humans, while maintaining the specificity and affinity of the parental non-human antibodies. Generally, a humanized antibody comprises one or more variable domains, wherein the HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and the FRs (or portions thereof) are human derived from antibody sequences. The humanized antibody will optionally also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are replaced with corresponding residues of a non-human antibody (eg, an antibody from which HVR residues are derived), eg, antibody specificity or affinity is restored or improved.

Humanized antibodies and methods of making them are described, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), see eg Riechmann et al. , Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); US Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al ., Methods 36:25-34 (2005) (describing specificity determining region (SDR) transplantation); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall'Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer , 83:252-260 (2000) (describing a “guided selection” approach to FR shuffling).

Human framework regions that can be used for humanization include: framework regions selected using “optimal” methods (see, eg, Sims et al. J. Immunol. J. Immunol. 151:2296 (1993)); Framework regions derived from the consensus sequence of human antibodies of specific subgroups of light or heavy chain variable regions (eg, Carter et al. Proc. Natl. Acad. Sci. USA , 89:4285 (1992); and Presta et al. J. Immunol. , 151:2623 (1993); human mature (somatically mutated) framework regions or human germline framework regions (see, eg, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from FR library selection (eg, J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

4. 4. Human Antibodies

In certain instances, an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody) provided herein is a human antibody. Human antibodies can be produced using a variety of techniques known in the art. Human antibodies are described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce an intact human antibody or an intact antibody comprising a human variable region in response to an antigen challenge. Such animals typically contain all or some of the human immunoglobulin loci that replace endogenous immunoglobulin loci, or which exist extrachromosomally or integrate randomly into the animal's chromosomes. In the transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see LLonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, US Pat. Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE ^™ technology; US Pat. No. 5,770,429 describing HuMab ^® technology; See US Pat. No. 7,041,870, which describes KM ^MOUSE® technology, and US Patent Application Publication No. US 2007/0061900, which describes VelociMouse® technology. Human variable regions from intact antibodies generated by such animals can be further modified, for example, by combining with different human constant regions.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (e.g., Kozbor J. Immunol. , 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications , pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al. ., J. Immunol ., 147: 86 (1991).) Human antibodies generated via human B cell hybridoma technology have also been described in Li et al. , Proc. Natl. Acad. Sci. USA , 103:3557-3562 (2006). Additional methods are described, for example, in US Pat. No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue , 26(4):265-268 (2006) (human-human high described in Bridomas). Human hybridoma technology (Trioma technology) is described in Vollmers and Brandlein, Histology and Histopathology , 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology , 27(3):185- 91 (2005).

Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human derived phage display libraries. Such variable domain sequences can then be combined with the desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

5. Library Derived Antibodies

An anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (eg, anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody) of the present invention is isolated by screening a complex library for antibodies with the desired activity or activities. can be For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), eg, McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004).

In certain phage display methods, the VH and VL gene repertoires are cloned separately by polymerase chain reaction (PCR) and recombined randomly in phage libraries, Winter et al., Ann. Rev. Immunol. , 12: 433-455 (1994). Phages typically display antibody fragments either as single chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high affinity antibodies to the immunogen without the requirement to construct hybridomas. Alternatively, see Griffiths et al., EMBO J, 12: 725-734 (1993) for a prototype repertoire. Finally, the prototype library is also described in Hoogenboom and Winter, J. Mol. Biol. , 227: 381:-388 (1992) cloned unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions and to undergo in vitro rearrangement. By achieving it, it can be prepared synthetically. Patent publications describing human antibody phage libraries include, for example: U.S. Patent No. 5,750,373, and U.S. Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

Anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (eg, anti-PD-L1 antagonist antibodies) or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

6. Antibody variants

In certain instances, amino acid sequence variants of an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) of the invention are contemplated. As detailed herein, anti-TIGIT antagonist antibodies and PD-1 axis binding antagonist antibodies (eg, anti-PD-L1 antagonist antibodies) can be optimized based on desired structural and functional properties. For example, it may be desirable to improve the binding affinity and/or other biological properties of an antibody. Amino acid sequence variants of an antibody can be made by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions, and/or insertions and/or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to arrive at the final construct if the final construct possesses desirable characteristics, eg, antigen-binding.

I. Substitution, insertion, and deletion variants

In certain instances, anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (eg, anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody) variants are provided having one or more amino acid substitutions. Sites of interest for substitutional mutagenesis include HVRs and FRs. Conservative substitutions are shown in Table 3 under the heading “preferred substitutions”. More substantial changes are presented in Table 3 under the heading of “Exemplary Substitutions”, which are further described below with reference to amino acid side chain classes. Amino acid substitutions are indicated for the desired activity, e.g., retained/improved antigen binding. , antibodies of interest and products screened for reduced immunogenicity, or improved ADCC or CDC.

usually
residue exemplary
substitution desirable
substitution Ala (A) Val; Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gln; His; Asp, Lys; Arg Gln Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Phe; norleucine Leu Leu (L) norleucine; Ile; Val; Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Ala; norleucine Leu

Exemplary and Preferred Amino Acid Substitutions

Amino acids can be grouped according to common side chain properties:

(1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;

(2) neutral hydrophilicity: Cys, Ser, Thr, Asn, Gin;

(3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that affect side chain orientation: Gly, Pro;

(6) Aromatics: Trp, Tyr, Phe.

Non-conservative substitutions will cause an exchange of a member of one of these classes for another class.

One type of substitutional variant involves the substitution of one or more hypervariable region residues of a parent antibody (eg, a humanized or human antibody). In general, the resulting variant(s) selected for further study will have modifications (eg, improvements) in certain biological properties (eg, increased affinity, decreased immunogenicity) relative to the parent antibody and /or will retain substantially certain biological properties of the parent antibody. Exemplary substitutional variants are affinity matured antibodies, which can be conveniently generated using, for example, phage display based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated, the variant antibodies displayed on phage, and screened for a particular biological activity (eg, binding affinity).

Alterations (eg, substitutions) can be made in the HVRs, eg, to improve antibody affinity. Such alterations are HVR "hotspots," ie residues encoded by codons that mutate with high frequency during somatic maturation (eg, Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or antigens and contacting residues, wherein the resulting variant VH or VL is tested for binding affinity. Affinity maturation by constructing a second library and reselecting is described, for example , in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some examples of affinity maturation, diversity is introduced into variable genes selected for maturation by any of a variety of methods (eg, error-prone PCR, chain shuffling, or oligonucleotides). -directed mutagenesis). A second library is then created. This library is then screened to identify any antibody variants with the desired affinity. Another method of introducing diversity involves HVR-directed methods, in which several HVR residues (eg, 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified using, for example, alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.

In certain instances, substitutions, insertions, or deletions may be made in one or more HVRs so long as the alteration does not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (eg, conservative substitutions provided herein) can be made to HVRs that do not substantially reduce binding affinity. Such alterations may be, for example, outside the antigen contacting residues of the HVRs. In certain examples of variants VH and VL set forth above, each HVR is either unaltered or comprises 1, 2, 3 or more amino acid substitutions.

A useful method for identification of residues or regions of an antibody that can be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science , 244:1081-1085. In this method, a target moiety or group of target moieties (eg, charged residues such as Arg, Asp, His, Lys, and Glu) is identified and converted to a neutral or negatively charged amino acid (eg, alanine or polyalanine). In turn, it is determined whether the interaction of the antigen with the antibody is affected. Additional substitutions may be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively, or in addition, the crystal structure of the antigen-antibody complex is used to identify contact points between the antibody and antigen. Such contact residues and neighboring residues can be targeted as candidates for substitution, or eliminated. Variants can be screened to determine whether they contain a desired property.

Amino acid sequence insertions include amino and/or carboxyl terminus fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies having an N-terminal methionyl residue. Other insertional variants of the antibody molecule include a fusion to the N or C terminus of the antibody to an enzyme (eg, in the case of ADEPT) or polypeptide that increases the serum half-life of the antibody.

II. glycosylation variants

In certain instances, an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (eg, anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody) of the invention increases or decreases the extent to which the antibody is glycosylated. may be changed. The addition or deletion of glycosylation sites in the anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (eg, anti-PD-L1 antagonist antibody) of the present invention is amino acid such that one or more glycosylation sites are created or removed. This can be done for convenience by altering the sequence.

When the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies made by mammalian cells typically comprise a branched, biantennary oligosaccharide attached generally by an N linkage to Asn297 of the CH2 domain of the Fc region. See, eg, Wright et al. TIBTECH 15:26-32 (1997). Oligosaccharides can include a variety of carbohydrates, such as mannose, N-acetyl glucosamine (GlcNAc), galactose and sialic acid, as well as fucose attached to GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some cases, modifications of the oligosaccharides of the antibodies of the invention are made to generate antibody variants with certain improved properties.

In one case, anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (eg, anti-PD-L1 antagonist antibody) variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to the Fc region. do. For example, the amount of fucose in such an antibody may be between 1% and 80%, between 1% and 65%, between 5% and 65% or between 20% and 40%. The amount of fucose is the sum of all sugar structures attached to Asn 297 (e.g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described, for example, in WO 2008/077546. In comparison, it is relatively determined by calculating the average amount of fucose in the sugar chain at Asn297. Asn297 refers to an asparagine residue located in the Fc region at approximately position 297 (EU numbering of Fc region residues); However, Asn297 may also be located approximately ± 3 amino acids upstream or downstream of position 297, ie between positions 294 and 300, due to minor sequence variations in the antibody. Such fucosylation may have improved ADCC function. See, eg, US Patent Publication Nos. 2003/0157108 (Presta, L.); See US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of documents relating to “defucosylated” or “fucose deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing afucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US 2003/ 0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al ., especially Example 11), and knockout cell lines such as alpha-1,6-fucosyltransferase gene, FUT8 , knockout CHO cells (such as , Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al. , Biotechnol. Bioeng ., 94(4): 680-688 (2006); and WO2003/085107). do.

In view of the above, in some embodiments, the methods of the present invention comprise an anti-TIGIT antagonist antibody (eg, an anti-TIGIT antagonist antibody disclosed herein, eg, tyragolumab) comprising an aglycosylation site mutation and/or the PD-1 axis administering a binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody) variant to a subject in connection with a fractionated dose escalation dosing regimen. In some cases, aglycosylation site mutations reduce effector function of the antibody. In some cases, the aglycosylation site mutation is a substitution mutation. In some cases, the antibody comprises a substitution mutation in the Fc region that reduces effector function. In some cases, the substitution mutation is at amino acid residues N297, L234, L235, and/or D265 (EU numbering). In some cases, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G. In some cases, the substitution mutation is at amino acid residue N297. In a preferred case, the substitution mutation is N297A.

Antitactile oligosaccharides in the Fc region of an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (eg, anti-PD-L1 antagonist antibody or anti-PD-L1 antagonist antibody) are bisected by GlcNAc, bisected oligosaccharides Anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody variants are further provided. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such variants are eg in WO 2003/011878 (Jean-Mairet et al.); US Pat. No. 6,602,684 to Umana et al.; and US 2005/0123546 (Umana et al .). Antibody variants having at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may possess improved CDC function. Such antibody variants are described, for example, in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and in WO 1999/22764 (Raju, S.).

III. Fc region variants

In certain instances, one or more amino acid modifications are altered by an anti TIGIT antagonist (eg, an anti TIGIT antagonist antibody disclosed herein, eg, tyragolumab) antibody and/or a PD-1 axis binding antagonist antibody (eg, anti introduced into the Fc region of a PD-L1 antagonist antibody (eg, atezolizumab) or an anti-PD-1 antagonist antibody), resulting in Fc region variants (see, eg, US 2012/0251531). The Fc region variant may comprise a human Fc region sequence (eg, a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising amino acid modifications (eg substitutions) at one or more amino acid positions.

In certain instances, the present invention contemplates anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibody variants) that retain some but not all effector functions. , this makes it a desirable candidate for applications where the half-life of an antibody in vivo is important, but also where certain effector functions (eg, complement and ADCC) are unnecessary or detrimental. In vitro and/or in vivo cytotoxicity assays may be performed to confirm reduction/depletion of CDC and/or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to confirm that the antibody lacks FcgR binding (and thus may not have ADCC activity), but retains FcRn binding ability. The main cells that modulate ADCC, NK cells, express only Fc (RIII), whereas monocytes express Fc (RI, Fc (RII and Fc (RIII). Fc expression on hematopoietic cells is: Ravetch and Kinet, Annu. Rev. See Immunol. 9:457-492 (1991), page 464, Table 3. A non-limiting example of an in vitro assay for assessing ADCC activity of a molecule of interest is US Pat. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)) Alternatively, non-radioactivity assay methods can be used (e.g., flow cytometry ACTI™ non-radioactive cytotoxicity assay (CellTechnology, Inc., Mountain View, CA); and CytoTox 96 ^® non-radioactive cytotoxicity assay (Promega, Madison, Wis.) location).Useful effector cells for this assay include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.Alternatively or additionally, ADCC activity of the molecule of interest can be determined in vivo , such as in animal models, such as as disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). Clq binding assay can also be carried out to confirm lack of CDC activity.See, for example, Clq and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. Assess complement activation To do this, a CDC analysis can be performed (eg, Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg, MS et al. Blood. 101:1045-1052 (2003); and Cragg, MS and MJ Glennie Blood. 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life measurements can also be performed using methods known in the art (eg, Petkova, SB et al. Int'l. Immunol. 18(12):1759-1769 (2006)) see).

Antibodies with reduced effector function include those with substitutions of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. Nos. 6,737,056 and 8,219,149). Such Fc mutants include Fc mutants having substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called "DANA" Fc mutants in which residues 265 and 297 are substituted with alanine. (see US Pat. Nos. 7,332,581 and 8,219,149).

In certain instances, proline at position 329 of the wild-type human Fc region in the antibody disrupts the proline sandwich inside the Fc/Fcγ receptor interface formed between glycine or arginine or proline 329 of Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII Amino acid residues large enough to be substituted (Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)). In certain instances, the antibody comprises at least one additional amino acid substitution. In one case, the additional amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and in yet another example the at least one additional amino acid substitution is L234A and L235A or S228P of a human IgG1 Fc region and L235E of the human IgG4 Fc region (see eg US 2012/0251531), and in yet another example the at least one further amino acid substitution is L234A and L235A and P329G of the human IgG1 Fc region.

Certain antibody variants with improved or reduced binding to FcRs are described. (See, eg, US Pat. No. 6,737,056; WO 2004/056312, and Shields et al. , J. Biol. Chem. 9(2): 6591-6604 (2001)).

In certain cases, the antibody variant comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333 and/or 334 (EU numbering of residues) of the Fc region.

In some cases, modifications are described, for example, in US Pat. Nos. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000), resulting in altered (ie, improved or reduced) Clq binding and/or complement dependent cytotoxicity (CDC) in the Fc region.

Antibodies with increased half-life and improved binding to neonatal Fc receptor (FcRn), which act as a causative agent for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al. , J. Immunol. 24:249 (1994)) are described in US2005/0014934A1 (Hinton et al.). These antibodies contain an Fc region therein with one or more substitutions that improve binding of the Fc region to FcRn. The Fc variants have Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or a substitution at one or more of 434, such as a substitution of Fc region residue 434 (US Pat. No. 7,371,826).

Duncan & Winter, Nature 322:738-40 (1988) relating to other examples of Fc region variants; US Patent No. 5,648,260; US Patent No. 5,624,821; and WO 94/29351.

In some aspects, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab) and/or an anti-PD-L1 antagonist antibody (eg, atezolizumab) is an Fc comprising an N297G mutation includes area.

In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab) and/or a PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody (eg, ate zolizumab) or anti-PD-1 antagonist antibody) comprises one or more heavy chain constant domains, wherein said one or more heavy chain constant domains comprise a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) ) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. In some examples, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some embodiments, each of the CH3 ₁ and CH3 ₂ domains comprises an overhang or cavity, wherein the overhang or cavity in the CH3 ₁ domain may be located in the cavity or overhang in the CH3 ₂ domain, respectively. In some cases, the CH3 ₁ and CH3 ₂ domains meet at the interface between the protrusion and the cavity. In some cases, each of the CH2 ₁ and CH2 ₂ domains comprises an overhang or cavity, wherein the overhang or cavity in the CH2 ₁ domain may be located in the cavity or overhang in the CH2 ₂ domain, respectively. In some cases, the CH21 and CH22 domains meet at the interface between the protrusion or cavity. In some cases, the anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody disclosed herein, eg, tiragolumab) and/or an anti-PD-L1 antagonist antibody (eg, atezolizumab) is an IgG1 antibody.

IV. Cysteine engineered antibody variants

In certain instances, an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody), wherein one or more residues of the antibody are replaced with cysteine residues. For example, it may be desirable to make "thioMAbs". In certain instances, the substituted residue appears at an accessible site of the antibody. By substituting these residues with cysteines, reactive thiol groups are thus positioned at accessible sites of the antibody, and the antibody is conjugated to other moieties, such as drug moieties or linker-drug moieties, to immunoconjugates as further described herein. can be used to create In certain instances, any one or more of the following residues are substituted with cysteine: V205 of the light chain (Kabat numbering); A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies can be generated as described, for example, in US Pat. No. 7,521,541.

V. Antibody Derivatives

In certain instances, an anti TIGIT antagonist antibody (eg, an anti TIGIT antagonist antibody (eg, tyragolumab) or variant thereof) of the invention provided herein and/or a PD-1 axis binding antagonist antibody (eg, For example, an anti-PD-L1 antagonist antibody of the invention (eg, atezolizumab or a variant thereof) is further modified to contain additional nonproteinaceous moieties known in the art and readily available. do. Suitable moieties for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly- 1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), and dextran or poly(n-vinyl pyrrolidone) polyethylene glycol, propropylene glycol homopolymer; prolylpropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (eg, glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer is attached, the polymers may be the same or different molecules. In general, the number and/or type of polymer used for derivatization will depend on considerations including, but not limited to, the particular property or function of the antibody being improved, whether the antibody derivative will be used in therapy under defined conditions, and the like. can be determined based on

In another instance, a conjugate of an antibody and a nonproteinaceous moiety that can optionally be heated by exposure to radiation is provided. In one case, the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). Radioactivity can be of any wavelength and does not harm normal cells, but includes, but is not limited to, a wavelength that heats the nonproteinaceous moiety at a temperature at which cells in proximity to the antibody-nonproteinaceous moiety are killed. it is not

Recombinant production methods

An anti-TIGIT antagonist antibody of the invention (eg, an anti-TIGIT antagonist antibody disclosed herein, such as tyragolumab) and/or a PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody (eg, atezolizumab)) or anti-PD-1 antagonist antibodies) can be prepared using recombinant methods and compositions, eg, as described in US Pat. No. 4,816,567, which is incorporated herein in its entirety.

For recombinant production of an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (eg, an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody), a nucleic acid encoding the antibody is isolated and in a host cell. is inserted into one or more vectors for further cloning and/or expression of Such nucleic acids are readily isolated and sequenced by conventional procedures (eg, by using oligonucleotide probes capable of binding specifically to genes encoding the heavy and light chains of the antibody).

Suitable host cells for cloning or expression of antibody encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, particularly when glycosylation and Fc effector function are not required. See, eg, US Pat. Nos. 5,648,237, 5,789,199, and 5,840,523 for antibody fragments and polypeptide expression in bacteria. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) Expression Thereafter, the antibody can be isolated from the bacterial cell paste in the soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast, including strains of fungi and yeast, in which the glycosylation pathway has been "humanized", resulting in the production of antibodies with a partially or fully human glycosylation pattern, are suitable for antibody encoding vectors. a cloning or expression host. Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. In particular, for transfection of Spodoptera frugiperda cells, various baculovirus strains that can be used with insect cells have been identified.

Plant cell cultures can also be utilized as hosts. See, for example, US Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978 and 6,417,429 (describing PLANTIBODIES ^™ technology for producing antibodies in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines include the monkey kidney CV1 cell line transformed with SV40 (COS-7); human embryonic kidney cell lines (eg, 293 or 293 cells as described in Graham et al. , J. Gen Virol. 36:59 (1977)); young hamster kidney cells (BHK); mouse Sertoli cells (eg, TM4 cells as described in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary gland tumors (MMT 060562); e.g. Mather et al. , Annals NY Acad. Sci TRI cells as described in 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR ^- CHO cells (Urlaub et al. , Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of specific mammalian host cell lines suitable for antibody production, see, eg, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

immunoconjugate

The invention also provides an anti-TIGIT antagonist of the invention conjugated to one or more cytotoxic agents such as chemotherapeutic agents or drugs for use in the methods or uses described herein (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and/or PD-1 axis binding antagonists (eg, anti-PD-L1 antagonist antibodies (eg, pemblorizumab)), growth inhibitory agents, toxins (eg, protein toxins, bacterial, fungal, plant or animal origin) of an enzyme-active toxin, or fragment thereof), or an immunoconjugate comprising a radioactive isotope.

In some cases, the immunoconjugate is an antibody to a maytansinoid (see US Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); auristatins (MMAE and MMAF), such as monomethylauristatin drug moieties DE and DF (see US Pat. Nos. 5,635,483 and 5,780,588 and 7,498,298); dolastatin; calicheamicin or a derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993) and Lode et al., Cancer Res. 58:2925-2928 (1998)); anthracyclines such as daunomycin or doxorubicin (Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med See Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and US Pat. No. 6,630,579); methotrexate; vindesine; taxanes such as docetaxel, paclitaxel, larotaxel, tecetaxel, and ortataxel; tricotecene; and an antibody-drug conjugate (ADC) conjugated to one or more drugs including, but not limited to, CC1065.

In still other examples, the immunoconjugate comprises diphtheria A chain, a nonbinding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modexin A chain, alpha -Sarsine, Aleurites fordii protein, Dianthin protein, Phytolaca americana protein (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, Cursine, Crotin, herein conjugated to an enzymatically active toxin or fragment thereof, including but not limited to, sapaonaria officinalis inhibitors, gelonin, mitozellin, restrictocin, phenomycin, enomycin, and trichothecene anti-TIGIT antagonist antibody (eg, tiragolumab) or a PD-1 axis binding antagonist (eg, anti-PD-L1 antagonist antibody (eg, atezolizumab)) as described in

In still other examples, the immunoconjugate is an anti-TIGIT antagonist antibody (eg, tyragolumab) as described herein that is conjugated to a radioactive atom to form a radioconjugate and/or a PD-1 axis binding antagonist as described herein. (eg, anti-PD-L1 antagonist antibody) (eg, atezolizumab). A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioactive isotopes of Lu. When the radioconjugate is used for detection, it is a radioactive atom for scintigraphic studies, such as tc99m or I123, or rotation for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI). labels such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of an antibody and a cytotoxic agent can be used with a variety of bifunctional protein-linked agents, such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl). ) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (eg dimethyl adipimidate HCl), active esters (eg disuccinimidyl water berate), aldehydes (eg glutaraldehyde), bis-azido compounds (eg bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (eg bis-( p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (eg toluene 2,6-diisocyanate) and bis-active fluorine compounds (eg 1,5-difluoro-2,4-di nitrobenzene) can be used. For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotides to antibodies. See WO94/11026. The linker may be a “cleavable linker” that facilitates release of the cytotoxic drug from the cell. For example, acid labile linkers, peptidase sensitive linkers, photolabile linkers, dimethyl linkers or disulfide containing linkers (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Pat. No. 5,208,020) may be employed. can

The immunoconjugates or ADCs herein are commercially available (eg, from Pierce Biotechnology, Inc., Rockford, IL., U.S.A.) BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzo 8) are expressly contemplated, but are not limited to, those conjugates prepared with crosslinker reagents, including but not limited to.

ADCs that do not include anti-TIGIT antagonist antibodies or PD-1 axis binding antagonists may also be used in the methods described herein. In some cases, the ADC is enfortumab vedotin or sacituzumab gobitecan.

D. Chemotherapeutic Agents

1. Platinum-based chemotherapeutic agents

Platinum-based chemotherapeutic agents include organic compounds containing platinum as an integral part of the molecule. Typically platinum-based chemotherapy is a coordination complex of platinum. These include, but are not limited to, carboplatin, cisplatin and oxaliplatin.

Platinum-based chemotherapeutic agents (eg, cisplatin, carboplatin, oxaliplatin, and satraplatin) are widely used to cause crosslinking of DNA as single adduct crosslinking, interchain crosslinking, interchain crosslinking, or DNA protein crosslinking. antitumor drugs used. Platinum-based chemotherapeutic agents typically act on the adjacent N-7 position of guanine, forming one or two intrachain crosslinks (Poklar et al. (1996). Proc. Natl. Acad. Sci. USA 93 (15). ): 7606-11;Rudd et al. (1995) Cancer Chemother. Pharmacol . 35 (4): 323-6). The resulting crosslinking inhibits DNA repair and/or DNA synthesis in cancer cells.

Carboplatin is an exemplary platinum coordination compound used in the methods described herein. The chemical name for carboplatin is platinum, diammine[l,l-cyclobutanedicarboxylacto(2-)-0,0']-, (SP42), carboplatin has the structural formula:

Caplatin is a crystalline powder with a molecular formula of C6H12N204Pt and a molecular weight of 371.25. It dissolves in water at a rate of about 14 mg/mL, and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide. Carboplatin predominantly causes interchain DNA crosslinking, and this effect is cell cycle non-specific. Carboplatin is available commercially as PARAPLATIN®, BIOCARN, BLASTOCARB, BLASTOPLATIN, CARBOKEM, CARBOMAX, CARBOPA, CARBOPLAN, CARBOTEEN, CARBOTINAL, CYTOCARB, DUCARB, KARPLAT, RBKEMOCARB, NAPROPLAT, NEOPLATIN, WOMASTSCINARBOARBO, ONCOIN, do.

Another exemplary platinum-based chemotherapeutic agent useful in the methods of the present invention is cisplatin having the structure:

2. Non-platinum-based chemotherapeutic agents

Non-platinum-based chemotherapeutic agents are another class of chemotherapeutic agents useful as part of the methods, uses, and compositions for use described herein. Exemplary non-platinum-based chemotherapeutic agents include antimetabolites (eg, pemetrexed and gemcitabine), topoisomerase II inhibitors (eg, doxorubicin, etoposide, teniposide, daunorubicin, mitoxantrone, amsa krine, carboxylic acid, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331), alkylating agents (eg, cyclophosphamide) and taxanes (eg, paclitaxel (eg, nanoparticle- albumin binding (nap)-paclitaxel), docetaxel, larotaxel, cabazitaxel, milataxel, and/or orataxel).

3. Antimetabolites

Antimetabolites interfere (in whole or in part) and inhibit endogenous (normal) metabolic processes within cells (eg, cancer cells). Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine and pralatrexate.

Gemcitabine is an exemplary antimetabolite for use in the methods described herein and has the structure

In some cases, pemetrexed may be administered as part of a method of the invention. Pemetrexed has the following structure:

4. Topoisomerase II Inhibitors

Inhibitors of topoisomerase II (such as etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid and HU-331 ) is also a widely used anticancer agent that stabilizes the topoisomerase IEDNA covalent complex (ie, the “cleavage complex”) following the formation of enzyme-mediated DNA cleavage. Accumulation of these cleavage complexes induces the apoptosis pathway.

Anthracyclines are a type of topoisomerase II inhibitor extracted from Streptomyces bacteria. Examples thereof include doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, rhodomycin, pyrarubicin, valrubicin, N-trifluoro-acetyl doxorubicin-14-valerate, Aclasinomycin, (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), 5-iminodaunomycin, mitoxantrone and aclasinomycin A (aclarubicin). In some embodiments, the anthracycline is administered in combination with doxorubicin (treatment with AC) in combination with an alkylating agent, such as cyclophosphamide.

Doxorubicin (Adriamycin®) is an exemplary topoisomerase II inhibitor used in the methods described herein. Its chemical name is 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8, 11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-(8S,10S)-5,12-naphthacenedione. Doxorubicin has the following structure:

Etoposide is an exemplary topoisomerase II inhibitor used in the methods described herein. Etoposide is generally administered as the prodrug epotoside phosphate, whose chemical name is 4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene--Dglucopyranoside] , 4' (dihydrogen phosphate).

Etoposide phosphate has the structure:

Etoposide phosphate, a phosphate ester of etoposide, is a semisynthetic derivative of podophyllotoxin and is converted to etoposide by dephosphorylation. Etoposide induces induction of DNA strand breaks by interaction with DNA-topoisomerase II or formation of free radicals, leading to cell cycle arrest (primarily in the G2 phase of the cell cycle) and cell death. Etoposide is ETOPOPHOS®, TOPOSAR™, VP-16, VEPESID®, ACTITOP, ASIDE, BIOPOSIDE, CTOP, CYTOP, EPOSED, ESIDE, ETHOPUL, ETOLON, ETONIS, ETOPLAST, ETOSID, ETOVEL, FYTOP, FYTO SID, LASTET, FYTO SID It is commercially available as ONCOSIDE, PLACID, POSID, RETOPSON, TEVASIDE, TOPOK, TOPOSIDE, and the like.

5. Taxanes

Taxanes are chemotherapeutic agents that can bind tubulin to promote microtubule assembly and stabilization, and/or prevent microtubule depolymerization. Taxanes included herein include the taxoid 10-deacetylbaccatin III and/or derivatives thereof. Exemplary taxanes are paclitaxel (ie, TAXOL ^® , CAS # 33069-62-4), docetaxel (ie, TAXOTERE ^® , CAS # 114977-28-5), larotaxel, cabazitaxel, mila taxel, tessetaxel and/or orataxel. In some embodiments, the taxane is an albumin-coated nanoparticle (eg, nano-albumin bound (NAP)-paclitaxel, ie, ABRAXANE® and/or Nap-docetaxel, ABI-008). In some embodiments, the taxane is nap-paclitaxel (Abraxane ^® ). In some embodiments, the taxane is formulated with CREMAPHOR ^® (eg, TAXOL ^® ) and/or Tween, such as polysorbate 80 (eg, Taxotere ^® ). . In some embodiments, the taxane is a liposomal encapsulated taxane. In some embodiments, the taxane is a prodrug form and/or a conjugated form of the taxane (eg, paclitaxel, paclitaxel polyglomex, and/or DHA covalently conjugated to linoleyl carbonate-paclitaxel). In some embodiments, the paclitaxel is formulated substantially free of surfactants (eg, in the absence of cremophor and/or twee-such as ^TOCOSOL® paclitaxel).

In some cases, paclitaxel is administered as part of a method of the invention. Paclitaxel may have the structure:

In some cases, the method or use comprises administering nano-albumin binding (NAP)-paclitaxel.

6. Alkylating agent

Alkylating agents are chemotherapeutic agents that cause DNA damage. Alkylating agents include nitrogen mustards, nitrosoureas, and alkyl sulfonates. Exemplary alkylating agents include cyclophosphamide, 1,3-bis(2-chloroethyl)-1-nitrosourea, 1,4-butanediol dimethanesulfonate, (2S)-2-amino-3-{4- [bis(2-chloroethyl)amino]phenyl}propanoic acid, 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2 -oxide, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. In some embodiments, the alkylating agent is cyclophosphamide. Cyclophosphamide can have the structure:

One of ordinary skill in the art will appreciate that any of the aforementioned chemotherapeutic agents may be administered in a variety of forms, such as salt forms contemplated as part of the present invention.

E. Exemplary Colony Stimulating Factors

Colony stimulating factors are proteins that stimulate the proliferation of cells. Colony stimulating factors include G-CSF (eg pegfilgrastim or filgrastim) and GM-CSF (eg sagramostim). In some embodiments, the colony stimulating factor is G-CSF (eg, pegfilgrastim or filgrastim). In some embodiments, the G-CSF is pegfilgrastim. In some embodiments, the G-CSF is filgrastim. In some embodiments, the colony stimulating factor is GM-CSF (eg, sagramostim). In some embodiments, the G-CSF is sagrammostim.

F. Exemplary VEGF antagonists

The present invention provides VEGF antagonists useful for treating cancer in a subject (eg, a human). The VEGF antagonist of the present invention includes any molecule capable of binding to VEGF, reducing VEGF expression levels, or neutralizing, blocking, inhibiting, eliminating, reducing or interfering with VEGF biological activity. Exemplary human VEGF is shown under UniprotKB/Swiss-Prot Accession No. P15692, Gene ID (NCBI): 7422.

In some cases, the VEGF antagonist is an anti-VEGF antibody. In some embodiments, the anti-VEGF antibody is bevacizumab, also known as “rhuMab VEGF” or “AVASTIN®”. Bevacizumab is described by Presta et al. ( Cancer Res . 57:4593-4599, 1997) is a recombinant humanized anti-VEGF monoclonal antibody. It contains a mutated human IgG1 framework region and an antigen binding complementarity determining region from the murine anti-hVEGF monoclonal antibody A.4.6.1 that blocks binding of human VEGF to its receptor. Approximately 93% of the amino acid sequence of bevacizumab, including most of the framework region, is derived from human IgG1, and about 7% of the sequence is derived from the murine antibody A4.6.1. Bevacizumab has a molecular weight of about 149,000 Daltons and is glycosylated. Bevacizumab and other humanized anti-VEGF antibodies are further described in US Pat. No. 6,884,879, issued Feb. 26, 2005, which is incorporated herein by reference in its entirety. In some cases, the anti-VEGF antibody comprises a heavy chain variable (VH) region sequence and a light chain variable (VL) region sequence of bevacizumab.

Further preferred antibodies include G6 or B20 family antibodies (eg G6-31, B20-4.1) as described in PCT Application Publication No. WO 2005/012359. For further preferred antibodies, see US Pat. Nos. 7,060,269, 6,582,959, 6,703,020; 6,054,297; WO98/45332; WO 96/30046; WO94/10202; EP 0666868B1; US Patent Application Publication Nos. 2006009360, 20050186208, 20030206899, 20030190317, 20030203409 and 20050112126; and Popkov et al. ( Journal of Immunological Methods 288:149-164, 2004). Other preferred antibodies comprise residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103 and C104, or alternatively comprise residues F17, Y21, Q22, Y25, D63, 183 and Q89 include those that bind to functional epitopes on human VEGF.

In other cases, the VEGF antagonist is an anti-VEGFR2 antibody or related molecule (eg, ramucirumab, tanivirumab, aflibercept), an anti-VEGFR1 antibody and related molecule (eg, icrucumab, aflibercept (VEGF trap) -Eye (Trap-Eye; EYLEA®), and Ziv-aflibercept (VEGF Trap; ZALTRAP®)), bispecific VEGF antibodies (eg, MP-0250, vanucizumab (VEGF-ANG2), or US 2001/0236388), a bispecific antibody comprising a combination of two of anti-VEGF, anti-VEGFR1, and anti-VEGFR2 arms, an anti-VEGFA antibody (eg, bevacizumab, sebacizumab), anti-VEGFB Antibodies, anti-VEGFC antibodies (eg, VGX-100), anti-VEGFD antibodies, and non-peptide small molecule VEGF antagonists (eg, pazopanib, axitinib, vandetanib, stivaga, caboxantinib, lenvatinib, nintedanib , orantinib, telatinib, dovitinig, cediranib, motesanib, sulfatinib, afatinib, foretinib, pamitinib, or tivozanib).

In a further aspect, the VEGF antagonist (eg, anti VEGF antibody (eg, bevacizumab)) according to any of the preceding cases, alone or in combination, as described in Section C above, any of the above features can be integrated

G. Additional Therapeutics

Additional therapeutic agents that may be used in the present invention (eg, used in combination with an anti-TIGIT antagonist antibody) include antibodies such as alemtuzumab (Campath), bevacizumab ( ^AVASTIN® , Genentech); cetuximab (ERBITUX ^® , Imclone); Panitumumab (VECTIBIX ^® , Amgen), Rituximab (RITUXAN ^® , Genentech/Biogen Idec), Pertuzumab (OMNITARG ^® , 2C4, Genentech ), trastuzumab (HERCEPTIN ^® , Genentech), tositumomab (bexar, Corixia), and antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG ^® , Wyeth )) is included. Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the disclosed compounds are: apolizumab, acelizumab, atlizumab, bapineuzumab, vibatuzumab mertansine, cantuzumab mertansine, sedelizumab , Sertolizumab Pegol, Sidfucituzumab, Sidtuzumab, Daclizumab, Eculizumab, Efalizumab, Epratuzumab, Erlizumab, Felbizumab, Fontolizumab, Gemtuzumab Ozogamicin, Ino tuzumab ozogamicin, iplimumab, rabetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motobizumab, natalizumab, nimotuzumab, nolovizumab, numizumab, okrelizumab , omalizumab, palivizumab, pascolizumab, pekfucituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslibizumab, reslizumab, recibizumab, lobelizumab, luplizumab , cibrotuzumab, ciplizumab, sontuzumab, tacatuzumab tetrajetan, tadozumab, talizumab, tefivazumab, tocilizumab, toralizumab, tucotuzumab selmorukin, tucusituzumab, Umaizumab, urtoxazumab, ustekinumab, vicilizumab, and anti-interleukin-12 (ABT- 874/J695, Wyeth Research and Abbott Laboratories).

Therapeutic antibodies also include antibodies that bind EGFR. Examples of antibodies that bind EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), Mab 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (US Pat. No. 4,943,533, Mendelsohn et al . . IMC-11F8 (Imclone), a fully human EGFR targeting antibody; antibodies that bind to type II mutant EGFR (US Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); and a human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies (known as: E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6 3 and E7.6. 3 and US 6,235,883; MDX-447 (meda Medarex Inc.) and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)). It can be conjugated with a toxic agent to generate an immunoconjugate (see eg EP659,439A2, Merck Patent GmbH).

Additional therapeutic agents that may be employed in the methods, compositions and uses provided herein include agents that target co-inhibitory targets (eg, CTLA-4, LAG3, TIM3, BTLA and/or VISTA), such as CTLA-4 antagonists, such as , an anti-CTLA-4 antagonist antibody (eg, ipilimumab (YERVOY®)); agents that target co-stimulatory targets (eg, CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR); radiotherapeutics; antiangiogenic agents; apoptotic agents; and antitubulin agents.

V. Pharmaceutical Compositions, Formulations and Kits

An anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) described herein, a VEGF antagonist, a chemotherapeutic agent (eg, a platinum-based chemotherapeutic agent (eg, carbo Platin or cisplatin) and non-platinum-based chemotherapeutic agents (eg, alkylating agents (eg, cyclophosphamide), taxanes (eg, paclitaxel, eg, nap-paclitaxel), and/or topoisomerase II inhibitors (eg, doxorubicin) . Anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (eg anti-PD-L1 antagonist antibody), VEGF antagonist, one or more chemotherapeutic agents, ADC (eg enfortumab vedotin or sassitu) Pharmaceutical compositions and formulations of zumab gobitecan), and/or CSF (eg, pegfilgrastim, filgrastim, or sagramostim) are prepared in one, two, three, four , or more than four agents are prepared in the form of a lyophilized formulation or aqueous solution by mixing with one or more optional pharmaceutically acceptable carriers ( Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Acceptable carriers are nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate and other organic acids, antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butal or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclo hexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as blood blue albumin, gelatin, or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt forming counterions such as sodium; metal complexes (such as Zn protein complexes); and/or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein are intercellular drug dispersing agents, such as soluble neutral active hyaluronase glycoprotein (sHASEGP), such as human soluble PH-20 hyaluronate glycoprotein, such as rHuPH20 (Hire ^HYLENEX® , Baxter International, Inc.). Certain exemplary sHASEGPs, including rHuPH20, and methods of using them are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, the sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinases.

Exemplary lyophilized antibody formulations are described in US Pat. No. 6,267,958. Aqueous antibody formulations include those described in US Pat. No. 6,171,586 and WO 2006/044908, the latter formulations comprising a histidine-acetate buffer.

An exemplary atezolizumab formulation comprises acetic acid, L-histidine, polysorbate 20 and sucrose having a pH of 5.8. For example, atezolizumab is administered in 1200 mg of atezolizumab formulated with acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821.6 mg) having a pH of 5.8. may be provided in a 20 mL vial containing zolizumab. In another example, atezolizumab is administered at 840 mg of atezolizumab formulated with acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) having a pH of 5.8. may be provided in a 14 mL vial containing zolizumab.

An exemplary tyragolumab formulation comprises a histidine solution containing polysorbate 20, sucrose, L-methionine and WFI. Tiragolumab may be presented in a 15 mL vial containing 10 mL of the tiragolumab drug product at an approximate concentration of tyragolumab antibody at 60 mg/mL.

The formulations herein may also contain more than one active ingredient as needed for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent. These active ingredients are suitably present in the complex in amounts effective for their intended purpose.

The active ingredient may be administered in microcapsules prepared, for example, by droplet formation techniques or by interfacial polymerization, such as, respectively, in colloidal drug delivery systems (eg, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules. This technique is described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of a shaped article, eg, a film, or microcapsules. Formulations used for in vivo administration are generally sterile. Sterility can be readily achieved, for example, by filtration through a sterile filtration membrane.

The present invention provides a kit, eg, comprising an anti TIGIT antagonist antibody, for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to any of the methods provided herein.

In another embodiment of the invention, there is provided a kit comprising an anti TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to any of the methods provided herein. . In some cases, the kit further comprises the PD-1 axis binding antagonist. In some cases, the article of manufacture or kit comprises a package insert comprising instructions for using an anti-TIGIT antagonist antibody in combination with the PD-1 axis binding antagonist to treat or delay the progression of cancer (eg, in a patient). additionally include

In another embodiment of the invention, there is provided a kit comprising a PD-1 axis binding antagonist for use in combination with an anti TIGIT antagonist antibody to treat a subject having cancer according to any of the methods provided herein. . In some cases, the kit further comprises an anti-TIGIT antagonist antibody. In some cases, the article of manufacture or kit further comprises a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody to treat or delay the progression of cancer in a patient. .

In another embodiment, the kit comprises tiragolumab for use in combination with atezolizumab to treat a subject having cancer according to any of the methods and the like described herein. In some embodiments, the kit further comprises atezolizumab. In some cases, the article of manufacture or kit further comprises a package insert comprising instructions for using tiragolumab in combination with atezolizumab to treat or delay the progression of cancer in a patient.

In another embodiment, the kit comprises atezolizumab for use in combination with tiragolumab to treat a subject having cancer according to any of the methods and the like described herein. In some embodiments, the kit further comprises tiragolumab. In some cases, the article of manufacture or kit further comprises a package insert comprising instructions for using atezolizumab in combination with tiragolumab to treat or delay the progression of cancer in a patient.

In some cases, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are in the same container or in separate containers. Suitable containers include, for example, bottles, vials, envelopes and syringes. The container may be formed from a variety of materials, such as glass, plastic (eg, polyvinyl chloride or polyolefin), or metal alloy (eg, stainless steel or hastelloy). In some cases, the container holds the formulation and a label on the container or a label associated with the container may indicate instructions for use. The article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some cases, the article of manufacture further comprises one or more of other agents (eg, chemotherapeutic agents and anti-neoplastic agents). Suitable containers for the one or more formulations include, for example, bottles, vials, envelopes and syringes.

In some embodiments, a kit comprising a PD-1 axis binding antagonist and an anti TIGIT antagonist antibody comprises a VEGF antagonist, a chemotherapeutic agent (eg, a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent), an ADC (eg, enfortumab) vedotin or sacituzumab govitecan), and/or CSF (eg, pegfilgrastim, filgrastim or sagramostim).

Any of the PD-1 axis binding antagonist and/or anti TIGIT antagonist antibodies described herein may be included in the article of manufacture or kit. Any of the above articles of manufacture or kits may comprise instructions for administering a PD-1 axis binding antagonist and/or anti TIGIT antagonist antibody to a subject according to any of the methods described herein.

VI. Example

title Example 1 Phase Ia/Ib, open label, dose escalation of tiragolumab as a single agent and in combination with atezolizumab with or without chemotherapy in patients with locally advanced or metastatic tumors Research Example 2 A Phase Ib/II, Open Label, Randomized Study of Atezolizumab and Chemotherapy in Combination with Tiragolumab Example 3 A Phase Ib, Open Label, Multiple Cohort Study of the Safety, Efficacy and Pharmacokinetics of Tiragolumab in Combination with Atezolizumab and Chemotherapy in Patients with Triple Negative Breast Cancer Example 4 Phase Ia/Ib, open-label, dose-escalation study of the safety and pharmacokinetics of tiragolumab as a single agent and in combination with atezolizumab and/or other anticancer therapies in patients with locally advanced or metastatic tumors Example 5 Example 5. Pharmacokinetics, Pharmacodynamics, Safety and Efficacy in Phase Ia/Ib Dose Escalation Study of Anti-TIGIT Antibody Tiragolumab as Single Agent and in Combination with Atezolizumab in Patients with Advanced Solid Tumors Example 6 Atezolizumab in combination with tiragolumab and bevacizumab for advanced liver cancer Example 7 A phase 3, randomized, double-blind, placebo-controlled study of atezolizumab plus carboplatin and etoposide with or without tiragolumab in patients with untreated diastolic small cell lung cancer Example 8 Tiragolumab plus atezolizumab plus pemetrexed and carboplatin/cisplatin vs pembrolizumab plus pemetrexed plus carboplatin/cisplatin in patients with previously untreated advanced non-squamous non-small cell lung cancer A phase II, randomized, double-blind, placebo-controlled study of Example 9 Safety of neoadjuvant and adjuvant tiragolumab plus atezolizumab with or without platinum-based chemotherapy in patients with previously untreated locally advanced resectable stage II, IIIA, or some stage IIIB non-small cell lung cancer and Phase II, open-label, multicenter studies evaluating efficacy Example 10 Materials and Methods for Studying GO42501 Example 11 Safety Assessment for the GO42501 Study Example 12 Statistical considerations and analysis plan for the GO42501 study Example 13 Efficacy of anti-TIGIT antagonist antibody in combination with PD-1 axis binding antagonist in cervical cancer patients Example 14 A Phase Ib, Open Label, Multiple Cohort Study of the Safety, Efficacy and Pharmacokinetics of Tiragolumab in Combination with Atezolizumab and Chemotherapy in Patients with Triple Negative Breast Cancer Example 15 Phase II, randomized, double-blind study of atezolizumab + tiragolumab and atezolizumab + placebo as first-line treatment in patients with recurrent/metastatic PD-L1-positive squamous cell carcinoma of the head and neck Example 16 A Phase Ib/II, Open Label, Multicenter, Randomized Comprehensive Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients with Muscle Invasive Bladder Cancer (MIBC) Example 17 WO39613 Materials and methods for research Example 18 Safety evaluation for WO39613 study Example 19 WO39613 Statistical considerations and analysis plan for study Example 20 A Phase Ib/II, Open Label, Multicenter, Randomized Comprehensive Study Evaluating the Efficacy and Safety of Tiragolumab in Combination with Atezolizumab in Patients with Metastatic Uroepithelial Carcinoma (mUC) Example 21 WO39613 Materials and methods for mUC studies Example 22 WO39613 Statistical considerations and analysis plan for mUC studies Example 23 Phase Ib/II, open-label, multicenter, randomized, comprehensive study evaluating the efficacy and safety of immunotherapy-based treatment combinations in patients with locally advanced or metastatic esophageal cancer Example 24 Materials and Methods for Studying YO39609 Example 25 Statistical considerations and analysis plan for the YO39609 study Example 26 PD-L1 as a predictive biomarker for tiragolumab plus atezolizumab treatment

Table of Contents of Examples

The following are examples of the methods of the present invention. It is understood that various other embodiments may be practiced in accordance with the general description set forth above.

Example 1. Phase Ia/Ib, Publication of the Safety and Pharmacokinetics of Tiragolumab as a Single Agent and Co-administered with Atezolizumab in Patients with Locally Advanced or Metastatic Tumors with or without Chemotherapy Label, dose escalation studies

This study investigated the safety of tiragolumab (MTIG7192A) as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) in patients with locally advanced or metastatic tumors; PK, pharmacodynamics, and preliminary anti-tumor activity are assessed. The specific study objectives and corresponding endpoints are summarized in Table 5.

purpose Corresponding evaluation variable Safety Goals: When administered as a single agent (Phase Ia) or in combination with atezolizumab (Phase Ib), including estimation of the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and characterization of dose limiting toxicity (DLT) To evaluate the safety and tolerability of tiragolumab.

To evaluate the safety and tolerability of tiragolumab in combination with atezolizumab and chemotherapy (Phase Ib Chemotherapy Expansion Cohort). Incidence and characteristics of DLT

Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0

Changes from baseline in target vital signs

Changes from baseline in targeted clinical laboratory test results, including electrocardiogram (ECG)

Number of cycles received and dose intensity


Incidence of anti-tyragolumab antibody (Phase Ia or Ib) and/or anti-Atesolizumab antibody (Phase Ib) and potential correlation with PK, pharmacodynamics, safety, and preliminary efficacy parameters Pharmacokinetic goals: To characterize the pharmacokinetic (PK) curves of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib).

To characterize the PK curve of atezolizumab with or without chemotherapy in combination with tiragolumab (Phase Ib alone).

To characterize the PK curves of cisplatin, carboplatin, pemetrexed, paclitaxel, and etoposide when administered in combination with atezolizumab and tiragolumab (Phase Ib Chemotherapy Expansion Cohort). Serum concentrations of tiragolumab administered as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) at specific time points for the following parameters:
- Area under the concentration-time curve (AUC)
(AUC)
- Maximum serum concentration (Cmax)
- Minimum Serum Concentration (Cmin)
- Removal rate (CL)
- volume of distribution in steady state
(Vss)

Other parameters such as accumulation ratio, half-life, and dose proportionality can also be calculated.

Serum Cmax and Cmin of Atezolizumab

Plasma concentrations of cisplatin, carboplatin, pemetrexed, paclitaxel, and etoposide at specific time points Activity Goals: To conduct a preliminary evaluation of the antitumor activity of tyragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) in patients with locally advanced or metastatic tumors. Objective Response - Defined as complete response (CR) or partial response (PR) according to the Solid Tumor Response Evaluation Criteria (RECIST) v.1.1, determined by the investigator and confirmed by a repeat assessment at least 4 weeks after initial documentation.

Duration of Objective Response (DoR) - defined as the time from the first occurrence of a documented objective response to documented disease progression or death from any cause, whichever occurs first, according to RECIST v1.1 as determined by the investigator.

PFS - defined as the time from the first study treatment to the onset of progression or death from any cause, whichever occurs first, per RECIST v.1.1 as determined by the investigator.

(e) Overall survival (OS)—defined as time from first study treatment to death from any cause.
Immunogenicity goals: measuring anti-tiragolumab and/or anti-atezolizumab antibodies, and
By measuring its relationship to other outcome measures (Phase Ib) and by evaluating its relationship to other outcome measures (Phase Ia) and anti-tyragolumab antibodies in combination with atezolizumab with or without chemotherapy
To characterize the immunogenic potential of tiragolumab administered as a single agent. Incidence of anti-drug antibodies (ADA) during study compared to prevalence of ADA at baseline

Purpose and endpoints

A. study design

It is locally advanced, relapsing, or metastatic refractory for which standard therapy does not exist, has proven ineffective or intolerable, is deemed inappropriate, or for which clinical trials of investigational agents are the accepted standard of care. This is the first phase 1, open-label, multicenter, global, dose-escalation study in humans designed to evaluate the safety, tolerability, and pharmacokinetics of tiragolumab as a single agent in patients with tumors. The study also indicated that there is no standard therapy for this, has been demonstrated to be ineffective or intolerable, is considered inappropriate, or for which clinical trials of an investigational agent are the accepted standard of care for, or against, anti-PD. -Atezolizumab with or without chemotherapy in patients with locally advanced, relapsed, or metastatic refractory tumors for which clinical trials of investigational agents using L1 antibodies are considered acceptable treatment options. Designed to enable evaluation of the safety, tolerability, and Pk of tiragolumab when administered together.

1 is a flow chart depicting Phase Ib Chemotherapy Expansion and Phase Ib Q4W Dosing Expansion. During the dose escalation phase, cohorts of approximately 3 to 6 patients each are evaluated at the escalating dose level to determine the MTD or maximum administered dose (MAD) for tiragolumab as a single agent or in combination with atezolizumab.

In the dose expansion phase, patients are enrolled and treated below the MTD or MAD of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib). Tiragolumab as a single agent (Phase Ia) or the combination of tiragolumab and atezolizumab (Phase Ib cohort without chemotherapy) was administered on Day 1 of each 21-day cycle or Day 1 of each 28-day cycle (Phase Ib). Q4W dose expansion) by IV infusion, and tiragolumab is administered prior to atezolizumab in the Phase Ib cohort without chemotherapy. In the absence of unacceptable toxicity or clinically strong evidence of disease progression, tiragolumab (Phase Ia) or tiragolumab in combination with atezolizumab (Phase Ia) or Treatment with phase Ib) is continued after cycle 1.

In the Phase Ib chemotherapy expansion cohort and Phase Ib Q4W dosing expansion cohort ( FIG. 1 ), a safety search for 3 patients was completed. All relevant safety data from the safety search must be thoroughly reviewed by the IMC and investigators before registration continues.

In the chemotherapy expansion cohort, tiragolumab and atezolizumab were combined with specific chemotherapy in each of the three cohorts as follows: carboplatin or cisplatin and pemetrexed in cohort A, carboplatin and paclitaxel in cohort B , and carboplatin or cisplatin and etoposide in cohort C (see Figure 1). In each cohort, treatment includes an induction phase and a maintenance phase. In this induction phase, the combination of tiragolumab and atezolizumab with chemotherapy is administered as an IV infusion on a 21-day cycle for 4 to 6 cycles for Cohorts A and B and 4 cycles for Cohort C. The number of induction treatment cycles for Cohort A and Cohort B is at the discretion of the investigator.

After the induction phase, patients who have not experienced disease progression or unacceptable toxicity continue treatment with maintenance therapy. During this maintenance phase, patients in Cohort B and Cohort C continue to receive tiragolumab and atezolizumab alone, while patients in Cohort A continue to receive tiragolumab and atezolizumab in combination with pemetrexed. In all chemotherapy expansion cohorts, atezolizumab is administered before tiragolumab. When given chemotherapy, it is administered after atezolizumab and tiragolumab.

All patients are closely monitored for adverse events throughout the study and for at least 90 days after administration of the last dose of study treatment, or until initiation of other anti-cancer systemic therapy, whichever occurs first. Adverse events are graded according to NCI CTCAE v4.0.

To characterize the PK properties, immunogenic response, and pharmacodynamic effects of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) at various time points before and after dosing a blood sample is taken from Depending on the results of the interim PK analysis, the frequency of PK sampling may be reduced later in the study.

Patients receive tumor assessments during screening and study, as measured by the Standard Response Evaluation Criteria for Solid Tumors (RECIST) v1.1 criteria. Patients may continue to receive study treatment even if the standard RECIST v1.1 criteria for disease progression in the Phase Ia or Ib portion of the study are met, provided they meet the criteria for continued treatment. Patients who withdraw from the Phase Ia portion of the study may be transferred to the Phase Ib portion of the study and receive treatment with tiragolumab in combination with atezolizumab, provided they meet the crossover criteria and consent to a biopsy of an accessible lesion. have.

have locally advanced, recurrent, or metastatic refractory malignancies that have progressed following available standard therapy; for which standard therapies do not exist, have proven ineffective or intolerable, or have been deemed inadequate; Alternatively, approximately 60 to 320 patients for which clinical trials of the investigational product are the accepted standard of care are enrolled in the study's expansion cohort. For the Phase Ib portion of the study, patients with or without chemotherapy for an investigational product in combination with an anti-PD-L1 antibody may be enrolled in the expansion cohort if they are considered an acceptable treatment option.

The expansion phase includes the safety, tolerability, PK variability, pharmacodynamic activity of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) in certain cancer settings, and In order to better characterize preliminary anti-tumor activity, we included a cohort of patients. Enrollment in the expansion cohort includes tyragolumab as a single agent (Phase Ia) or with or without chemotherapy as determined by the study investigator based on assessment of accumulated safety, tolerability, PK, pharmacodynamics, and antitumor activity data. It is initiated at a selected dose level below the MAD or MTD of tiragolumab (Phase Ib) in combination with zolizumab.

In the Phase Ia portion of the study, up to about 40 patients were diagnosed with PD-, including NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC, UBC, and CRC (including CRCs with low MSS or MSI) GEJ cancers. Enroll in a planned expansion cohort of L1 selected and/or TIGIT selected multiple tumor indications.

In the Phase Ib portion of the study (no chemotherapy), approximately 20-40 patients are enrolled in each of the following planned indication-specific expansion cohorts: NSCLC: no cancer immunotherapy (CIT) experience (e.g., anti-PD-L1/ no prior treatment for PD-1); NSCLC: CIT treated (eg, including prior treatment with anti-PD-L1/PD-1); RCC; TNBC; melanoma; HNSCC; OC; including GC and GEJ cancers; UBC; CRC (including MSS or CRC with low MSI); Biopsy cohort of specific tumor indications including melanoma, OC, RCC and UBC.

In the Phase Ib chemotherapy expansion portion of the study, approximately 20-40 patients are enrolled in each of the following planned chemotherapy expansion cohorts (see Figure 1):

Cohort A:

- Induction phase - Atezolizumab and Tiragolumab -

In combination with cisplatin or carboplatin and pemetrexed

- Maintenance phase - Atezolizumab and Tiragolumab -

In combination with pemetrexed

Cohort B:

- Induction phase - Atezolizumab and Tiragolumab -

Carboplatin and Paclitaxel

- Maintenance phase - Atezolizumab and Tiragolumab

Cohort C:

- Induction phase - Atezolizumab and Tiragolumab -

In combination with cisplatin or carboplatin and etoposide

- Maintenance phase - Atezolizumab and Tiragolumab

Treatment combinations for each cohort are shown in Table 6.

treatment cohort induction period
(4 or 6 times in a 21-day cycle) retainer
(21 day cycle) A Atezolizumab + Tiragolumab +
Cisplatin or Carboplatin + Pemetrexed Atezolizumab + Tiragolumab +
Pemetrexed B Atezolizumab + Tiragolumab +
Carboplatin + Paclitaxel Atezolizumab +
Tiragolumab C Atezolizumab + Tiragolumab +
Cisplatin or Carboplatin + Etoposide Atezolizumab +
Tiragolumab

Treatment regimens in the chemotherapy expansion cohort

B. Phase Ib Chemotherapy Expansion Cohort: Dose and Dosing

In the induction phase, patients in certain chemotherapy expansion cohorts receive the following doses and administrations:

Cohort A was atezolizumab 1200 mg IV, tiragolumab 600 mg IV, followed by cisplatin 75 mg/m ² IV or carboplatin AUC 6 mg/mL min IV and pemetrexed 500 every day 1 of a 21-day cycle. A combination of mg/m ² IV is administered. In the absence of disease progression or unacceptable toxicity, 4 to 6 cycles of induction phase treatment are administered.

Cohort B receives atezolizumab 1200 mg IV, tiragolumab 600 mg IV, followed by a combination of carboplatin AUC 6 mg/mL min IV and paclitaxel 200 mg/m ² IV on Day 1 of a 21-day cycle . In the absence of disease progression or unacceptable toxicity, 4 to 6 cycles of induction phase treatment are administered.

Cohort C is atezolizumab 1200 mg IV, tiragolumab 600 mg IV, then cisplatin 75 mg/m2 IV or carboplatin AUC 5 mg/mL min IV on day 1 of every 21-day cycle, then every 21 days Receive etoposide 100 mg/m ² IV on days 1 to 3 of the cycle. In the absence of disease progression or unacceptable toxicity, 4 cycles of induction treatment are administered.

After the induction phase, if there is no unacceptable toxicity, clinically serious disease progression, and/or loss of clinical benefit, at the discretion of the investigator after careful evaluation and thorough discussion of potential risks and benefits with the patient, the maintenance phase continue treatment at In the maintenance phase, patients in certain chemotherapy expansion cohorts receive the following doses and administrations:

Cohort A received atezolizumab 1200 mg IV, tiragolumab 600 mg IV, followed by pemetrexed 500 mg/m ² IV on day 1 of every 21-day cycle; Cohort B receives atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV on Day 1 of every 21-day cycle; Cohort C receives atezolizumab 1200 mg IV followed by tyragolumab 600 mg IV on the day of every 21-day cycle.

In the case of toxicity and no disease progression, individual chemotherapy or immunotherapy agents are independently discontinued.

C. Phase Ib Q4W Dosing Expansion Cohort

The purpose of the Phase Ib Q4W Dosing Expansion Cohort was to evaluate safety, tolerability, PK, and prospects in patients treated with tiragolumab 840 mg IV in combination with atezolizumab 1680 mg IV on a dosing schedule of every 4 weeks (28 days). To better characterize efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity.

The Phase Ib Q4W cohort includes about 20-40 patients with tumors that can be selected for PD-L1 and/or TIGIT based on prospective testing of tumor tissue during screening or re-screening. Patients with insufficient or unavailable archival tissue may be eligible for enrollment in this cohort if permitted by the Medical Monitor based on the investigator's discussion. Patients with tumor types for which clinical trials of investigational agents in combination with anti-PD-L1 antibodies are considered acceptable treatment options may be enrolled in this expansion cohort.

D. Additional inclusion criteria for patients in the expanded cohort for each indication in Phase Ib

The NSCLC cohort (CIT naive) is considered anti-PD-L1/PD-1 and/or anti-CTLA-4 when CIT (including anti-PD-L1/PD-1 agents) has been approved as a treatment for NSCLC by local regulatory authorities. With histologically confirmed refractory, advanced NSCLC not previously treated with CIT (investigation or approval), including patients considered. Patients whose tumors have known sensitizing epidermal growth factor receptor (EGFR) mutations must also have experienced disease progression (during or after treatment) or intolerance to treatment with the EGFR tyrosine kinase inhibitor(s). Patients whose tumors have known anaplastic lymphoma kinase (ALK) rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ALK tyrosine kinase inhibitor(s). Patients whose tumors have known ROS1 rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ROS1 tyrosine kinase inhibitor(s). Patients whose tumors have the BRAFV600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib.

The NSCLC cohort (CIT treated) includes patients with histologically confirmed refractory, advanced NSCLC who have previously been treated with CIT (investigation or approval), including anti-PD-L1/PD-1. Patients whose tumors have a known sensitizing EGFR mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with the EGFR tyrosine kinase inhibitor(s). Patients whose tumors have known ALK rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ALK tyrosine kinase inhibitor(s). Patients whose tumors have known ROS1 rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ROS1 tyrosine kinase inhibitor(s). Patients whose tumors have the BRAFV600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib. The patient must have previously experienced documented disease progression on CIT monotherapy and/or combination therapy (research or approval) that should include anti-PD-L1/PD-1.

Approximately 10 experienced the best documented response for an identified PR or CR assessed by the investigator according to RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy or combination therapy More than one patient may be enrolled. At any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or combination therapy, at least about 10 subjects experienced a documented best response to investigator-assessed SD according to RECIST v1.1 A patient may be enrolled. Experienced best documented response to investigator-assessed progressive disease (PD) according to RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or combination therapy More than about 10 patients may be enrolled. Previous anti-PD-L1/PD-1 as monotherapy and/or combination therapy should represent the most recent systemic anticancer therapy administered prior to enrollment in the expansion cohort. Patients who discontinue previous anti-PD-L1/PD-1 monotherapy and/or combination therapy, primarily for toxicity or intolerance, are not eligible for this expansion cohort enrollment.

The TNBC cohort includes patients with histologically confirmed refractory, advanced estrogen receptor (ER) negative, progesterone receptor (PgR) negative, and human EGFR 2 (HER2) negative breast adenocarcinoma (triple negative). Triple negative status should be documented as defined in the American Society of Clinical Oncology (ASCO-CAP) guidelines. Less than 1% of tumor cell nuclei are immune to ER, less than 1% of tumor cell nuclei are immune to progesterone receptor, and HER2 test is negative for IHC 1+, IHC 0 or ISH (intra-tissue hybridization). This indicates

The CRC cohort was histologically confirmed

patients with refractory, advanced adenocarcinoma of the colon or rectum. Patients with tumors of cecal origin are not eligible.

diger Siewert et al. (2000)에 의해 해부학적 식도위 접합부 위 1 내지 5 cm 이내에 종양 중심이 위치하는 말단 식도의 선암종으로서 정의된 유형 1 GEJ 종양을 가진 환자는 상기 연구에 적격이다. 식도암(편평세포 암종 또는 선암종)을 가진 환자는 의료 모니터와의 논의 후에 적격이 될 수 있다. 종양이 HER2 양성인 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 HER2 표적화 항체/HER2 억제제(들)을 이용한 치료에 불내성을 경험했어야 한다. HER2 양성은, 원발성 종양 또는 전이성 병변에 대한 국소 실험실 검사에 의해 평가된 바와 같이, IHC 3+ 또는 IHC 2+/ISH+(여기서, ISH 양성은 2 이상의 HER2:CEP17 비율로 정의됨)로 정의된다. 불충분하거나 입수 불가능한 조직(예컨대, 보관 및/또는 생검)으로 인해 HER2 검사를 받지 않아 종양의 HER2 상태를 알 수 없는 환자는 여전히 적격일 수 있다.The GC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic or recurrent gastric or GEJ adenocarcinoma (not suitable for curative therapy). R

diger Siewert et al. (2000) patients with type 1 GEJ tumors, defined as adenocarcinomas of the distal esophagus with a tumor center located within 1 to 5 cm above the anatomical gastroesophageal junction, are eligible for this study. Patients with esophageal cancer (squamous cell carcinoma or adenocarcinoma) may be eligible after discussion with a medical monitor. Patients whose tumors are HER2 positive must also have experienced disease progression (during or after treatment) or intolerance to treatment with the HER2 targeting antibody/HER2 inhibitor(s). HER2 positivity is defined as either IHC 3+ or IHC 2+/ISH+ (wherein ISH positivity is defined as a HER2:CEP17 ratio of 2 or greater), as assessed by local laboratory tests for the primary tumor or metastatic lesion. Patients whose tumor's HER2 status is unknown because they have not undergone HER2 testing due to insufficient or unavailable tissue (eg, archival and/or biopsy) may still be eligible.

The HNSCC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent squamous cell carcinoma of the head and neck (oral, oropharyngeal, hypopharyngeal, or larynx) for which curative therapy is not suitable. Patients with HNSCC in other primary anatomical locations of the head and neck, patients with HNSCC of unknown primary, or patients with nonsquamous histological tumors are not eligible. Patients with HNSCC of the nasopharynx may be eligible. The HPV status for HNSCC should be known.

The UBC cohort includes patients with histologically confirmed refractory advanced transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, bladder, and urethra). Patients with mixed tissue should have a dominant transitional cell pattern.

The melanoma cohort includes patients with histologically confirmed refractory, advanced metastatic melanoma. When CIT (including anti-PD-L1/PD-1 agents and/or anti-CTLA-4 agents) has been approved for the treatment of melanoma by local regulatory authorities, for investigational agents in combination with its anti-PD-L1 antibody Clinical trials include patients with melanoma who are considered an acceptable treatment option. Patients with a BRAFV600 mutation whose tumor is known must also have experienced disease progression (during or after treatment) or intolerance to the BRAF inhibitor(s) and/or MEK inhibitor(s). Enrollment is managed so that no more than about 20% of patients in this cohort have ocular (uveal) melanoma.

The OC cohort includes patients with histologically confirmed refractory, advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Borderline ovarian epithelial neoplasms (eg, low malignant tumors, atypical proliferative tumors) are excluded.

The RCC cohort includes patients with histologically confirmed refractory, advanced RCC with a component of clear cell histology and/or a component of sarcoma histology. When CITs (including anti-PD-L1/PD-1 agents) have been approved by local regulatory authorities for the treatment of RCC, clinical trials of their investigational agents in combination with their anti-PD-L1 antibodies are considered acceptable treatment options. Include patients with RCC considered.

E. Dosage and administration

The dose of atezolizumab administered in combination with tiragolumab in the Phase Ib portion of the study was 1200 mg IV every 3 weeks, except in the Phase Ib Q4W dosing cohort where atezolizumab 1680 mg IV Q4W was administered. The dose is fixed and does not depend on body weight. In all Phase Ib cohorts that did not include chemotherapy, atezolizumab is administered after the tiragolumab infusion and subsequent observation period. In the Phase Ib chemotherapy expansion cohort, atezolizumab is administered prior to tiragolumab.

The initial dose of atezolizumab is delivered over 60 (±10) minutes. If the first infusion is well tolerated without infusion-related adverse events, the second infusion may be delivered over 30 (± 10) minutes. If a 30 minute infusion is well tolerated, all subsequent infusions can be delivered over 30 (±10) minutes. For Cycle 1, atezolizumab dosing is followed by a 90-minute observation period. A 30-minute observation period may follow after all subsequent atezolizumab infusions. Patients who have previously received atezolizumab in other clinical trials may receive the initial dose at the fastest rate previously permitted.

Chemotherapy in the Phase Ib Expansion Cohort

Chemotherapy is administered following an infusion of atezolizumab and tiragolumab followed by an observation period. During the induction phase, chemotherapy cycles are included in the predetermined number of induction chemotherapy cycles when at least one chemotherapy component is administered at least once during a 21-day cycle. Cycles for which no chemotherapy component was given are not included in the total number of induction chemotherapy cycles.

Patients receive antiemetics and IV hydration for chemotherapeutic agents according to local standards of care and manufacturer's guidelines. However, due to the immunomodulatory effect of steroids, steroid premedication should be minimized to the extent clinically feasible.

Cohort A - atezolizumab + tyragolumab + carboplatin/cisplatin + pemetrexed

On Day 1 of each 21-day cycle, all eligible patients will receive drug infusions in the following order:

Induction: atezolizumab > tyragolumab > pemetrexed > carboplatin or cisplatin

After 4 to 6 cycles in the induction phase, the patient initiates maintenance therapy in the following order of administration:

Maintenance: atezolizumab > tyragolumab > pemetrexed

study drug capacity and route Induction phase (4 to 6 cycles) retainer Pemetrexed 500 mg/m ² IV Q3W ~10 min infusion per day Q3W ~10 min infusion per day carboplatin AUC 6 IV Q3W ~30 to 60 minutes infusion per day Not applicable or cisplatin 75 mg/m ² IV Q3W 1 to 2 hours infusion per day Not applicable

Treatment regimens for pemetrexed and carboplatin or cisplatin

AUC = area under the concentration-time curve; IV = intravenous; Q3W = Every 3 weeks.

Table 8 lists the recommended infusion times for therapeutic administration of pemetrexed and carboplatin or cisplatin and pemetrexed during the maintenance phase during the induction phase.

pre-medication capacity and route hour Dexamethasone 20 mg PO 12 hours and 6 hours prior to paclitaxel (or depending on the institution's standard of care) Diphenhydramine (or equivalent) 50 mg IV 30-60 minutes before paclitaxel Cimetidine (or lantidine) (or equivalent) 300 mg (or 50 mg) IV (or equivalent) 30-60 minutes before paclitaxel

Pre-administration of paclitaxel

IV = intravenous; PO = oral

Cohort B - Atezolizumab + Tiragolumab + Carboplatin + Paclitaxel

On Day 1 of each 21-day cycle, all eligible patients received drug infusion.

It is administered in the following order.

Induction: atezolizumab > tyragolumab > paclitaxel > carboplatin

Table 8 lists the proposed pre-dosing for induction treatment for patients in Cohort B. Table 9 lists the suggested infusion times for therapeutic administration of paclitaxel and carboplatin during the induction phase.

study drug capacity and route induction period
(4 to 6 cycles) paclitaxel 200 mg/m ² IV (175 mg/m ² IV for patients of Asian race/ethnicity) ^a About 180 minutes per day of Q3W carboplatin AUC 6 IV About 30 to 60 minutes per day of Q3W

Treatment regimens for paclitaxel and carboplatin

AUC = area under the concentration-time curve; IV = intravenous; Q3W = Every 3 weeks.

Cohort C - atezolizumab + tyragolumab + carboplatin or cisplatin + etoposide

On Day 1 of each 21-day cycle, all eligible patients are infused with study drug in the following order:

Induction: atezolizumab > tyragolumab > cisplatin or carboplatin > etoposide

After the induction phase, the patient initiates maintenance therapy in the following order of administration:

Maintenance: Atezolizumab > Tiragolumab

Table 10 lists the suggested infusion times for therapeutic administration of carboplatin or cisplatin and etoposide during the induction phase.

study drug capacity and route Induction period (4 cycles) carboplatin AUC 5 IV For 30 to 60 minutes per day of Q3W or cisplatin 75 mg/m ² IV For 60-120 minutes per day of Q3W etoposide 100 mg/m ² IV For 60 minutes on days 1, 2 and 3 of Q3W

Treatment regimens for carboplatin or cisplatin and etoposide

IV = intravenous; Q3W = Every 3 weeks.

cisplatin

Guidance for cisplatin administration in various cohorts is presented in Table 11.

Chemotherapy Expansion Cohort hour capacity and route duration A Day 1: 30 minutes after completion of pemetrexed 75 mg/m ² IV 60-120 minutes C Day 1: After the end of the observation period for tiragolumab 75 mg/m ² IV 60-120 minutes

Cisplatin Administration Times and Instructions

IV = intravenous

Remarks: Patients should receive appropriate antiemetic therapy and adequate hydration before and after cisplatin administration. Refer to local clinical practice guidelines for details.

carboplatin

Guidelines for cisplatin administration in various cohorts are presented in Table 12.

Chemotherapy Expansion Cohort hour capacity and route duration A Day 1: 30 minutes after completion of pemetrexed AUC 6 mg/mL/min IV 30-60 minutes B Day 1: After completion of paclitaxel AUC 6 mg/mL/min IV 30-60 minutes C Day 1: After the end of the observation period for tiragolumab AUC 5 mg/mL/min IV 30-60 minutes

Carboplatin Administration Times and Instructions

AUC = area under the time concentration curve; IV = intravenous

NOTE: Standard antiemetics should be given with carboplatin administration according to local practice guidelines, and the carboplatin dose of AUC 5 or AUC 6 is calculated using the Calvert formula (Calvert et al., J. Clin. Oncol . 1989, 7:1748-56):

here: CrCl　=　Creatinine clearance, mL/min

Age 　 = 　 Age of the patient

wt　=　Patient's weight, kg

Scr　=　serum creatinine, mg/dL

For patients with abnormally low serum creatinine levels, estimate the GFR using a minimum creatinine level of 0.8 mg/dL or limit the upper limit of the estimated GFR to 125 mL/min.

If a patient's GFR is estimated based on serum creatinine measurements by isotopic dilution mass spectrometry, the FDA will advise physicians to consider limiting the dose of carboplatin for the desired exposure (AUC) to avoid potential toxicity from overdose. recommend that Based on the Calvert formula listed on the carboplatin label, the maximum dose can be calculated as follows:

분/mL)　　(GFR　　25 mL/분)Maximum Carboplatin Dose (mg) = Target AUC (mg)

min/mL) (GFR 25 mL/min)

This maximum dose is based on an estimate of GFR with an upper limit of 150 mL/min in patients with normal renal function. GFR estimates higher than this are not used.

For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg.

For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg.

For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg.

Pemetrexed

Guidelines for administration of pemetrexed in Cohort A are presented in Table 13.

Chemotherapy Expansion Cohort hour capacity and route duration A Day 1: After the end of the observation period for tiragolumab 500 mg/m ² IV 10 minutes

Pemetrexed dosing times and instructions

IV = intravenous

The pre-dosage dose administered is in accordance with the prescribing information. All patients eligible for pemetrexed therapy should avoid taking nonsteroidal anti-inflammatory drugs with a long elimination half-life for at least 5 days prior to, the day of, and at least 2 days post-administration of pemetrexed.

paclitaxel

Guidelines for administration of paclitaxel in Cohort B are presented in Table 14.

Chemotherapy Expansion Cohort hour capacity and route duration B Day 1: After the end of the observation period for tiragolumab 200 mg/m ² IV (175 mg/m ² IV for patients of Asian race/ethnicity) 3 hours

Paclitaxel Administration Times and Instructions

IV = intravenous

Patients of Asian ethnicity/ethnicity have a lower starting dose of paclitaxel at 175 mg/m2 IV over 3 hours. The lower starting dose of paclitaxel is based on the higher incidence of overall hematological toxicity in patients from Asian countries compared to patients from non-Asian countries, as observed in an internal safety review of lung cancer clinical trials. As used in this study, Asian race/ethnic refers to a pan-ethnic/ethnic group that includes diverse population groups of ancestral origin or residing in East Asia, Southeast Asia, or South Asia. The application of the above term to a particular patient is at the discretion of the treating investigator and should be based on the patient's clinical characteristics and country of origin.

etoposide

Guidelines for administration of etoposide in Cohort C are presented in Table 15.

Chemotherapy Expansion Cohort hour capacity and route duration C Day 1: After completion of cisplatin/carboplatin 100 mg/m ² IV 60 minutes Days 2 and 3: On days 2 and 3, only etoposide is delivered. 100 mg/m ² IV 60 minutes

Etoposide Administration Times and Instructions

IV = intravenous

Example 2. A Phase Ib/II, Open Label, Randomized Study of Atezolizumab and Chemotherapy in Combination with Tiragolumab

This study included atezolizumab and chemotherapy (nanoparticle albumin-bound paclitaxel (nap-paclitaxel) and gemcitabine) in combination with tiragolumab in patients who had never received prior systemic therapy for metastatic pancreatic ductal adenocarcinoma (PDAC). to evaluate the efficacy, safety, and pharmacokinetics of This study evaluates the efficacy, safety, and pharmacokinetics of an immunotherapy-based treatment combination in patients with metastatic PDAC.

A. Study Design

Patients in Cohort 1 are randomly assigned to either a control group (chemotherapy) or an experimental group consisting of atezolizumab in combination with tiragolumab and chemotherapy. Enrollment in the experimental group proceeds in two stages: the preliminary stage and the expansion stage. About 20 patients are enrolled in the preliminary phase. Randomization will be discontinued for safety evaluation in at least 6 patients. The safety assessment is based on safety data obtained from at least 6 patients who received at least one dose of treatment (i.e., one dose of each agent for a given combination) and completed a safety follow-up evaluation for at least one full treatment cycle. . If the combination is determined to be sufficiently safe, registration of the group is resumed. If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients can be enrolled in that group during the expansion phase. Additional subgroup analyzes may be possible by enrolling additional patients to ensure a balance between treatment groups with respect to demographic and baseline characteristics, including potential predictive biomarkers.

Patients are randomly assigned to treatment groups, and the rate of randomization depends on the number of groups open for enrollment (e.g., if a group is discontinued while a group is added or a preliminary analysis of results is pending). However, the probability of being assigned to the control group must be less than or equal to 35%.

End of the study is defined as the date the last patient completed the last visit (LPLV), including survival follow-up visits conducted by phone or hospital. The total study duration from screening of the first patient to study termination is approximately 3-5 years.

The activity schedule is summarized in Table 16.

Treatment cycle (28 day cycle) ^a cycle 1 ^b cycle ≥ 2 trace ^c 1 day 8 days (± 3 days) 15 days (± 3 days) 1 day 8 days (± 3 days) 15 days (± 3 days) cure. stop. ^c every 3 months Molecular Profile of Pancreatic Cancer (if available) Whenever updated information is provided vital signs X X X X X X X weight X X X X X X X full physical examination ^e X limited physical examination ^f X X X X X X ECOG whole body activity X X X ECG Perform as clinically indicated hematology ^h X ^{i, j} X ⁱ X ⁱ X ⁱ X ⁱ X ⁱ X chemistry ^k X ^{i, j} X ⁱ X ⁱ X ⁱ X ⁱ X ⁱ X Coagulation (INR and aPTT) X ^{i, j} Perform as clinically indicated X TSH, free T3 (or total T3), free T4 ^l X ^{i, j, l} X Viral serology (if applicable) x ^m x ^m x ^m C-reactive protein X ^{i, j} X ⁱ CA19-9 X ⁱ X ⁱ X pregnancy test X ^{i, j} X ⁱ X X ⁿ urine test ^o Perform as clinically indicated Serum autoantibody sample ^p Conducted as clinically indicated ^q PK sample see table 17 ADA sample see table 17 biomarker sample see table 17 Blood sample for RBR (optional) ^r X tumor biopsy X ^s Tumor biopsy (optional) x ^t Tumor Response Assessment X ^u,v concomitant drug ^w X X X X X X X adverse reaction ^x X X X X X X x ^x x ^x Atezolizumab administration ^{y, z} X X X X Tiragolumab administration ^z,aa X X X X Nap-paclitaxel and gemcitabine administration ^z,bb X X X X X X Survival tracking and chemotherapy X ^cc

activity schedule

ADA = anti-drug antibody; atezo + chem + tyra = atezolizumab + chemotherapy (nap-paclitaxel and gemcitabine) + tyragolumab; CIT = cancer immunotherapy; CT = computed tomography; Discon. = abort; ECOG = Eastern Corporate Oncology Group; eCRF = electronic case report form; HBV = hepatitis B virus; nap-paclitaxel = nanoparticle albumin bound paclitaxel; PK = pharmacokinetics; RBR = study biosample repository; RECIST v1.1 = Response Evaluation Criteria for Solid Tumors, version 1.1; T3 = triiodothyronine; T4 = thyroxine; Treat. = treatment; TSH = thyroid stimulating hormone.

Unless otherwise specified, on the day of treatment, all assessments must be performed prior to dosing.

^a If visitation is not possible due to public holidays, vacations, or other circumstances, visits outside the designated period are possible with the consent of the medical monitor.

^b It is recommended to start treatment within 7 days of randomization.

^c The patient must return to the hospital for a treatment discontinuation visit within 30 days of administration of the last dose of study treatment. If disease progression is confirmed, the visit may be used as a treatment discontinuation visit. Then, the patient undergoes a follow-up evaluation.

^d Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure in the patient's sitting position, pulse oximetry, and body temperature. Adverse events Record new or worsening clinically significant abnormalities on the eCRF. For the first infusion of atezolizumab, vital signs should be measured within 60 minutes prior to that infusion and, if clinically indicated, every 15 (±5) minutes during that infusion and 30 (±10) minutes after that infusion. Should be. For subsequent infusions, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 30 (±10) minutes after the infusion. For the first infusion of tiragolumab, vital signs should be measured within 60 minutes prior to the infusion, every 15 (±5) minutes during the infusion and at 30 (±10) minutes after the infusion. For subsequent infusions of tiragolumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 15 (±10) minutes after the infusion. do.

^e A full physical examination should include evaluation of the head, eyes, ears, nose, and throat, and cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, urogenital, and nervous system. Adverse events Record new or worsening clinically significant abnormalities on the eCRF.

_f Conduct limited symptom-directed testing as clinically indicated at designated time points and at other time points. Adverse events Record new or worsening clinically significant abnormalities on the eCRF.

^g It is recommended that the patient rest in the supine position for at least 10 minutes prior to recording the ECG.

^h Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential counts (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).

ⁱ Laboratory studies must be conducted within 96 hours prior to Day 1 of Cycle 1 and within 24 hours prior to the designated follow-up visit during the treatment period.

^j If the screening laboratory evaluation was performed within 96 hours prior to Day 1 of Cycle 1, no repeat is necessary.

^k Chemistry panel (serum or plasma) contains bicarbonate or total carbon dioxide (if considered as the local standard of care), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.

^l TSH, free T3 (or total T3 for sites not subjected to free T3), and free T4 at screening and on day 1 of cycle 1 and every third cycle thereafter (i.e., cycle 4, cycle 7, cycle 10) etc) are evaluated.

^m Patients with positive quantitative HBV DNA at screening (must be < 500 IU/mL according to eligibility criteria) on Day 1 of each 3rd cycle (i.e., Cycle 3, Cycle 6, Cycle 9, etc.), upon discontinuation of treatment (±7 days), and additional HBV DNA testing at 3, 6, 9, and 12 months (±14 days at each time point) after discontinuation of treatment. Study treatments and procedures may proceed while HBV DNA is being processed, but results should be reviewed by investigators as soon as they are available. If HBV DNA increases to < 500 IU/mL, a medical monitor should be consulted before continuing study treatment, and it is recommended that a hepatologist or gastroenterologist with expertise in hepatitis B be consulted.

ⁿ All women of childbearing age have a urine or serum pregnancy test at the designated on-treatment visit and 3 and 6 months after administration of the last dose of study treatment. If the urine pregnancy test is positive, it should be confirmed with a serum pregnancy test.

^o including pH, specific gravity, glucose, protein, ketones and blood; Allow the dipstick.

^p autoantibody assays include antinuclear antibodies, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibodies, and perinuclear anti-neutrophil cytoplasmic antibodies.

^q For patients presenting with signs or symptoms suggestive of an autoimmune disease (eg, lupus erythematosus), the autoantibody assay should be repeated.

^r If not approved for RBR sampling, it does not apply. Only patients who have provided informed written consent to participate at the location of participation.

^s If the investigator determines that it is clinically feasible, the patient will receive a tumor biopsy sample collection at the time determined by the investigator that there is unacceptable toxicity or loss of clinical benefit. Biopsies should be performed within 40 days of confirmation of unacceptable toxicity or loss of clinical benefit or prior to the next anticancer therapy, whichever is earlier. In addition, patients enrolled during the expansion phase will receive tumor biopsy samples 4 weeks (±7 days) after initiation of treatment, unless on-treatment tissue samples have already been collected from at least 15 patients treated with the same CIT combination and are determined to be measurable. (if determined clinically feasible).

^t Patients who consent to elective biopsy will receive tumor biopsy sample collection 4 weeks (± 7 days) after initiation of treatment and, if deemed clinically feasible (patients enrolled during the expansion phase, who are already undergoing in-treatment biopsy) does not apply to patients), additional in-treatment biopsies may be taken at other times at the discretion of the investigator.

^u Patients should be treated at baseline, regardless of dose delay, until radiological disease progression according to RECIST v1.1, every 6 weeks for the first 48 weeks after initiation of treatment, except in patients who continue treatment after radiological disease progression. ± 1 week), thereafter every 12 weeks (± 2 weeks), and these patients receive tumor assessments every 6 weeks (± 1 week) until loss of clinical benefit as determined by the investigator receive Therefore, for patients who discontinue treatment for reasons other than disease progression, tumor evaluation should continue according to schedule, even if new chemotherapy not specified in the protocol is started.

^v All measurable and/or evaluable lesions identified at baseline should be re-evaluated at each subsequent tumor assessment according to the tumor assessment schedule described above (see footnote “t”). At the time of screening, the same radiological procedure used to evaluate the site of disease should be used for subsequent tumor evaluation (eg, the same contrast agent protocol for CT scans).

^w Includes any medications (eg, prescription drugs, over-the-counter medications, vaccines, herbal or homeopathic remedies, nutritional supplements) taken by the patient in addition to protocol essential study treatments from 10 days prior to study treatment initiation until the treatment discontinuation visit.

^x After initiation of study treatment, all adverse events are recorded until 30 days after administration of the last study treatment dose or until initiation of new systemic anticancer therapy, whichever occurs first Continue to record until day 135 after or until initiation of new systemic chemotherapy, whichever occurs first. After this period, all deaths, regardless of cause, must be reported. The investigator will follow-up each adverse event until each adverse event has resolved to a baseline grade or better, the adverse event has been assessed as stable by the investigator, the patient is missed from follow-up, or the patient withdraws consent. Should be. Every effort should be made to follow-up all serious adverse events considered to be related to the study treatment or trial-related procedures until final results can be reported.

^y Atezolizumab is administered as an IV infusion at a fixed dose of 840 mg on days 1 and 15 of each 28-day cycle. The initial dose of atezolizumab is delivered over 60 (±15) minutes. Subsequent infusions are delivered over 30 (±10) minutes if the previous infusion was well tolerated without infusion-related adverse events, and over 60 (±15) minutes if the patient experienced infusion-related adverse events from the previous infusion.

^z Continue treatment until there is unacceptable toxicity or loss of clinical benefit as determined by the investigator.

^aa Tiragolumab is administered as an IV infusion at a fixed dose of 420 mg on days 1 and 15 of each 28-day cycle. The initial dose of tiragolumab is delivered over 60 (±10) minutes. Subsequent infusions are delivered over 30 (±10) minutes if the previous infusion was well tolerated without infusion-related adverse events, and over 60 (±10) minutes if the patient experienced infusion-related adverse events from the previous infusion. On Day 1 of Cycle 1, tiragolumab is administered 60 minutes after completion of the atezolizumab infusion. The interval between subsequent infusions is 30 minutes if the previous infusion of atezolizumab was well tolerated without an IRR, or 60 minutes if the patient experienced an IRR with a previous infusion of atezolizumab.

^bb On days 1, 8, and 15, patients were administered nap-paclitaxel 125 mg/m ² as an IV infusion over 30 (±5) minutes followed by gemcitabine 1000 mg/m ² for 30 (±5) minutes. administered by IV infusion. On Day 1 of Cycle 1, nap-paclitaxel is administered 60 minutes after completion of the tiragolumab infusion to allow observation after the tiragolumab administration. The interval between subsequent infusions is 30 minutes if the previous infusion of tiragolumab was well tolerated without an IRR, or 60 minutes if the patient experienced an IRR with a previous infusion of tiragolumab.

^cc After discontinuation of treatment (unless patient withdraws consent or study ends), survival follow-up and new chemotherapy (targeted and information on immunotherapy). If the patient requests withdrawal from follow-up, the request must be documented in the original document and signed by the investigator. If a patient withdraws from the study, study staff may use public information sources (eg, local records) to obtain information on survival status only.

Assessment and monitoring

All patients are closely monitored for adverse events throughout the study, and adverse events are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Patients receive tumor assessments every 6 weeks (from Day 1 of Cycle 1) for the first 48 weeks, and then every 6 or 12 weeks thereafter. Response is assessed by the investigator using RECIST v1.1. Responses according to modified RECIST v1.1 to immune-based therapeutics (iRECIST) are determined programmatically based on investigator-assessed individual lesion data. Once clinical activity is demonstrated in an experimental arm, a tumor assessment scan for that arm may be submitted for evaluation by an independent review facility.

Baseline tumor tissue samples are collected from all patients, eg, via biopsies performed at the start of the study. If the investigator determines that a biopsy cannot be performed, if the tissue is obtained within 3 months prior to enrollment and the patient has not received any chemotherapy since the biopsy, the archived tumor tissue may be submitted after obtaining medical monitor approval. . If the investigator determines that it is clinically feasible, tumor tissue is collected from patients who discontinued Phase 1 due to unacceptable toxicity, disease progression according to RECIST v1.1, or loss of clinical benefit as determined by the investigator. For patients enrolled in the experimental arm in the expansion phase, tumor tissue during treatment 4 weeks after initiation of phase 1 therapy, unless tissue samples have already been collected from at least 15 patients treated with the same CIT combination and are determined to be measurable. Collect samples (if determined clinically feasible). The sample is utilized for biomarker studies (see Evidence for Biomarker Evaluation).

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are taken at various time points prior to and during study therapy administration (Table 17). Based on review of real-time safety data and available PK data, treatment regimens can be modified.

visit hour sample type Day 1 of Cycle 1 Prior to study treatment Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Tiragolumab PK (serum)
Tiragolumab ADA (serum)
Biomarkers (plasma, serum, PBMC) 30 minutes after atezolizumab injection Atezolizumab PK (serum) 30 minutes after tiragolumab injection Tiragolumab PK (serum) 15 days of cycle 1 Prior to study treatment Biomarkers (plasma, serum) Day 1 of Cycle 2 Prior to study treatment Atezolizumab PK (serum) Atezolizumab ADA (serum)
Tiragolumab PK (serum)
Tiragolumab ADA (serum)
Biomarkers (plasma, serum, PBMC) Day 1 of Cycle 3 Prior to study treatment Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Tiragolumab PK (serum)
Tiragolumab ADA (serum) 30 minutes after tiragolumab injection Tiragolumab PK (serum) Day 1 of Cycle 4 Research treatment transfer Atezolizumab PK (serum)
Atezolizumab ADA (serum)
Tiragolumab PK (serum)
Tiragolumab ADA (serum)
Biomarkers (plasma, serum) Day 1 of Cycle 8 Research treatment transfer Atezolizumab PK (serum) Atezolizumab ADA (serum)
Tiragolumab PK (serum)
Tiragolumab ADA (serum)
Biomarkers (plasma, serum) Day 1 of Cycle 12 and Cycle 16 Research treatment transfer Atezolizumab PK (serum) Atezolizumab ADA (serum)
Tiragolumab PK (serum)
Tiragolumab ADA (serum) Treatment discontinuation visit (last dose ≤ 30 days) upon visit Atezolizumab PK (serum) Atezolizumab ADA (serum)
Tiragolumab PK (serum)
Tiragolumab ADA (serum)
Biomarkers (plasma, serum)

Pharmacokinetic, immunogenicity and schedule of biomarker samples

ADA = anti-drug antibody; atezo + chem + tyra = atezolizumab + chemotherapy (nap-paclitaxel and gemcitabine) + tyragolumab; nap-paclitaxel = nanoparticle albumin-bound paclitaxel; PBMC = peripheral blood mononuclear cells; PK = Pharmacokinetics.

NOTE: Based on new safety or efficacy data, the number of PK and ADA samples may be reduced or sample collection may be stopped altogether. In addition, collected samples may not be analyzed unless warranted. Based on the new biomarker data, the number of biomarker samples may be reduced or sample collection may be stopped altogether.

laboratory, biomarkers, and other biological samples

Exploratory biomarker studies include genes or genetic features associated with tumor immunobiology, PD-L1, cytokines associated with T cell activation, T cell receptor repertoire, carcinoembryonic antigens, or density, localization, and activation of immune cells and subsets thereof. analysis for status, but may involve DNA or RNA extraction, analysis of somatic mutations, and the use of NGS (including WES).

The following laboratory test samples are sent to the local laboratory at the study site for analysis:

혈액학: WBC 수, RBC 수, 헤모글로빈, 헤마토크릿, 혈소판 수, 및 감별 계산(호중구, 호산구, 호염기구, 단핵구, 림프구, 기타 세포)을 포함한다.

Hematology: Includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential counts (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).

화학 패널(혈청 또는 혈장): 중탄산염 또는 이산화탄소(해당 지역의 치료 표준으로 고려되는 경우), 나트륨, 칼륨, 마그네슘, 염화물, 포도당, BUN 또는 요소, 크레아티닌, 총 단백질, 알부민, 인, 칼슘, 총 빌리루빈, ALP, ALT, 및 AST를 포함한다.

Chemistry panel (serum or plasma): bicarbonate or carbon dioxide (if considered the local standard of care), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin , ALP, ALT, and AST.

응고: INR 및 aPTT

Coagulation: INR and aPTT

갑상선 기능 검사: 갑상선 자극 호르몬, 유리 트리아이오도티로닌(T3)(또는 유리 T3가 실시되지 않은 부위의 경우 총 T3), 및 유리 티록신(T4로도 공지됨)

Thyroid function tests: thyroid stimulating hormone, free triiodothyronine (T3) (or total T3 for sites where free T3 has not been administered), and free thyroxine (also known as T4)

페리틴 및 γ-글루타밀 전이효소

Ferritin and γ-glutamyltransferase

HIV 혈청 검사, 현지 규정에 따라 허용되지 않는 경우를 제외

HIV serological testing, except where not permitted by local regulations

HAV 혈청학: HAV IgM

HAV Serology: HAV IgM

HBV 혈청학: HBsAg, 총 HBcAb, 및 (HBsAg 검사가 음성이고 총 HBcAb 검사가 양성인 경우) HBV DNA.

HBV serology: HBsAg, total HBcAb, and HBV DNA (if HBsAg test is negative and total HBcAb test is positive).

If a patient is HBsAg test negative at screening and a total HBcAb test is positive, HBV DNA testing should also be performed to determine whether the patient has HBV infection.

HCV serology: HCV antibody and (if HCV antibody test is positive) HCV RNA

If a patient is HCV antibody positive at screening, HCV RNA testing should also be performed to determine whether the patient has active HCV infection.

HEV 혈청학: HEV IgM

HEV Serology: HEV IgM

C 반응성 단백질

C-reactive protein

LDH

LDH

CA19-9

CA19-9

EBV 혈청학:

EBV Serology:

- EBV VCA IgM

- EBV VCA IgG or EBNA IgG

- EBV PCR (only if clinically indicated)

임신 검사

pregnancy test

All women of childbearing potential receive a serum pregnancy test at screening in Stage 1. Urine or serum pregnancy tests are performed at designated follow-up visits. If the urine pregnancy test is positive, it should be confirmed with a serum pregnancy test.

A woman has no chance of becoming pregnant if she is non-menstrual, has not reached postmenopausal status (≥ 12 consecutive months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of the ovaries and/or uterus). considered to be

소변 검사(pH, 비중, 포도당, 단백질, 케톤, 및 혈액)

Urine tests (pH, specific gravity, glucose, protein, ketones, and blood)

Dipstick urinalysis is permitted. However, patients with a protein 2+ or higher in a dipstick urine test at screening should have a 24-hour urine collection for protein if the bevacizumab-containing arm is open to enrollment.

The following laboratory test samples are sent to a central laboratory or regional laboratory at the study site for analysis:

가용성 CD25

Availability CD25

The following samples are sent to one or more central laboratories or sponsors for analysis:

Serum samples for autoantibody analysis: antinuclear antibody, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody

검증된 분석을 통한 PK 분석을 위한 혈장 또는 혈청 샘플

Plasma or serum samples for PK analysis with validated assays

검증된 분석을 통한 면역원성 분석을 위한 혈장 또는 혈청 샘플

Plasma or serum samples for immunogenicity analysis with validated assays

바이오마커에 대한 탐색적 연구를 위한 혈장, 혈청, 및 말초혈액단핵세포(PBMC) 샘플

Plasma, Serum, and Peripheral Blood Mononuclear Cell (PBMC) Samples for Exploratory Study of Biomarkers

PD-L1 발현의 결정 및 바이오마커에 대한 탐색적 연구를 위해 기준선에서 수집한 종양 조직 샘플

Tumor tissue samples collected at baseline for determination of PD-L1 expression and for exploratory studies of biomarkers

Baseline tumor tissue samples of primary lesions or metastatic lesions are collected from all patients, preferably via biopsies performed at the start of the study. If the investigator determines that a biopsy cannot be performed, if tissue is obtained from a biopsy performed within 3 months prior to enrollment and the patient has not received any chemotherapy since that biopsy, the stored tumor tissue will be removed after obtaining medical monitor approval. can be submitted

A minimum of 16 slides containing representative FFPE tumor specimens in paraffin blocks (preferred) or unstained, freshly excised serial sections should be submitted along with the relevant pathology report. If only 10 to 15 slides are available, the patient may still be eligible for the study after obtaining approval from the medical monitor.

Tumor tissue should be of good quality based on total and viable tumor content. Samples should contain at least 50 viable tumor cells that preserve cellular context and tissue structure, regardless of needle gauge or retrieval method. Samples collected via excision, core needle biopsy (minimum 3 cores, 18 gauge or larger needles [16 gauge needles preferred], embedded in a single paraffin block) or via excision, incision, punch or forceps biopsy are acceptable. Fine needle aspiration (defined as a sample that does not preserve tissue structure and does not produce a cell suspension and/or smear), brushing, cell pellets of pleural effusion, and wash samples are not permitted. Tumor tissue from calcified bone metastases is not acceptable.

Remaining archived tumor tissue blocks will be returned to the site upon request or 18 months after final closure of the study database, whichever occurs first.

확장 단계 동안 실험군에 등록한 환자: 바이오마커에 대한 탐색 연구를 위해 치료 시작 후 4주(±7일)에 수집한 종양 조직 샘플(시험자가 임상적으로 가능한 것으로 판단한 경우)

Patients enrolled in the experimental arm during the expansion phase: tumor tissue samples collected 4 weeks (±7 days) after initiation of treatment for exploratory studies for biomarkers (if determined clinically feasible by the investigator)

If an on-treatment tissue sample has already been collected from at least 15 patients treated with the same CIT combination and is determined to be evaluable, no sample is collected.

Samples collected via excision, core-needle biopsy (preferably at least 3 cores), or via excision, incision, punch or forceps biopsy are preferred.

바이오마커에 대한 탐색적 연구를 위해 시험자가 임상적으로 타당하다고 판단하는 경우, 허용할 수 없는 독성, RECIST v1.1에 따른 질병 진행, 또는 시험자가 결정한 임상 이익 손실 시점에 수집한 종양 조직 샘플

For exploratory studies of biomarkers, tumor tissue samples collected at the time point of clinical benefit determined by the investigator for unacceptable toxicity, disease progression according to RECIST v1.1, or loss of clinical benefit as determined by the investigator for an exploratory study of a biomarker

Biopsies should be performed within 40 days of confirmation of unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to the next anticancer therapy, whichever is earlier. Samples collected via excision, core-needle biopsy (preferably at least 3 cores), or via excision, incision, punch or forceps biopsy are preferred.

Atezolizumab Dosage and Schedule

Atezolizumab is administered at a fair dose of 840 mg every two weeks (Q2W) (840 mg on Days 1 and 15 of each 28-day cycle).

Tiragolumab Dosage and Schedule

Tiragolumab is administered at a fair dose of 420 mg Q2W (420 mg on days 1 and 15 of each 28-day cycle). The mean concentration after the 420 mg Q2W dose is expected to be equal to the concentration of 600 mg every 3 weeks (Q3W). A fixed tiragolumab dose of 600 mg IV Q3W was selected based on pharmacokinetic (PK), efficacy, and safety data available from study GO30103 in which patients were administered either single agent tiragolumab or in combination tiragolumab and atezolizumab. . No MTD was reached and no DLTs were observed with tiragolumab monotherapy or tiragolumab at the 2-1200 mg Q3W dose in combination with atezolizumab 1200 mg Q3W. In addition, the development of anti-drug antibodies (ADA) to tiragolumab was observed in 3 of 145 evaluable patients who received tiragolumab (2-600 mg Q3W dose) in combination with atezolizumab. Complete occupancy of peripheral TIGIT receptors on CD4 ⁺ , CD8 ⁺ and NK cells was observed starting at the 30 mg Q3W dose of tiragolumab and maintained at all higher doses. Antitumor activity (partial response on radiography) was observed at doses of 30 to 600 mg Q3W of tyragolumab when co-administered with atezolizumab 1200 mg Q3W.

Dosage and administration

Patients should be assessed for unacceptable toxicity or clinical benefit as determined by the investigator after an integrated assessment of radiological and biochemical data, local biopsy results (if available), and clinical condition (e.g., worsening of symptoms such as pain secondary to disease). Treat as outlined until loss of

Participants will receive an atezolizumab 840 mg IV infusion on days 1 and 15 of each 28-day cycle according to the guidelines outlined in Table 18.

Participants will receive a tyragolumab 420 mg IV infusion on days 1 and 15 of each 28-day cycle according to the guidelines outlined in Table 19. On Day 1 of Cycle 1, tiragolumab is administered 60 minutes after completion of the atezolizumab infusion. The interval between subsequent infusions is 30 minutes if the previous atezolizumab infusion was given without a premedication and was well tolerated without an infusion-related reaction (IRR), or 60 minutes if the patient experienced an IRR with a previous atezolizumab infusion. to be.

Participants received a nap-paclitaxel 125 mg/m ² IV infusion on days 1, 8 and 15 of each 28-day cycle, followed by an IV infusion over 30 (5) minutes, followed by gemcitabine 1000 mg/m ² is administered as an IV infusion over 30 (10) minutes. On Day 1 of Cycle 1, nap-paclitaxel is administered 60 minutes after completion of the tyragolumab infusion. The interval between subsequent infusions is 30 minutes if the previous infusion of tiragolumab was well tolerated without an IRR, or 60 minutes if the patient experienced an IRR with a previous infusion of tiragolumab.

first injection subsequent injection

아테졸리주맙 주입 이전에 예비 투약은 허용하지 않는다.

상기 주입 전 60분 이내에 활력 징후(맥박수, 호흡수, 혈압, 맥박 산소 측정 및 체온)를 기록한다.

아테졸리주맙을 60(±15) 분에 걸쳐 주입한다.

임상적으로 지시된 경우, 상기 주입 동안 15(±5)분마다 및 상기 주입 후 30(±10)분에 활력 징후를 측정한다.

환자에게 주입후 증상 지연 가능성에 관하여 알려주고 이러한 증상이 발생하는 경우 연구 담당의에게 연락하도록 지시한다.

No premedication prior to atezolizumab infusion is permitted.

Vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry and body temperature) are recorded within 60 minutes prior to the infusion.

Atezolizumab is infused over 60 (±15) minutes.

When clinically indicated, vital signs are measured every 15 (±5) minutes during the infusion and at 30 (±10) minutes after the infusion.

Inform the patient of the potential for post-infusion symptom delay and instruct the study physician to contact if these symptoms develop.

If a patient experiences an infusion-related reaction associated with a previous infusion, a premedication of antihistamines, antipyretics and/or analgesics may be administered for subsequent doses at the investigator's discretion.

Vital signs should be recorded within 60 minutes prior to infusion.

Atezolizumab is infused over 30 (±10) minutes if the previous infusion was well tolerated without an infusion-related reaction, or over 60 (±15) minutes if the patient experienced an infusion-related reaction with the previous infusion± .

If the patient has experienced an infusion-related reaction with a previous infusion or is clinically indicated, vital signs should be measured during infusion and 30 (±10) minutes after infusion.

First and subsequent atezolizumab infusion administration

first injection subsequent injection

티라골루맙 주입 이전에 예비 투약은 허용하지 않는다.

상기 주입 전 60분 이내에 활력 징후(맥박수, 호흡수, 혈압, 맥박 산소 측정 및 체온)를 기록한다.

티라골루맙을 60 (±10)분에 걸쳐 주입한다.

활력 징후는 주입 동안 15(±5)분마다 및 주입 후 30(±10)분에 기록한다.

환자는 티라골루맙 주입 완료 후 60분 동안

환자에게 주입후 증상 지연 가능성에 관하여 알려주고 이러한 증상이 발생하는 경우 연구 담당의에게 연락하도록 지시한다.

Premedication prior to tiragolumab infusion is not permitted.

Vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry and body temperature) are recorded within 60 minutes prior to the infusion.

Tiragolumab is infused over 60 (±10) minutes.

Vital signs are recorded every 15 (±5) minutes during infusion and 30 (±10) minutes after infusion.

The patient was infused for 60 minutes after completion of the tiragolumab infusion.

Inform the patient of the potential for post-infusion symptom delay and instruct the study physician to contact if these symptoms develop.

If a patient experiences an infusion-related reaction associated with a previous infusion, a premedication of antihistamines, antipyretics and/or analgesics may be administered for subsequent doses at the investigator's discretion.

Vital signs should be recorded within 60 minutes prior to infusion.

Tiragolumab is infused over 30 (±10) minutes if the previous infusion was well tolerated without an infusion-related reaction, or over 60 (±10) minutes if the patient experienced an infusion-related reaction with the previous infusion.

Observe the patient for 30 minutes after completion of the tiragolumab infusion if the previous infusion was well tolerated without an infusion-related reaction, or for 60 minutes after completion of the tiragolumab infusion if the patient experienced an infusion-related reaction from the previous infusion.

If the patient has experienced an infusion-related reaction with a previous infusion or is clinically indicated, vital signs should be recorded during infusion and 15 (±10) minutes after infusion.

Administration of First and Subsequent Tiragolumab Infusions

capacity change

There were no dose changes for atezolizumab or tiragolumab in this study. For the management of drug-related toxicity, the dose of nap-paclitaxel can be reduced by up to 2-fold by 25 mg/m ² (single dose level), and the dose of gemcitabine is 200 mg/m 2 as outlined in Table 20. It can be reduced up to a factor of 2 by m ² (one dose level).

If a further dose reduction is indicated for nap-paclitaxel and/or gemcitabine after 2 dose reductions, the drug (or both drugs, if applicable) will be discontinued, but the patient may continue on other study treatment at the investigator's discretion have. After the dose reduction, the dose may be increased during subsequent administration at the discretion of the investigator.

initial capacity first dose reduction Second dose reduction Nap-paclitaxel 125 mg/m ² 100 mg/m ² 75 mg/m ² Gemcitabine 1000 mg/m ² 800 mg/m ² 600 mg/m ²

Reducing the recommended dose for nap-paclitaxel and gemcitabine

combination therapy

Combination therapy includes any drugs (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) taken by the patient in addition to protocol essential study remedies from 10 days prior to initiation of study treatment until the discontinuation visit.

Patients are allowed to use the following regimens during the study period:

현지 진료/기관 지침 또는 미국임상종양학회의 조혈 CSF에 대한 지침(Smith et al. 2006) 및 미국혈액학회/미국임상종양학회의 ESA에 대한 지침(Rizzo et al. 2010)에 따른 집락 자극 인자(CSF), 예컨대 과립구 집락 자극 인자(G-CSF) 및 적혈구 생성 자극제(ESA).

Colony-stimulating factors (according to local practice/institutional guidelines or the American Society of Clinical Oncology guidelines for hematopoietic CSF (Smith et al. 2006) and the American Society of Hematology/American Society for Clinical Oncology guidelines for ESA (Rizzo et al. 2010)) CSF), such as granulocyte colony stimulating factor (G-CSF) and erythropoiesis stimulating agent (ESA).

There is limited evidence supporting the use of a long-acting (PEGylated) form of G-CSF in patients receiving weekly chemotherapy (ie, nap-paclitaxel). Therefore, the investigator should consider giving preference to the existing G-CSF formulation.

경구 피임약

pill

호르몬 대체 요법

hormone replacement therapy

예방적 또는 치료적 항응고 요법(예컨대, 안정적인 용량의 와파린 또는 저분자량 헤파린)

Prophylactic or therapeutic anticoagulant therapy (eg, stable doses of warfarin or low molecular weight heparin)

비활성화 인플루엔자 예방 접종

Inactivated influenza vaccination

연구 치료제 개시 후 식욕 자극제로서 투여된 메게스트롤 아세테이트

Megestrol acetate administered as an appetite stimulant after initiation of study treatment

미네랄로코르티코이드(예컨대, 플루드로코르티손)

Mineralocorticoids (such as fludrocortisone)

만성 폐쇄성 폐질환 또는 천식에 투여되는 흡입용 코르티코스테로이드

Inhaled corticosteroids for chronic obstructive pulmonary disease or asthma

기립성 저혈압 또는 부신피질 기능부전에 투여된 저용량 코르티코스테로이드

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency

전립선 암에 대한 성선자극호르몬 방출 호르몬 또는 길항제를 이용한 호르몬 요법

Hormone therapy using gonadotropin releasing hormone or antagonist for prostate cancer

하기에 개략된 바와 같은 완화 방사선 요법(예컨대, 공지된 골 전이의 치료 또는 통증의 증상 완화):

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

Palliative radiation therapy is acceptable as long as it does not interfere with the evaluation of tumor target lesions (eg, the lesion to be investigated should not be the only site of measurable disease). Treatment with nap-paclitaxel and gemcitabine should be withheld during palliative radiation therapy. Treatment with atezolizumab and tiragolumab may be continued during palliative radiation therapy.

뇌에 대한 방사선 요법은 하기와 같이 개략된다:

Radiation therapy to the brain is outlined as follows:

Patients with stable extracranial tumor burden or responsive to study treatment and subsequently found to have 3 or fewer brain metastases should receive radiation therapy to the brain (stereotactic radiosurgery or whole brain radiation therapy) if all of the following criteria are met: You can get:

- The patient has no evidence of progression or bleeding after completion of CNS directed therapy.

- The patient does not require continuous corticosteroids as therapy for CNS disease.

Patients requiring corticosteroid therapy for more than 7 days after completion of radiation therapy should discontinue study treatment.

- If necessary, administer anticonvulsants at a stable dose.

Premedication of antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent infusions of atezolizumab and tiragolumab at the discretion of the investigator.

In general, the investigator should administer the patient's treatment with adjuvant therapy as clinically indicated in accordance with local standard practice. Patients experiencing infusion-related symptoms may be treated with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice, depending on the symptoms. have. Severe infusion-related reactions presenting with dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation or dyspnea should be managed with adjuvant therapy as clinically indicated (e.g., adjuvant oxygen and β ₂ adrenergic agonists). .

Selection Criteria

The patient meets the following criteria:

사전 동의서에 서명할 당시의 연령 18세 이상

At least 18 years of age at the time of signing the informed consent form

0 또는 1의 ECOG 전신 활동도

ECOG systemic activity of 0 or 1

조직학적 또는 세포학적으로 확인된 전이성 PDAC

Histologically or cytologically confirmed metastatic PDAC

The definitive diagnosis of metastatic PDAC is made by evaluating histopathological data within the context of clinical and radiological data.

Patients with endocrine or acinar pancreatic carcinoma of the pancreas are not eligible for the study.

PDAC에 대한 선행 전신 치료 없음

No prior systemic treatment for PDAC

시험자가 결정한 기대 수명 ≥ 3개월

Life expectancy determined by the investigator ≥ 3 months

중앙 시험을 통한 PD-L1 및/또는 추가 바이오마커 상태 결정에 적합한 대표적인 종양 표본의 입수 가능성

Availability of representative tumor specimens suitable for determining PD-L1 and/or additional biomarker status via central trials

Baseline tumor tissue samples are preferably collected from all patients via biopsies performed at the start of the study. If the investigator determines that a biopsy cannot be performed, if tissue is obtained from a biopsy performed within 3 months prior to enrollment and the patient has not received any chemotherapy since that biopsy, the stored tumor tissue will be removed after obtaining medical monitor approval. can be submitted

A minimum of 16 slides containing either formalin-fixed, paraffin-embedded tumor specimens in paraffin blocks (preferred) or unstained, freshly cut serial sections, along with the relevant pathology report, should be submitted prior to study enrollment. If only 10 to 15 slides are available, the patient may still be eligible for the study after obtaining approval from the medical monitor.

서명한 사전 동의서

signed informed consent

조사관의 판단으로, 연구 프로토콜을 준수할 만한 능력

Ability, in the investigator's judgment, to comply with the study protocol

RECIST v1.1에 따른 측정 가능한 질병(적어도 하나의 표적 병변)

Measurable disease according to RECIST v1.1 (at least one target lesion)

Previously irradiated lesions can be considered measurable disease only if progressive disease is clearly documented at the site after irradiation.

연구 치료제 개시 전 14일 이내에 수득한 하기와 같은 실험실 결과로 정의되는 적절한 혈액 및 말단 장기 기능:

Adequate blood and terminal organ function as defined by the following laboratory results obtained within 14 days prior to initiation of study treatment:

- ANC ≥ 1.5 x 10 ⁹ /L (1500/μL), no support of granulocyte colony stimulating factor within 14 days prior to screening laboratory test

- Number of WBCs ≥ 2.5 x 10 ⁹ /L (2500/μL)

- Lymphocyte count ≥ 0.5 x 10 ⁹ /L (500/μL)

- Platelet count ≥ 100 x 10 ⁹ /L (100,000/μL), no transfusion within 7 days before screening laboratory test

- Hemoglobin ≥ 90 g/L (9.0 g/dL)

The patient may be transfused to meet the above criteria after discussion with the medical monitor.

AST, ALT and ALP ≤ 2.5 x upper limit of normal (ULN), except for:

Patients with documented liver metastases: AST and ALT ≤ 5 ULN

Patients with documented liver or bone metastases: ALP ≤ 5 x ULN

- Serum bilirubin ≤ 1.5 x ULN, except for:

Known Gilbert's Disease Patients: Serum Bilirubin Levels ≤ 3 x ULN

- Creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula)

- Serum albumin ≥ 25 g/L (2.5 g/dL)

- For patients not receiving anticoagulants: INR or aPTT ≤ 1.5 x ULN

치료적 항응고 요법을 투여 받은 환자의 경우: 안정적인 항응고 요법

For patients receiving therapeutic anticoagulant therapy: stable anticoagulant therapy

생검을 위해 접근 가능한 종양

Accessible tumors for biopsy

가임 여성의 경우: 금욕 유지(이성간 성교 금지) 또는 피임 방법 사용에 대한 동의 및 난자 기증 자제에 대한 동의

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods and to refrain from egg donation

남성의 경우: 금욕을 유지하기로 동의(이성간 성교 금지) 또는 피임법 사용에 대한 동의 및 정자 기증을 자제에 대한 동의.

For men: Consent to maintain abstinence (no heterosexual intercourse) or consent to use of contraceptive methods and consent to refrain from donating sperm.

safety

Measures are taken to ensure the safety of patients participating in this study, including using strict selection and exclusion criteria and closely monitoring patients during the study period. Administration of study treatment is conducted in a monitoring environment with immediate access to trained staff and appropriate equipment and medications to manage potentially severe reactions. Adverse events are reported as described.

Verbose terms of adverse events correspond to synonym terms in the Medical Dictionary for Regulatory Activities, and severity of adverse events is graded according to NCI CTCAE v4.0.

Safety is assessed through a summary of adverse events, changes in laboratory test results, changes in vital signs and ECGs, and exposure to study drug. Exposure and safety follow-up periods for combination therapy are summarized for each treatment group within each phase.

Treatment-related adverse events occurring after initiation of treatment are summarized. For each patient, the maximum severity reported for each adverse event is used for the summary by severity grade. All treatment-related adverse events, serious adverse events, adverse events leading to discontinuation of study treatment, grade 3 adverse events, deaths, and causes of death are listed and summarized by mapped term, appropriate synonym level, and NCI CTCAE severity grade. Relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry, and body temperature) and ECG data are displayed hourly and identified by grade, where appropriate. In addition, shift tables from selected laboratory trials are used to summarize baseline and post-baseline maximum severity ratings. Changes in vital signs and ECG are summarized.

Atezolizumab is associated with the following risks: IRR and immune-mediated hepatitis, pneumonia, colitis, pancreatitis, diabetes, hypothyroidism, hyperthyroidism, adrenal insufficiency, pituitary gland, Guillain-Barré syndrome, myasthenia gravis or myasthenia gravis, meningoencephalitis, myocarditis, nephritis and myositis. Immune-mediated responses may involve any organ system and may lead to hemophagocytic lymphohistiocytosis and macrophage activation syndrome (considered a potential risk for atezolizumab).

The following are the most common adverse reactions observed with nap-paclitaxel in patients with PDAC: neutropenia, fatigue, peripheral neuropathy, nausea, hair loss, peripheral edema, diarrhea, fever, vomiting, decreased appetite, rash and dehydration. The following adverse events were also observed: myelosuppression (mainly neutropenia, anemia, thrombocytopenia), cranial nerve palsy, hypersensitivity reactions, pneumonia, myalgia, arthralgia, cardiac toxicity (myocardial disorders, heart failure, angina pectoris, tachycardia, ventricular arrhythmias) ), edema, cystic macular edema, Stevens-Johnson syndrome/toxic epidermal necrosis, sepsis, injection site reaction/extravascularization, hepatotoxicity (drug-induced liver injury), acute renal failure, hemolytic uremic syndrome, and drug-induced lupus erythematosus.

The most common adverse reactions observed with gemcitabine were nausea/vomiting, anemia, hepatic transaminaemia, neutropenia, increased ALP, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea and peripheral edema.

IRR is the identified risk of tiragolumab. Although the clinical evaluation of tiragolumab is limited and not all risks are known, as an antagonist of TIGIT, tiragolumab is expected to improve T cell and NK cell proliferation, survival and function. Thus, tiragolumab may increase the risk of autoimmune inflammation (also called immune-mediated adverse reaction). In addition, lymphopenia via antibody dependent cytotoxicity (ADCC) is a theoretical risk due to the intact Fc effector function of tiragolumab.

Because tyragolumab is a therapeutic monoclonal antibody and targets immune cells, hypersensitivity reactions, target-mediated cytokine release, and/or IRRs associated with novel ADA may occur. Clinical signs and symptoms of these reactions may include stiffness, chills, wheezing, itching, flushing, rash, hypotension, hypoxemia and fever. IRR has been reported in patients treated with tiragolumab alone or in combination with atezolizumab. Most reactions were mild to moderate and manageable.

To minimize the risk of IRR and its sequelae, an initial dose of tiragolumab is administered over 60 minutes followed by an observation period of 60 minutes. If the preceding infusion is well tolerated, subsequent infusion and observation times can be shortened. All infusions of tiragolumab are administered in an appropriate medical setting.

Nonclinical models have suggested a role for disruption of TIGIT signaling in autoimmunity. In the knockout model (TIGIT −/−), loss of TIGIT signaling resulted in exacerbation of hyperproliferative T cell responses and experimental autoimmune encephalitis (EAE). EAE was induced by immunization of TIGIT −/− and wild-type B6 mice with suboptimal doses of myelin oligodendrocyte glycoprotein peptide. In contrast to wild-type B6 mice, the majority of TIGIT-/- mice are medium (Joller et al. 2011).

According to clinical experience with therapies to enhance anti-tumor T cell responses, the development of an autoimmune inflammatory condition is a common risk and can therefore be considered a potential risk for tyragolumab. These immune-mediated adverse events have been described in virtually all organ systems and include, but are not limited to, colitis, hepatitis, pneumonia, endocrinopathy, ocular toxicity, pancreatic toxicity, neurological toxicity, myocarditis, nephritis, myositis, and rash.

Patients with a history of autoimmune diseases were excluded from this study. In addition, patients with a history of serious immune-mediated adverse events related to prior immunotherapy or unresolved adverse events at baseline after discontinuation of prior immunotherapy were excluded from this study.

In this study, certain immune-mediated adverse events are considered adverse events of special interest and captured accordingly.

Given the IgG1 backbone of tyragolumab with intact Fc effector function, ADCC-mediated lymphocyte count reduction is a potential risk. However, in a repeat-dose toxicity study in cynomolgus monkeys, there was no tyragolumab-related decrease in total lymphocyte count.

In a phase 1 study of solid tumors (study GO30103), transient lymphocyte counts were observed without clinical sequelae in patients treated with tiragolumab alone or in combination with atezolizumab. Because tiragolumab has the potential to cause lymphopenia, patients with lymphocyte counts less than 0.5 x 10 ⁹ /L (500/μL) are excluded from the study. Complete blood counts are monitored throughout the study.

The following adverse events are potential overlapping toxicities associated with the concomitant use of atezolizumab, nap-paclitaxel, gemcitabine, and tiragolumab: immune-mediated toxicity including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, etc., gastrointestinal Toxicity, blood toxicity and skin toxicity.

On Day 1 of each cycle, the patient had an ANC of 1.5×10 ⁹ /L (1500/μL) and a platelet count of 100×10 ⁹ /L (100,000/μL) to receive treatment with nap-paclitaxel and gemcitabine. should be more than

Discontinuation of treatment due to toxicity

Atezolizumab and/or tiragolumab may be temporarily discontinued in patients who experience toxicity considered to be related to the study treatment. When corticosteroids are initiated for the treatment of toxicity, oral prednisone or equivalent should be gradually reduced over a period of at least 1 month to 10 mg/day or less or equivalent before resumption of the drug. If atezolizumab or tiragolumab is discontinued for more than 12 weeks, the patient should discontinue the drug. However, the drug may be withheld for more than 12 weeks so that the patient can gradually reduce the corticosteroid before resuming treatment. Atezolizumab or tiragolumab may be resumed after withholding for more than 12 weeks if the medical monitor agrees that the patient has a potential for clinical benefit.

Based on the available characterization of the mechanism of action, tiragolumab may induce adverse reactions similar to but independent of atezolizumab. Tiragolumab may also aggravate the frequency or severity of adverse events associated with atezolizumab or have toxicity that does not overlap with atezolizumab. As these scenarios may not be distinguishable from each other in the clinical setting, immune-mediated adverse events should generally be attributable to both drugs, and treatment discontinuation due to immune-mediated adverse events applies to both tiragolumab and atezolizumab. should be

Nap-paclitaxel and/or gemcitabine may be temporarily discontinued in patients experiencing toxicity considered to be related to the study treatment. If nap-paclitaxel or gemcitabine is withheld for more than 56 days due to toxicity, the patient should discontinue both chemotherapeutic agents. However, nap-paclitaxel or gemcitabine may be resumed after withholding beyond 56 days if the medical monitor agrees that the patient is likely to benefit clinically.

If atezolizumab is discontinued, tiragolumab should also be discontinued, but nap-paclitaxel and gemcitabine may be continued if the patient is likely to achieve clinical benefit as determined by the investigator. If nap-paclitaxel, gemcitabine, or tiragolumab is discontinued, other drugs may be continued as determined by the investigator if the patient is likely to achieve clinical benefit.

statistics

The final study analysis is based on patient data collected through study discontinuation. Unless otherwise specified, efficacy analyzes are based on an efficacy evaluable population defined as all patients receiving at least one dose of each drug for their assigned treatment regimen, and safety analyzes are based on administration of any amount of study treatment. It is based on a safety evaluable population defined as all patients received.

Data are described and summarized according to sample size. Continuous variables are summarized using mean, standard deviation, median, and range. Categorical variables are summarized using counts and percentages. For small sample sizes, a list is used instead of a table.

This study was not designed to consider explicit analytical power and Type I error for hypothesis analysis. Instead, this study was designed to obtain preliminary efficacy, safety, and PK data for an immunotherapy-based treatment combination when administered to patients with metastatic PDAC.

Table 21 shows the estimated ORR differences between the experimental and control groups with 90% confidence intervals, the sample size is 15 patients each in the preliminary phase, and asymptotic normality is assumed.

Experimental group (n = 15) Control (n = 15) Difference in Objective Response Rate (in percentage points) (90% CI) ^a 7 (46.7%) 4 (26.7%) 20% (-8%,48%) 8 (53.3%) 4 (26.7%) 26.7% (-2%, 55%) 9 (60.0%) 5 (33.3%) 26.7% (-2%, 56%) CI = confidence interval.
^a Asymptotic confidence limits (not corrected for continuity due to very small sample size).

Differences in estimated objective response rates between experimental and control groups of 15 patients each (preliminary phase)

Table 22 shows the estimated ORR differences between the experimental and control groups with 90% confidence intervals, the sample size covers 40 patients each in the preliminary phase and the expansion phase, and asymptotic normality is assumed.

Experimental group (n = 40) Control (n = 40) Difference in Objective Response Rate (in percentage points) (90% CI) ^a 16 (40%) 10 (25%) 15% (-5%,35%) 18 (45%) 10 (25%) 20% (0%, 40%) 20 (50%) 12 (30%) 20% (0%, 40%) 22 (55%) 12 (30%) 25% (5%, 45%) CI = confidence interval.
^a Asymptotic confidence limits (not corrected for continuity due to very small sample size).

Differences in estimated objective response rates between experimental and control groups of 15 patients each (preliminary phase)

Purpose and endpoints

A summary of the study objectives and corresponding endpoints can be found in Table 23.

purpose Corresponding evaluation variable

면역요법 기반 치료 조합의 유효성 평가Primary efficacy goals:

Evaluating the effectiveness of immunotherapy-based treatment combinations

Objective Response - Defined as a complete response or partial response in two consecutive runs, spaced at least 4 weeks apart, as determined by the investigator per RECIST v1.1. Secondary efficacy goals:

Evaluating the effectiveness of immunotherapy-based treatment combinations

Post-Randomization PFS - defined as the time from randomization to the first onset of disease progression or death from any cause, whichever occurs first, as determined by the investigator per RECIST v1.1.

OS after randomization - defined as time from randomization to death from any cause

OS at a specific point in time (eg 6 months)

DOR - defined as the time from the first occurrence of a reported objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator per RECIST v1.1

Disease Control - defined as stable disease or complete or partial response for at least 12 weeks, as determined by the investigator per RECIST v1.1 Exploratory validity goals:

Evaluating the effectiveness of immunotherapy-based treatment combinations

Objective response - determined by the investigator according to iRECIST

PFS after randomization - determined by the investigator according to iRECIST
DOR, determined by the examiner according to iRECIST

Disease Control - determined by the investigator according to iRECIST

Change from baseline in CA19-9 at subsequent time points Safety Goals:

Evaluating the effectiveness of immunotherapy-based treatment combinations

The incidence, nature, and severity of adverse events and laboratory abnormalities, with severity determined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0.

Changes from baseline in vital signs and ECG parameters

Changes from baseline in target clinical laboratory test results Exploratory pharmacokinetic purposes:

Characterizing the PK Curves of Drugs Administered as Part of an Immunotherapy-Based Treatment Combination

To evaluate the potential relationship between drug exposure and the efficacy and safety of immunotherapy-based treatment combinations

Plasma or serum concentrations of each drug at specified time points (if appropriate)

Relationship between plasma or serum concentrations or PK parameters (if appropriate based on available data) and efficacy endpoints for each drug

Relationship between plasma or serum concentrations or PK parameters (if appropriate based on available data) and efficacy endpoints for each drug Exploratory Immunogenicity Purposes:

Assessing the immune response to drugs administered as part of an immunotherapy-based treatment combination

Assessing the potential effects of ADA

For drugs for which ADA formation is measured: the presence of ADA during the study relative to the presence of ADA at baseline.

For drugs for which ADA formation is measured: the relationship between ADA status and efficacy, safety, or PK endpoints The purpose of exploratory biomarkers:

Biomarkers that predict response to study treatment (i.e., predictive biomarkers), biomarkers associated with progression to a more severe disease state (i.e., prognostic biomarkers), and biomarkers associated with resistance to study treatment , biomarkers associated with susceptibility to adverse events occurring, biomarkers that may provide evidence of research treatment (i.e., pharmacodynamic biomarkers), or biomarkers that may increase knowledge and understanding of disease biology. check

Relationships between biomarkers in blood and tumor tissue and efficacy, safety, PK, immunogenicity, or other biomarker endpoints

Purpose and corresponding endpoints

ADA = anti-drug antibody; DOR = duration of response; iRECIST = modified RECIST v1.1 for immune-based therapeutics; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST = Criteria for evaluating the response of solid tumors.

The objective response at a single time point is determined by the investigator using RECIST v1.1. The overall response following iRECIST is not captured in the eCRF, but is calculated programmatically based on investigator-assessed individual lesion data recorded in the eCRF.

Validity analysis

The primary efficacy endpoint is objective response. ORR, the proportion of patients with a complete or partial response, is calculated for each group with a 90% confidence interval (Clopper-Pearson method). ORR differences between experimental and control groups are calculated as 90% confidence intervals. Confidence intervals are estimated by the asymptotic normality method according to the sample size.

Secondary efficacy endpoints are PFS, OS, OS, duration of response (DOR) at a specific time point (eg, 6 months), and disease control PFS, DOR, and disease control are determined by the investigator according to RECIST v1.1. DOR is derived for efficacy endpoints with full or partial responses. For patients with no documented disease progression or death during the study phase, PFS and DOR are censored and cleared on the day of the last tumor assessment. Patients still alive at the time of OS analysis are censored on the last day survival is known.

The Kaplan-Meier method is used to estimate the median of PFS, OS, and DOR with 90% confidence intervals constructed using the Brookmeyer and Crowley method. The OS ratio at any point in time is estimated using the Kaplan-Meier method with a 90% confidence interval calculated based on Greenwood's estimate of variance. Disease control rate, which is the proportion of patients with stable disease and partial or complete response for at least 12 weeks, is calculated for each treatment arm with a 90% confidence interval estimated using Klopper-Pearson's exact method.

Exploratory efficacy endpoints were investigator-determined objective response, PFS, DOR, and disease control according to iRECIST; Changes from baseline in CA19-9 at subsequent time points during the two phases. DOR is derived for efficacy endpoints with full or partial responses. CA19-9 changes from baseline over time are summarized. In addition, the proportion of patients with a CA19-9 maximal reduction greater than or equal to 50% from baseline, or other thresholds, can be calculated for each treatment arm with a 90% confidence interval estimated using the Klopper-Pearson's exact method.

Pharmacokinetic analysis

Rare samples may be collected for potential PK analysis of atezolizumab (patients receiving at least one dose of atezolizumab) and certain drugs given in combination with atezolizumab (patients receiving at least one dose of the drug). can Serum or plasma concentrations of various study drugs can be reported as individual values and summarized by treatment group, cycle, and date (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean) as appropriate and data permitting. coefficient of variation) can be Individual and median serum or plasma concentrations of various study drugs can be plotted by treatment group and cycle and day. PK data for combination drugs can be compared with historical data available from internal and published previous studies. Atezolizumab concentration data can be integrated with data from other studies that use established population PK models to derive PK parameters such as clearance, volume of distribution, and area under the curve.

Immunogenicity assay

Immunogenicity may be assessed for atezolizumab and other study therapies, where appropriate (see the group-specific appendix for details). Immunogenicity assays included all patients who underwent at least one antidrug antibody (ADA) assessment. Patients are grouped according to treatment received, or according to assigned treatment if no treatment was received prior to study discontinuation.

For atezolizumab, the number and proportion of ADA-positive and ADA-negative patients at baseline (baseline prevalence) and post-baseline (post-baseline incidence) are summarized by treatment group. When determining post-baseline incidence rates, if a patient is ADA-negative at baseline or has missing data but has an ADA response following study drug exposure (treatment-induced ADA response), or is ADA positive at baseline and the titer of one or more post-baseline samples is equal to the baseline sample. A patient is considered ADA positive if it is at least 0.60 titer units greater than the titer of (treatment-enhanced ADA response). The patient is ADA negative at baseline or data is missing and all samples after baseline are negative, or if the patient is ADA positive at baseline but has no post-baseline samples whose titers are greater than or equal to 0.60 titer units greater than those of the baseline samples (treatment impacts). not received), the patient is considered ADA negative.

For other study treatments for which ADA is tested, ADA positivity is determined according to standard methods established for previous studies of these drugs. The relationship between ADA status and safety, efficacy, PK and biomarker endpoints can be analyzed and reported through descriptive statistics.

Example 3. A Phase Ib, Open Label, Multiple Cohort Study of the Safety, Efficacy and Pharmacokinetics of Tiragolumab in Combination with Atezolizumab and Chemotherapy in Patients with Triple Negative Breast Cancer

This example describes a Phase Ib, open-label, multi-cohort study designed to evaluate the safety, efficacy, and pharmacokinetics of tiragolumab in combination with atezolizumab and chemotherapy in patients with metastatic triple negative breast cancer (TNBC). . This study consists of the following cohorts:

Cohort A enrolls patients with unresectable locally advanced or metastatic programmed cell death ligand 1 (PD-L1) positive TNBC (primary metastatic TNBC) who have not received prior systemic therapy for metastatic breast cancer. Patients receive tiragolumab in combination with atezolizumab and nap-paclitaxel.

A. study design

This Phase Ib, multi-cohort, open-label, multicenter, global study included patients with unresectable locally advanced or metastatic PD-L1-positive TNBC (Cohort A, termed metastatic TNBC) who had not received prior systemic therapy for metastatic breast cancer. It was designed to investigate the safety and tolerability, preliminary efficacy, and pharmacokinetics of tiragolumab in combination with atezoluzumab and nap-paclitaxel in subjects. PD-L1 positivity is assessed using the SP142 PD-L1 IHC assay. 2 depicts the study design for Cohort A.

Eligible patients (i.e., PD-L1-positive patients) will receive tiragolumab (840 mg) and atezolizumab (1680 mg) by IV infusion on Day 1 of a 28-day cycle plus an additional 28-day cycle. Enrolled to receive nap-paclitaxel (100 mg/m2) by IV infusion on days 1, 8, and 15.

In the absence of disease progression or unacceptable toxicity, nap-paclitaxel is administered with a target of at least 6 cycles without a maximum.

To evaluate the mechanism of action and possible resistance mechanisms of drug combinations in the tumor microenvironment, tumor tissues can optionally be collected prior to dosing on Day 1 of Cycle 2.

To test the mechanisms of resistance to drug combinations in the tumor microenvironment, all patients underwent mandatory tumor biopsy collection (if clinically feasible) at first evidence of disease progression as assessed by the investigator according to RECIST v1.1 ( before initiation of a new anticancer drug).

Patients receive tumor assessments every 8 weeks (± 7 days) at baseline and for the first 48 weeks after Day 1 of Cycle 1, regardless of treatment delay. After completion of the Week 48 tumor assessment, tumor assessments will be performed every 12 weeks (± 7 days), regardless of treatment delay, until disease progression, withdrawal of consent, death, or study termination, as determined by the investigator per RECIST v1.1, whichever occurs first, as determined by the investigator per RECIST v1.1 should be carried out

Study treatment is discontinued upon disease progression as determined by the investigator per RECIST v1.1. In the case of ambiguous findings of progression (e.g., very small or uncertain new lesions or lymph nodes; cystic changes or necrosis of existing lesions), treatment may be continued until the next scheduled evaluation according to RECIST v1.1 assessed by the investigator. If progress is confirmed at the next scheduled evaluation, the date of progress should be the earlier date when progress was suspected.

B. Dosage and administration

The treatment regimen is summarized in FIG. 2 .

On the scheduled infusion days of atezolizumab, tiragolumab, and chemotherapy, the atezolizumab and tiragolumab infusion are followed by chemotherapy.

After atezolizumab infusion (1680 mg), patients receive 840 mg of tiragolumab.

Administration of atezolizumab, tiragolumab, and chemotherapy is performed in a monitored environment with immediate access to trained personnel and appropriate equipment and medications to manage potentially severe reactions.

For detailed instructions on drug preparation, storage, and administration, see the pharmacy instructions.

Tiragolumab and Atezolizumab

In Cohort A, patients receive a 1680 mg fixed dose of atezolizumab as a Q4W IV infusion on Day 1 of each 28-day cycle, after which a fixed dose of 840 mg of tyragolumab is administered to patients in each 28-day cycle. Administered as a Q4W IV infusion on Day 1. The tiragolumab dose is fixed and does not vary with body weight. Tiragolumab and atezolizumab infusions (including observation period) are administered according to the guidelines summarized in Table 24.

first injection subsequent injection Atezolizumab injection

아테졸리주맙 주입 이전에 예비 투약은 허용하지 않는다.

상기 주입 전 60분 이내에 활력 징후(맥박수, 호흡수, 혈압, 및 체온)를 기록한다.

아테졸리주맙을 60(±15)분에 걸쳐 주입한다.

임상적으로 지시된 경우, 상기 주입 동안 15(±5)분마다 및 상기 주입 후 30(±10)분에 활력 징후를 기록해야 한다.

환자에게 주입후 증상 지연 가능성에 관하여 알려주고 이러한 증상이 발생하는 경우 연구 담당의에게 연락하도록 지시한다.

No premedication prior to atezolizumab infusion is permitted.

Vital signs (pulse rate, respiration rate, blood pressure, and body temperature) are recorded within 60 minutes prior to the infusion.

Atezolizumab is infused over 60 (±15) minutes.

If clinically indicated, vital signs should be recorded every 15 (±5) minutes during the infusion and at 30 (±10) minutes after the infusion.

Inform the patient of the potential for post-infusion symptom delay and instruct the study physician to contact if these symptoms develop.

If a patient experiences an infusion-related reaction related to a previous infusion, a premedication of antihistamines and/or antipyretics may be performed for subsequent doses at the investigator's discretion.

Vital signs should be recorded within 60 minutes prior to infusion.

Atezolizumab is infused over 30 (±10) minutes if the previous infusion was well tolerated without an infusion-related reaction, or over 60 (±15) minutes if the patient experienced an infusion-related reaction with the previous infusion± .

If the patient has experienced an infusion-related reaction with a previous infusion or is clinically indicated, vital signs should be measured during infusion and 30 (±10) minutes post-infusion. Observation period after atezolizumab infusion

Following the atezolizumab infusion, the patient begins a 60-minute observation period prior to the infusion of tiragolumab.

Vital signs are recorded 30 (±10) minutes after atezolizumab infusion.

If the patient is well tolerated by a previous infusion of atezolizumab without infusion-related adverse events, the observation period prior to infusion of tiragolumab may be reduced to 30 minutes.

If the patient has experienced an infusion-related adverse event from a previous infusion, the observation period should be 60 minutes.

If clinically indicated, vital signs should be recorded 15 (±10) minutes after atezolizumab infusion. Injection of tiragolumab

Premedication prior to tiragolumab infusion is not permitted.

Vital signs (pulse rate, respiration rate, blood pressure, and body temperature) are recorded within 60 minutes prior to the infusion.

Tiragolumab is infused over 60 (±10) minutes.

Vital signs are recorded every 15 (±5) minutes during infusion and 30 (±10) minutes after infusion.

If a patient experiences an infusion-related reaction during any previous infusion of tyragolumab, an antihistamine and/or antipyretic agent may be administered for a subsequent dose at the investigator's discretion.

Vital signs should be recorded within 60 minutes prior to infusion of tiragolumab.

Tiragolumab should be infused over 30 (±10) minutes if the previous infusion was well tolerated without an infusion-related reaction, or over 60 (±10) minutes if the patient experienced an infusion-related reaction with the previous infusion. .

If clinically indicated, vital signs should be recorded during infusion. Observation period after tiragolumab infusion

Following the tiragolumab infusion, the patient begins a 60-minute observation period prior to subsequent chemotherapy infusions.

Vital signs should be recorded 30 (±10) minutes after tiragolumab infusion.

Patients are informed of possible post-infusion symptom delays and instructed to contact the study physician if these symptoms develop.

If the patient tolerates the previous infusion well with no infusion-related adverse events, the period of observation before subsequent chemotherapy infusions can be reduced to 30 minutes.

If clinically indicated, vital signs should be recorded 15 (±10) minutes after tyragolumab infusion.

Patients are informed of possible post-infusion symptom delays and instructed to contact the study physician if these symptoms develop.

Administration of first and subsequent tiragolumab infusions and atezolizumab infusions

Nap-paclitaxel

Nap-paclitaxel is administered according to local prescribing information. The starting dose level of nap-paclitaxel in this study was 100 mg/m administered intravenously to patients over 30 minutes on days 1, 8, and 15 of each 28-day cycle (3-week dosing/1 week off schedule). ² is Nap-paclitaxel should be administered after atezolizumab and tiragolumab. Nap-paclitaxel is administered alone on days 8 and 15 of each cycle. Doses of nap-paclitaxel should not be administered more frequently than every 7 days.

Institutions should follow the institution's standard of care to determine nap-paclitaxel doses for obese patients and adjust the dose for changes in patient body weight. The injection site should be closely monitored for possible infiltration during drug administration.

In the absence of disease progression or unacceptable toxicity, nap-paclitaxel is administered with a target of at least 6 cycles without a maximum.

For more information on the preparation and administration of nap-paclitaxel, see local prescribing information.

capacity change

There were no dose changes for atezolizumab or tiragolumab in this study. See Table 25 for administration of nap-paclitaxel (ie, dose adjustment and treatment discontinuation rules).

Nap-paclitaxel starting capacity 125 mg/m ² first dose 100 mg/m ² second dose stop

Reducing the Recommended Dose for Nap-Paclitaxel

C. combination therapy

Combination therapy includes any drugs (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient in addition to protocol essential treatment from 7 days prior to study drug initiation until the treatment discontinuation visit.

accepted therapy

Patients are allowed to use the following regimens during the study period:

연간 실패율이 1% 미만인 경구 피임약

Oral contraceptives with an annual failure rate of less than 1%

호르몬 대체 요법

hormone replacement therapy

예방적 또는 치료적 항응고 요법(예컨대, 안정적인 용량의 와파린 또는 저분자량 헤파린)

Prophylactic or therapeutic anticoagulant therapy (eg, stable doses of warfarin or low molecular weight heparin)

비활성화 인플루엔자 예방 접종

Inactivated influenza vaccination

식욕 자극제로 투여되는 메게스트롤 아세테이트

Megestrol acetate administered as an appetite stimulant

미네랄로코르티코이드(예컨대, 플루드로코르티손)

Mineralocorticoids (such as fludrocortisone)

만성 폐쇄성 폐질환 또는 천식에 투여되는 코르티코스테로이드

Corticosteroids given for chronic obstructive pulmonary disease or asthma

기립성 저혈압 또는 부신피질 기능부전에 투여된 저용량 코르티코스테로이드

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency

골격성 사건의 예방을 위한 비스포스포네이트

Bisphosphonates for the prevention of skeletal events

하기에 개략된 바와 같은 완화 방사선 요법(예컨대, 공지된 골 전이의 치료 또는 통증의 증상 완화):

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

Palliative radiation therapy is acceptable as long as it does not interfere with the evaluation of tumor target lesions (eg, the lesion to be investigated should not be the only site of measurable disease). Treatment with tiragolumab and atezolizumab may be continued during palliative radiation therapy. Treatment with nap-paclitaxel should be discontinued according to institutional standards.

Premedication of antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent infusions of atezolizumab and tiragolumab at the discretion of the investigator.

care

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines should be considered. If no alternative is possible, systemic corticosteroids and TNF-α inhibitors may be administered at the investigator's discretion.

For the treatment of certain adverse events associated with atezolizumab therapy, systemic corticosteroids are recommended at the discretion of the investigator.

forbidden therapy

The use of the following combination therapies is contraindicated as follows:

보건 기관의 승인을 받았거나 임상시험 단계에 있는지 여부와 상관없이, 연구 치료제를 시작하기 전 다양한 기간 동안, 작용제에 따라서, 및 질병 진행이 문서화되고 환자가 완화 방사선 요법을 제외하고 연구 치료제를 중단할 때까지, 암 치료를 위한 병용 요법(화학요법, 호르몬 요법, 면역요법, 방사선 요법 및 한약 요법을 포함하지만, 이에 제한되지는 않음)

Whether approved by the health agency or in the clinical trial phase, for various periods of time prior to initiation of study treatment, depending on agent, and when disease progression is documented and patients discontinue study treatment except for palliative radiation therapy. combination therapy for cancer treatment (including but not limited to chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy)

연구 치료제 개시 전 및 연구 치료제 동안 28일 이내의 임상시험 요법

Investigational therapy within 28 days prior to initiation of study treatment and during study treatment

연구 치료제 개시 전 4주 이내, 아테졸리주맙 치료 중, 및 연구 치료제의 최종 용량 투여 후 5개월 동안 독성 약화 생백신(예컨대, 플루미스트(FLUMIST)^®)

Toxic attenuated live vaccine (eg, ^FLUMIST® ) within 4 weeks prior to initiation of study treatment, during atezolizumab treatment, and 5 months after administration of the last dose of study treatment

연구 치료제 개시 전 및 연구 치료제 동안 4주 또는 5회의 약물 제거 반감기(둘 중 더 긴 것) 이내의 전신 면역자극제(인터페론 및 IL-2를 포함하지만, 이에 제한되지는 않음) - 상기 제제는 아테졸리주맙 및 티라골루맙과 병용 투여 시 자가면역 질환의 위험을 증가시킬 가능성이 있기 때문임.

Systemic immunostimulants (including but not limited to interferon and IL-2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment - the agent is This is because co-administration with zumab and tiragolumab may increase the risk of autoimmune disease.

Systemic immunosuppressive agents (including azathioprine, methotrexate, and thalidomide) during study treatment, as these agents have the potential to alter the efficacy and safety of atezolizumab and tiragoluumab.

화학요법으로 인한 호중구 감소증의 감소를 위해 연구 중인 새로운 분자인 플리나불린은 G-CSF/GMCSF의 대체물로 허용되지 않는다.

Plinabulin, a new molecule being studied for the reduction of chemotherapy-induced neutropenia, is not an acceptable replacement for G-CSF/GMCSF.

D. Selection Criteria

Patients must meet the following general criteria for study enrollment:

서명한 사전 동의서

signed informed consent

사전 동의서에 서명할 당시의 연령 ³ 　18세의 여성 및 남성

Age at time of signing informed consent ³ 18 years of age for women and men

연구 프로토콜을 준수할 능력

Ability to comply with research protocols

0 또는 1의 ECOG 전신 활동도

ECOG systemic activity of 0 or 1

연구 치료제 개시 전

Before starting research treatment

Adequate blood and end organ function (of Cycle 1) defined by the following laboratory results obtained within 14 days.

1 day):

- ANC ³ 1.5 ´ 109/L (1500/νL) -

No G-CSF support within 2 weeks before 1 day of cycle 1

- Lymphocyte count ³ 0.5 ´ 109/L (³ 500/νL)

- Platelet count ³ 100 ´ 109/L (³ 100,000/νL) -

No transfusions within 2 weeks before Day 1 of Cycle 1

- Hemoglobin ³ 90 g/L (³ 9 g/dL)

To meet the above criteria, the patient will receive a blood transfusion or receive erythropoietic therapy.

can receive

- AST, ALT, and ALP ￡ 2.5 ´ Upper limit of normal (ULN)

- Serum bilirubin ￡ 1.5 ´ U, except for:

Gilbert's disease patients known to have serum bilirubin levels of ￡　3　 lULN can enroll.

- INR and aPTT ￡ 1.5 ´ ULN

This only applied to patients who did not receive therapeutic anticoagulation; Patients on anticoagulant therapy should use a stable dose.

- Creatinine clearance ³ 30 mL/min (calculated using the Cockcroft-Gault formula)

- Serum albumin ³ 25 g/L (³ 2.5 g/dL)

선별 검사시 HIV 검사 음성

HIV test negative at screening

선별 검사시 B형 간염 표면 항원 (HBsAg) 검사 음성

Hepatitis B surface antigen (HBsAg) test negative at screening

선별 검사시 B형 간염 표면 항체(HBsAb) 검사 양성, 또는

positive hepatitis B surface antibody (HBsAb) test at screening, or

HBsAb negative at screening with one of the following

- Total hepatitis B core antibody (HBcAb) negative

- Quantitative hepatitis B virus (HBV) DNA after positive total HBcAb test

< 500 IU/mL

The HBV DNA test is only performed on patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test.

선별 검사시 C형 간염 바이러스(HCV) 항체 검사 음성, 또는 선별 검사시 HCV 항체 검사 양성 후 HCV RNA 검사 음성.

Hepatitis C virus (HCV) antibody test negative at screening test, or HCV RNA test negative after HCV antibody test positive at screening test.

The HCV RNA test is only performed on patients with a positive HCV antibody test.

가임 여성의 경우: 금욕 유지(이성간 성교 금지) 또는 하기에 정의된 바와 같이 피임 방법 사용에 대한 동의 및 난자 기증 자제에 대한 동의

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods as defined below and to refrain from egg donation

Women during the treatment period and at least 5 months after the last dose of atezolizumab, 90 days after the last dose of tiragolumab, 1 month after the last dose of nap-paclitaxel, 6 months after the last dose of carboplatin or doxorubicin, or Abstinence should be maintained until the later of 12 months after the last dose of cyclophosphamide or a contraceptive method with a failure rate of <1% per year should be used. Women should refrain from donating eggs during the same period as above.

A woman has no chance of becoming pregnant if she is non-menstrual, has not reached postmenopausal status (without confirmed cause (³ 12 consecutive months of amenorrhea) other than menopause, and has not undergone surgical sterilization (removal of the ovaries and/or uterus). considered to exist

Examples of contraceptive methods that, when used correctly and consistently, have a failure rate of < 1% per year include combined (estrogen and progesterone-containing) hormonal contraception associated with ovulation inhibition, progesterone-only hormonal contraception associated with ovulation inhibition, bilateral tubal occlusion; male infertility; intrauterine device; intrauterine

hormone release system; and sexual abstinence.

The reliability of sexual abstinence should be evaluated with respect to the duration of the clinical study and the desired and general lifestyle of the patient.

Periodic abstinence (eg, calendar, ovulation, symptomatic body temperature, or postovulatory methods) and withdrawal are not acceptable methods of contraception.

Women wishing to become pregnant after discontinuation of study treatment should seek advice on oocyte preservation prior to initiation of study treatment due to the potential for irreversible infertility due to chemotherapy treatment.

For Men: Consent to maintain abstinence (abstain from heterosexual intercourse) or use contraceptive methods, and to refrain from donating sperm, as provided below:

With a female partner of childbearing potential or a pregnant female partner, during treatment and for 90 days after the last dose of tiragolumab, or 6 months after the last dose of nap-paclitaxel, carboplatin, doxorubicin, or cyclophosphamide, whichever is more Until a later date, men must either maintain abstinence or use an additional method of contraception with a failure rate of < 1% per year. Men should refrain from donating sperm during the same period.

The reliability of sexual abstinence should be evaluated with respect to the duration of the clinical trial and the patient's preferred daily lifestyle.

Periodic abstinence (eg, calendar, ovulation, symptomatic body temperature, or postovulatory methods) and withdrawal are not acceptable methods of contraception.

Men wishing to have children after initiation of study treatment should seek advice on sperm conservation prior to initiating study treatment due to the potential for irreversible infertility due to chemotherapy treatment.

폐경 후가 아닌 여성(비치료 유발 무월경 ³ 12개월) 또는 불임 시술을 받은 여성의 경우, 연구 치료제 개시 전 14일 이내에 음성 혈청 임신 검사 결과가 필요하다.

For non-postmenopausal women (non-treatment-induced amenorrhea ³ 12 months) or women who have undergone sterilization, a negative serum pregnancy test result is required within 14 days prior to initiation of study treatment.

예정된 방문, 치료 계획, 실험실 검사, 및 기타 연구 절차를 준수하려는 의지 및 능력

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other research procedures

Patients in Cohort A must meet the following cancer-specific criteria for study enrollment:

기대 수명 ³ 12주

Life expectancy ³ 12 weeks

전이성 또는 국소 진행성 절제 불가능, 조직학적으로 문서화된 TNBC(국소 검사에 의해 결정된 바와 같이 HER2, ER 및 프로게스테론 수용체(PgR) 발현의 부재)

Metastatic or locally advanced unresectable, histologically documented TNBC (absence of HER2 , ER and progesterone receptor (PgR) expression as determined by local examination)

HER2 negative is defined as one of the following by local laboratory assessment (Wolff et al. 2018):

Intra-tissue hybridization (ISH) unamplified (ratio of HER2 to CEP17 < 2.0 or single probe average number of HER2 gene copies < 4 signals/cell), or IHC 0 or IHC 1 +.

ER and PgR negatives are defined as <1% of cells expressing hormone receptors as determined by IHC analysis.

중앙에서 검사하고 PD-L1 양성인 것으로 밝혀진 전이성 TNBC 종양이 있는 환자만 등록한다.

Enroll only patients with metastatic TNBC tumors that have been centrally tested and found to be PD-L1-positive.

Tumor samples obtained from recurrent metastatic or locally advanced disease (if applicable) should be submitted when clinically feasible.

Representative FFPE tumor specimens from paraffin blocks (preferred) or at least 20 unstained slides (archival specimens or fresh pretreated tissue from relapsed disease)

Tumor tissue should be of good quality based on total and viable tumor content, and should be assessed for PD-L1 expression as determined using the Ventana (SP142) PD-L1 IHC assay prior to enrollment, with positivity being a central It is defined as ≧1% of the tumor area occupied by infiltrating immune cells expressing PD-L1-expressing tumors of any intensity measured in the laboratory. Patients whose tumor tissue cannot be assessed for PD-L1 expression are not eligible.

If multiple tumor specimens are submitted, a patient may be eligible if at least one specimen is evaluable and positive for PD-L1 expression (regardless of whether the tissue is from archival specimens or from recurrent disease).

Acceptable samples include core-needle biopsies (minimum 3 cores) for deep tumor tissue, or excision, incision, punch or forceps biopsies for skin, subcutaneous or mucosal lesions.

FFPE tumor specimens in paraffin blocks are preferred.

Fine needle aspiration, brushing, cell pellets in pleural effusion, bone metastases, and wash samples are not permitted. Tumor tissue from bone metastases cannot be evaluated for PD-L1 expression and is therefore not acceptable.

수술 불가능, 국소 진행성, 또는 전이성 TNBC에 대한 선행 화학요법 또는 표적 전신요법 없음

No prior chemotherapy or targeted systemic therapy for inoperable, locally advanced, or metastatic TNBC

Prior radiation therapy for metastatic disease is not permitted. There is no minimum washout period required for radiation therapy. The patient must recover from the effects of radiation.

Prior chemotherapy (including taxanes) and/or CIT (anti-PD-L1 or anti-PD-1 agents only) in neoadjuvant or adjuvant treatment settings is permitted if treatment is completed ³ 12 months prior to initiation of study therapy.

RECIST v1.1에 따라 시험자가 평가한 측정 가능한 질병

Measurable disease assessed by the investigator according to RECIST v1.1

Previously irradiated lesions can be considered measurable disease only if disease progression is clearly documented at the site after irradiation.

E. Exclusion Criteria

Patients meeting any of the following criteria are excluded from study enrollment:

연구 치료 중, 티라골루맙 치료 후 90일 이내, 아테졸리주맙 치료 후 5개월 이내, 냅-파클리탁셀, 카보플라틴 또는 독소루비신 치료 후 6개월 이내, 또는 시클로포스파미드 치료 후 12개월 이내 중 더 늦은 날짜까지 임신 또는 수유 중인 경우

During study treatment, within 90 days of treatment with tiragolumab, within 5 months of treatment with atezolizumab, within 6 months of treatment with nap-paclitaxel, carboplatin, or doxorubicin, or within 12 months of treatment with cyclophosphamide, whichever is later If you are pregnant or lactating by the date

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

유의미한 간 질환(예컨대, 간경변, 조절되지 않는 주요 발작 장애, 또는 상대정맥 증후군)을 포함하여 프로토콜 준수 또는 결과 해석에 영향을 미칠 수 있는 유의미한 조절되지 않는 동시 질병의 증거

Evidence of significant concurrent uncontrolled disease that could affect protocol compliance or interpretation of results, including significant liver disease (e.g., cirrhosis, uncontrolled major seizure disorder, or superior venous syndrome)

상당한 심혈관 질환, 예컨대 뉴욕 심장 협회 심장 질환(부류 II 이상), 연구 치료제 개시 전 3 개월 이내 심근경색증, 불안정 부정맥, 또는 불안정 협심증

Significant cardiovascular disease, such as New York Heart Association heart disease (Class II or higher), myocardial infarction within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

Patients with known LVEF <53% are excluded.

Patients with known coronary artery disease or congestive heart failure who do not meet the above criteria.

감염 합병증, 세균혈증 또는 중증 폐렴으로 인한 입원을 포함하지만, 이에 제한되지는 않는 연구 치료제 개시 전 4주 이내의 중증 감염

Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for infectious complications, bacteremia, or severe pneumonia

연구 치료제 개시 전 2주 이내에 경구 또는 IV 항생제를 이용한 치료

Treatment with oral or IV antibiotics within 2 weeks prior to initiation of study treatment

Patients receiving regular antibiotic prophylaxis (eg, to prevent exacerbation of chronic obstructive pulmonary disease or for tooth extraction) are eligible.

연구 치료제 개시 전 28일 이내의 주요 수술 또는 진단 이외의 연구 동안 주요 수술 절차의 필요성 예상되는 경우

Major surgery within 28 days prior to initiation of study treatment or the need for major surgical procedures during non-diagnostic studies

The placement of a central venous access catheter (eg, port or the like) is acceptable as it is not considered a major surgical procedure.

키메라성 또는 인간화 항체 또는 융합 단백질에 중증 알러지성, 과민성, 또는 다른 과민증 반응의 병력

History of severe allergic, hypersensitivity, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

CHO 세포 또는 티라골루맙 또는 아테졸리주맙 제제의 임의의 성분에서 생성된 생물의약품에 대한 알려진 과민성 또는 알레르기

Known hypersensitivity or allergy to biologics produced from CHO cells or any component of the tiragolumab or atezolizumab formulations.

중증 근무력증, 근염, 자가면역 간염, 전신성 홍반 루푸스, 류마티스 관절염, 염증성 장 질환, 항인지질 증후군과 관련된 혈관 혈전증, 베게너 육아종증, 쇼그렌 증후군, 길랭-바레 증후군, 다발성 경화증, 혈관염 또는 사구체신염을 포함하지만 이에 제한되지는 않는 자가면역 질환의 활성 또는 병력

myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis Activity or history of autoimmune disease, but not limited to this

Patients with a history of autoimmune-mediated hypothyroidism on stable doses of thyroid replacement hormone may be eligible for this study.

Patients with type 1 diabetes mellitus controlled with a stable insulin dosing regimen are eligible for this study.

Patients with eczema, psoriasis, chronic lichen simplex or vitiligo with only dermatological symptoms (eg, no psoriatic arthritis) are allowed if the following conditions are met:

- The rash occupies < 10% of the body surface area

- Disease is well controlled at baseline and requires only low titer topical steroids

- No acute exacerbation of an underlying condition requiring ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids in addition to psoralen within the past 12 months

- Caution should be exercised when considering atezolizumab in patients who have previously experienced severe or life-threatening skin adverse reactions while receiving other immunostimulatory anticancer drugs.

선행 동종이계 줄기 세포 이식 또는 고형 장기 이식

Prior allogeneic stem cell transplantation or solid organ transplantation

특발성 폐 섬유증(폐렴을 포함), 약물 유발 폐렴, 조직성 폐렴(즉, 폐쇄성 세기관지염, 잠복성 조직성 폐렴)의 병력, 또는 선별 검사시 흉부 컴퓨터 단층촬영(CT) 스캔에서 활동성 폐렴의 증거

A history of idiopathic pulmonary fibrosis (including pneumonia), drug-induced pneumonia, systemic pneumonia (i.e., bronchiolitis obliterans, latent systemic pneumonia), or evidence of active pneumonia on a chest computed tomography (CT) scan at screening

A history of radiation pneumonitis (fibrosis) in the field of radiation is acceptable.

선별 검사시 EBV 바이러스 캡시드 항원(VCA) IgM 검사 양성

Positive EBV virus capsid antigen (VCA) IgM test at screening

EBV polymerase chain reaction (PCR) testing should be performed as clinically indicated to screen for active or suspected chronic active infection.

Patients with a positive EBV PCR test are excluded.

활동성 결핵(TB)

Active tuberculosis (TB)

연구 치료제의 개시 전 4주 이내에 독성 약화 생백신을 투여 또는 연구 중에 독성 약화 생백신이 필요할 것으로 예상되는 경우

Administered live attenuated vaccine within 4 weeks prior to initiation of study treatment, or if live attenuated vaccine is expected to be required during the study

Patients must agree not to receive a live, attenuated vaccine (eg, Flumist ^® ) within 28 days prior to initiation of study treatment, during treatment, or within 5 months after administration of the last dose of study treatment.

항 PD-1 또는 항 PD-L1 치료 항체를 제외하고 항 CTLA-4를 포함한 CD137 작용제 또는 면역 관문 차단 요법을 이용한 선행 치료

Prior treatment with CD137 agonists, including anti-CTLA-4, or immune checkpoint blockade, excluding anti-PD-1 or anti-PD-L1 therapeutic antibodies

연구 치료제 개시 전 4주 이내 또는 약물의 5회 약물 제거 반감기(둘 중 더 늦은 날짜) 이내에 전신 면역자극제(인터페론 또는 IL-2를 포함하지만 이제 제한되지는 않음)를 이용한 치료

Treatment with systemic immunostimulants (including but not limited to interferon or IL-2) within 4 weeks prior to initiation of study therapy or within 5 drug elimination half-lives of the drug, whichever is later

연구 치료제 개시 전 2주 이내에 전신 면역억제제(프레드니손,

Systemic immunosuppressants (prednisone,

treatment with, but not limited to, dexamethasone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents, or when systemic immunosuppressants are expected to be required during the study

Patients receiving acute, low-dose, systemic immunosuppressants (eg, single dose of dexamethasone for nausea) can be enrolled in this study.

Patients with a history of allergic reactions to IV contrast media requiring steroid pretreatment should have baseline and follow-up tumor assessments using magnetic resonance imaging (MRI).

Inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (eg, fludrocortisone) for patients with orthostatic hypotension, and low-dose adjuvant corticosteroids for adrenal insufficiency may be used.

Patients in Cohort A who meet any of the following exclusion criteria are excluded from study enrollment:

FFPE 종양 조직이 SP142 PD-L1 IHC 분석에서 결정된 대로 PD-L1 음성이고, 양성은 임의의 강도의 PD-L1 발현 종양 침윤성 면역 세포가 차지하는 종양 면적의 ≥1%로 정의함

FFPE tumor tissue is PD-L1 negative as determined in the SP142 PD-L1 IHC assay, and positive is defined as ≥1% of the tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells of any intensity

수술 및/또는 방사선으로 확실하게 치료되지 않은 척수 압박 또는 질병이 연구 치료제 개시 전 > 2주 동안 임상적으로 안정적이라는 증거가 없는 사전에 진단 및 치료된 척수 압박

Spinal cord compressions that have not been reliably treated with surgery and/or radiation or previously diagnosed and treated spinal cord compressions with no evidence that the disease is clinically stable > 2 weeks prior to initiation of study treatment

하기의 기준이 모두 충족되는 경우, 치료된 무증상 CNS 전이를 제외하고 공지된 중추신경계(CNS) 질환:

Known central nervous system (CNS) diseases except for asymptomatic CNS metastases treated if all of the following criteria are met:

-Only supratentorial and cerebellar metastases are allowed (i.e. no metastases to the midbrain, pons, medulla or spinal cord)

- No need for continuous corticosteroids as therapy for CNS disease

- No stereotactic irradiation within 7 days or whole brain irradiation within 14 days prior to initiation of study treatment

- No evidence of intermediate progression between completion of CNS-directed therapy and screening radiographic studies

Note: Patients with new asymptomatic CNS metastases detected on screening scans should receive radiotherapy and/or surgery for CNS metastases. After treatment, the patient may be eligible without the need for an additional brain scan prior to enrollment if all other criteria are met.

연수막성 질환

leptomeningeal disease

조절되지 않는 흉막 삼출, 심낭 삼출 또는 복수

Uncontrolled pleural effusion, pericardial effusion, or ascites

Patients with indwelling catheters (eg PLEURX ^® ) are permitted.

통제되지 않는 종양 관련 통증

Uncontrolled tumor-related pain

Patients requiring opioid analgesia should be on stable therapy at the start of the study.

Symptomatic lesions that can be treated with palliative radiation therapy (eg, bone metastases or metastases causing nerve impingement) should be treated prior to enrollment. The patient must recover from the effects of radiation. The patient must recover from the effects of radiation.

Asymptomatic metastatic lesions where further growth may result in functional deficits or refractory pain (eg, epidural metastases not currently associated with spinal cord compression) should be considered for local area therapy where appropriate prior to enrollment.

Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or Ca+2 >12 mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring the use of continuous bisphosphonate therapy

In particular, patients receiving bisphosphonate therapy to prevent skeletal events and without a history of clinically significant hypercalcemia are eligible.

연구 치료 개시 전 5년 이내에 TNBC 이외의 악성 종양이 있는 경우 - 전이 또는 사망의 무시할 수 있는 위험(예컨대: 5년간의 OS > 90%)이 있고 예상되는 치료 결과를 가지고 치료된 경우는 제외함(예컨대, 자궁 경부 또는 기저부, 국소 전립선 암 또는 편평 세포 피부암의 조직 내에서 적절하게 치료된 암종)

Non-TNBC malignancy within 5 years prior to initiation of study treatment - except for cases with negligible risk of metastasis or death (e.g. OS > 90% over 5 years) and treated with expected treatment outcome ( Adequately treated carcinoma within tissue of, e.g., cervical or basal, focal prostate cancer or squamous cell skin cancer)

냅-파클리탁셀 또는 이의 임의의 부형제에 대한 공지된 과민증

Known hypersensitivity to nap-paclitaxel or any excipient thereof

F. analysis

A safety analysis is performed in all patients.

The efficacy analysis uses an ITT approach for Cohort A and Cohort B, where all enrolled patients are included in the analysis, regardless of whether the patient is receiving the assigned study drug. Analyzes based on subsets of the ITT population may also be performed.

Hypothesis analysis is two-sided unless otherwise specified.

sample size

The objective of Cohort A is to estimate the effect of tiragolumab in combination with atezolizumab and nap-paclitaxel on the primary efficacy endpoint defined as objective response. Compared with historical data, response rates are considered promising or not promising for future development. There is no formal hypothesis analysis. Statistics are presented as two-sided 90% CI. When making recommendations to continue or discontinue development, consider the entirety of the data, including results for secondary efficacy endpoints, including, but not limited to, analysis results for PFS, OS, and subgroups.

The primary efficacy analysis is to estimate the actual proportion of patients expected to obtain a CR or PR (ie, ORR). Data from completed and ongoing studies in similar disease settings can be used as historical controls for comparison. Based on currently available data, the confirmed historical response rate in locally advanced unresectable or metastatic PD-L1-positive TNBC is approximately 53% ( ^TECENTRIQ® US Package Insert).

The 40 patient sample size provides adequate precision for the lower bound and point estimates of the two-sided 90% CI, to rule out a probability of a response that is not clinically of interest of <53%, assuming an observed response rate of 67.5%. considered sufficient. Specifically, if at least 27 out of 40 patients respond, it can be concluded that the response rate is greater than 53%. Updated estimates of the proportion of patients expected to achieve a response are expected to be available from ongoing studies up to the time of efficacy analysis and serve as reference data.

Table 26 lists the two-tailed 90% Klopper-Pearson's exact CIs for the true probability of achieving a response for the observed range of rates, based on a sample of 40 patients. The probabilities of detecting positive and negative signals based on point estimates of the observed ORR at various thresholds and the underlying true ORR are presented in Tables 27 and 28.

Observed proportion of patients achieving a response (n = 40) Two-sided 90% Klopper-Pearson confidence interval for true population response (n = 40) p _estimate = 0.675 (27 of 40 patients)

p_추정

0.79587.53370

p _estimate

0.79587 p _estimate = 0.700 (28 out of 40 patients) 0.55972

p _estimate

0.81688 p _estimate = 0.725 (29 of 40 patients) 0.58612

p _estimate

0.83748 p _estimate = 0.750 (30 of 40 patients) .61294

p _estimate

0.85763

Two-tailed Clopper-Pearson exact confidence intervals for the true probability of achieving a response

Actual default ORR Probability of observed response rate > 73% 53% 0.4% 68% 22.1% 73% 46.8% NOTE: Results are based on simulations of 1e6 runs.

Probability of showing a positive signal (observed ORR above the selected threshold)

Actual default ORR Probability of observed response rate < 58% Probability of observed response rate < 63% 53% 76.6% 91.4% 68% 10.7% 27.8% 73% 2.5% 9.6%

Probability of presenting a negative signal (observed ORR below the selected threshold)

Safety analysis

Safety assessments include the incidence, nature and severity of adverse events, protocol-essential vital signs, laboratory abnormalities, and other protocol-specific tests considered important for the safety assessment of the study. Adverse events are graded according to NCI CTCAE v5.0.

Safety is assessed by ADA-measured adverse events, changes in laboratory test results, changes in vital signs, exposure to study treatment, and summary of immunogenicity and presented in treatment groups.

Verbose descriptions of adverse events are mapped to MedDRA terminology.

Treatment emergency response (defined as a response that occurs at or after the first dose of study treatment) is summarized in MedDRA terminology, appropriate MedDRA level, and NCI CTCAE v5.0 grade, regardless of relationship to investigator-assessed study drug. If the same adverse event occurs multiple times for each patient, the maximum reported severity is used for the summary.

The following and treatment-related adverse events are summarized separately: Adverse Events Leading to Study Drug Discontinuation, Adverse Events Leading to Dose Reduction or Discontinuation, Grade 3 Adverse Events, Grade 5 Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest .

All deaths and causes of death are summarized.

Relevant laboratory values are summarized by time point, along with identified NCI CTCAE Grade 3 and Grade 4 values where appropriate. NCI CTCAE grade changes are tabulated by treatment group.

Analysis of exposure, adverse events, laboratory and vital signs data

Safety depends on exposure to study treatment, adverse events, changes in laboratory test results, and changes in vital signs and ECGs.

Evaluate through a summary.

Study treatment exposures (eg, duration of treatment, total dose administered, and number of cycles and dose changes) are summarized along with descriptive statistics.

Verbose terms of adverse events correspond to synonymous terms in MedDRA, and the severity of adverse events is graded according to NCI CTCAE v5.0. All adverse events, serious adverse events, adverse events leading to death, adverse events of particular interest, and adverse events leading to discontinuation of study treatment (i.e., treatment-related adverse events) occurring at or after administration of the first dose of study treatment These are summarized according to the mapped terms, appropriate synonym levels, and severity ratings. For reactions of variable severity, the highest rating in that summary is used. Deaths and causes of death are summarized.

Relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry, and body temperature) and ECG data are displayed hourly and identified by grade, where appropriate. In addition, tables of changes from selected laboratory tests are used to summarize baseline and post-baseline maximum severity ratings. Changes in vital signs and ECG are summarized.

Validity analysis

Primary effectiveness goal

The primary efficacy objective for Cohort A is to evaluate the efficacy of tiragolumab in combination with atezolizumab and nap-paclitaxel based on the following endpoints.

ORR - 시험자가 RECIST v1.1을 사용하여 결정한 CR 또는 PR을 가진 환자의 비율로 정의됨

ORR - defined as the proportion of patients with CR or PR as determined by the investigator using RECIST v1.1

Confirmation of PR or CR is required. Patients who do not meet the above criteria, including those without a post-baseline tumor assessment, are considered non-responders. ORR is defined as the proportion of patients with an objective response.

Once all patients have undergone at least two tumor assessments, efficacy data are reviewed first.

secondary effectiveness goal

The secondary efficacy goal for Cohort A is to obtain prior data on the efficacy of tiragolumab in combination with atezolizumab and nap-paclitaxel based on the following endpoints.

PFS - RECIST v1.1에 따라 시험자가 결정한 대로 등록 시점부터 질병 진행의 첫 발생 또는 임의의 원인으로 인한 사망에 이르기까지의 시간(중 먼저 발생한 시간)으로 정의함.

PFS - defined as the time from enrollment to the first onset of disease progression or death from any cause (whichever occurs first) as determined by the investigator per RECIST v1.1.

Data for patients who did not experience disease progression or who died are censored on the last known date of survival and progression-free before or on the same day as the clinical deadline for that respective analysis. Patients without post-baseline information are censored on the enrollment date.

DOR - RECIST v1.1에 따라 시험자가 결정한 대로, 보고된 객관적 반응의 최초 발생 시점부터 질병 진행 또는 임의의 원인으로 인한 사망(중 먼저 발생한 시간)시까지의 시간으로 정의함

DOR - defined as the time from the first occurrence of a reported objective response to disease progression or death from any cause (whichever comes first), as determined by the investigator in accordance with RECIST v1.1

Data for patients who have not experienced disease progression or who have died are censored on the date of last tumor evaluation. If no tumor evaluation is performed after the date of first occurrence of CR or PR, data for DOR is censored on the date of first occurrence of CR or PR.

OS - 등록에서부터 임의의 원인으로 인한 사망까지의 시간으로 정의함

OS - defined as the time from enrollment to death from any cause

Patients not reported to have died at the time of analysis are censored on the date of the last known survival. Patients without post-baseline information are censored on the enrollment date.

Pharmacokinetic analysis

Samples are collected for PK analysis and exposures in this study are compared with exposures obtained in previous studies. Serum concentrations of tiragolumab and atezolizumab and plasma concentrations of nap-paclitaxel, carboplatin, doxorubicin and cyclophosphamide are reported as individual values and summarized by treatment group and cycle (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation).

Individual and median serum tiragolumab and atezolizumab concentrations are plotted by treatment group and day. Tiragolumab and atezolizumab concentration data can be integrated with data from other studies that use established population PK models to derive PK parameters such as clearance, volume of distribution, and AUC as warranted by the data. have. Potential correlations of PK parameters with dose, safety, efficacy, or biomarker outcomes can be investigated.

Immunogenicity assay

Immunogenicity assays include patients undergoing any ADA assessment, and patients are classified according to treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients during the treatment and follow-up period will be summarized by treatment group.

The relationship between ADA status and safety, efficacy, and PK endpoints can be analyzed and reported through descriptive statistics.

Biomarker analysis

Although no formal statistical analysis of exploratory biomarkers is performed, the data can be analyzed in the context of this study and in conjunction with data from other studies.

Example 4. Phase Ia/Ib, Open Label, Dosage Regarding the Safety and Pharmacokinetics of Tiragolumab as a Single Agent and in Combination with Atezolizumab and/or Other Anticancer Therapies in Patients with Locally Advanced or Metastatic Tumors incremental study

This example describes the first phase 1, open label, multicenter, global, dose escalation study in humans designed to evaluate:

(Phase Ia) Locally progressive, recurrent, for which no standard therapy exists, has proven ineffective or intolerable, or has been deemed inappropriate, or for which clinical trials of investigational agents are the accepted standard of care. , or the safety, tolerability, and PK of tiragolumab as a single agent in patients with metastatic refractory tumors; and

(Phase Ib) patients with locally advanced, recurrent, or metastatic refractory tumors for which standard therapy has not been available, has proven ineffective, intolerable, or deemed inappropriate; or in combination with standard of care in patients for whom clinical trials of an investigational product are considered the accepted standard of care, or for which clinical trials of an investigational product using anti-PD-L1 antibodies are considered an acceptable treatment option. Safety, tolerability, and PK of tiragolumab when administered as

A. Study Design

It is locally advanced, relapsing, or metastatic refractory for which standard therapy does not exist, has proven ineffective or intolerable, is deemed inappropriate, or for which clinical trials of investigational agents are the accepted standard of care. This is the first phase 1, open-label, multicenter, global, dose-escalation study in humans designed to evaluate the safety, tolerability, and pharmacokinetics of tiragolumab as a single agent in patients with tumors. This is assessed in the Phase Ia portion of the study.

This study also included patients with locally advanced, recurrent, or metastatic refractory tumors for which standard therapy did not exist, demonstrated ineffective or intolerable, or considered inappropriate; or in combination with standard of care in patients for whom clinical trials of an investigational product are considered the accepted standard of care, or for which clinical trials of an investigational product using anti-PD-L1 antibodies are considered an acceptable treatment option. designed to enable evaluation of the safety, tolerability, and PK of tiragolumab when administered as It is studied in multiple cohorts of the Phase Ib portion of the study.

Ib상: 티라골루맙 및 아테졸리주맙의 용량 증량 코호트(도 4)

Phase Ib: Dose Escalation Cohort of Tiragolumab and Atezolizumab (Figure 4)

Ib상: 티라골루맙 및 아테졸리주맙의 적응증별 확장 코호트(도 4)

Phase Ib: Indication-Specific Expansion Cohort of Tiragolumab and Atezolizumab (Figure 4)

Ib상: 티라골루맙 및 아테졸리주맙의 연속 생검 코호트(도 4)

Phase Ib: Serial Biopsy Cohort of Tiragolumab and Atezolizumab (Figure 4)

Ib상: 티라골루맙 및 아테졸리주맙의 4주마다(Q4W) 투약 확장 코호트(도 4)

Phase Ib: Every 4 weeks (Q4W) Dosing Expansion Cohort of Tiragolumab and Atezolizumab (Figure 4)

Ib상: 화학요법을 병용한 티라골루맙 및 아테졸리주맙의 확장 코호트(코호트 A 내지 코호트 D; 도 5)

Phase Ib: Expansion Cohort of Tiragolumab and Atezolizumab in Combination Chemotherapy (Cohort A to Cohort D; FIG. 5)

Ib상: 비화학요법을 병용한 티라골루맙의 확장 코호트(코호트 NC1 및 NC2; 도 6)

Phase Ib: Expansion cohort of tiragolumab with non-chemotherapy (cohorts NC1 and NC2; FIG. 6 )

The Phase Ib portion of this study will be activated after DLT assessments for at least two dose levels of single agent tyragolumab have been completed and all relevant single agent safety data have been thoroughly reviewed with the investigator and IMC. When deemed appropriate, the Phase Ib portion will be initiated at a dose level below the initial tiragolumab dose level using the same dose escalation plan and comprehensive safety monitoring plan as in the Phase Ia portion. In addition, patients undergoing the Phase Ia portion of the study with single agent tiragolumab may be offered the option to transition to the Phase Ib portion of the study.

Both the Phase Ia and Ib portions of the study consist of a screening period, a treatment period, and a post-treatment follow-up period. Patients are enrolled in two phases, a dose escalation phase and a dose expansion phase; See Figures 3 and 4 for phase Ia and Ib. Figure 4 further depicts serial biopsies and Q4W cohorts, while Figure 5 depicts the Phase Ib chemotherapy expansion cohort and Figure 6 depicts the Phase Ib non-chemotherapy expansion cohort. During the dose escalation phase, cohorts of approximately 3 to 6 patients each are evaluated at the escalating dose level to determine the MTD or maximum administered dose (MAD) for tiragolumab as a single agent or in combination with atezolizumab. To obtain additional safety and pharmacodynamic data to more fully inform dose selection for the expansion cohort, additional patients may be enrolled for cohort replenishment at dose levels shown not to exceed the relevant MTD according to the dose escalation criteria described below. have. For purposes of dose escalation decisions, the patient is not included as part of the DLT evaluable population.

In the dose expansion phase, patients are enrolled and treated below the MTD or MAD of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab and/or other anticancer therapies (Phase Ib).

Tiragolumab as a single agent (Phase Ia), or a combination of Tiragolumab and Atezolizumab, Tiragolumab and Atezolizumab and Bevacizumab, or Tiragolumab and Pembrolizumab (Phase Ib cohort without chemotherapy) ) are administered by IV infusion on Day 1 of each 21-day cycle and on Day 1 of each 28-day cycle (Phase Ib Q4W dosing extension). Tiragolumab is administered before atezolizumab, bevacizumab, or pembrolizumab in the Phase Ib cohort without chemotherapy. In the absence of unacceptable toxicity or strong clinical evidence of disease progression, tiragolumab (Phase Ia) or atezolizumab and/or other anticancer therapies should be combined based on a favorable assessment of the investigator's benefits and risks. Treatment with concomitant tiragolumab (Phase Ib) can be continued after cycle 1.

A safety investigation of 3 patients was completed in the Phase Ib chemotherapy and non-chemotherapy expansion cohorts and in the Phase Ib Q4W dosing expansion cohort. All relevant safety data from the safety search will be thoroughly reviewed by the IMC and investigators prior to continuing registration.

Tiragolumab and atezolizumab in combination with specific chemotherapy in each of the four chemotherapy expansion cohorts: carboplatin or cisplatin and pemetrexed in Cohort A, carboplatin and paclitaxel in Cohort B, and carbople in Cohort C Latin or cisplatin and etoposide, capecitabine in cohort D. In cohorts A, B, and C, treatment consists of an induction phase and a maintenance phase. In the induction phase, the combination of tiragolumab and atezolizumab in combination with chemotherapy is administered via IV infusion at 21 day cycles for 4 to 6 cycles for Cohort A and B and 4 cycles for Cohort C. do. The number of induction treatment cycles for Cohort A and Cohort B is at the discretion of the investigator.

After the induction phase, patients who have not experienced disease progression or unacceptable toxicity continue treatment with maintenance therapy. During this maintenance phase, patients in Cohort B and Cohort C continue to receive tiragolumab and atezolizumab alone, while patients in Cohort A continue to receive tiragolumab and atezolizumab in combination with pemetrexed.

In this maintenance phase, Cohort A continues with a 21-day cycle with atezolizumab, tiragolumab and pemetrexed. In Cohort B, patients enrolled in protocol GO30103 version 4 continue their 21-day cycle with atezolizumab and tiragolumab. In Cohort B, patients enrolled in protocol GO30103 version 5 or later begin a 28-day cycle with atezolizumab and tiragolumab. Cohort C begins a 28-day cycle with atezolizumab and tiragolumab.

In Cohort D, patients are treated with tiragolumab, atezolizumab and capecitabine until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Patients are orally administered capecitabine at a dose of 1250 mg/m ² twice daily (BID) from days 1 to 14 of each 21-day cycle. The first dose of capecitabine on Day 1 of Cycle 1 is administered at the hospital prior to the atezolizumab and tiragolumab infusions. The combination of tiragolumab and atezolizumab is administered as an IV infusion on a 21-day cycle.

In all chemotherapy expansion cohorts, atezolizumab is administered before tiragolumab.

All patients are closely monitored for adverse events throughout the study. Adverse events are graded according to NCI CTCAE v4.0.

To characterize the PK properties, immunogenic response, and pharmacodynamic effects of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) at various time points before and after dosing a blood sample is taken from Depending on the results of the interim PK analysis, the frequency of PK sampling may be reduced later in the study.

Patients receive tumor assessments during screening and study, as measured by the Standard Response Evaluation Criteria for Solid Tumors (RECIST) v1.1 criteria.

Patients may continue to receive study treatment even if the standard RECIST v1.1 criteria for disease progression in the Phase Ia or Ib portion of the study are met, provided they meet the criteria for continued treatment ( FIG. 7 ). Patients who withdraw from the Phase Ia portion of the study may be transferred to the Phase Ib portion of the study and receive treatment with tiragolumab in combination with atezolizumab, provided they meet the crossover criteria and consent to a biopsy of an accessible lesion. There is (Fig. 8).

Tiragolumab (Phase Ia) or tiragolumab and atezolizumab, chemotherapy in addition to tiragolumab and atezolizumab, bevacizumab in addition to tiragolumab and atezolizumab, or tiragolumab and pembrolizumab ( Patients who permanently discontinue phase Ib) must return to the hospital for a treatment discontinuation visit within 30 days of administration of the last dose of study treatment. Additional monitoring and documentation of adverse events of particular interest should be performed for up to 90 days after administration of the last dose of study treatment, irrespective of initiation of other systemic anticancer therapies. Monitoring and documentation of all other adverse events will occur for up to 90 days after administration of the last dose of study treatment, or until initiation of other anticancer systemic therapy, whichever occurs first. All patients in the study are followed for survival and follow-up anti-cancer therapy information approximately every 3 months until death, loss of follow-up, or study termination, unless the patient requests withdrawal from follow-up.

The IMC periodically evaluates the cumulative safety data of all patients treated in this study. Safety summary data will be assessed by IMC after completion of DLT assessments for the first two dose cohorts in the Phase Ia (single-agent tyragolumab) portion of the study. The IMC reviewed safety data and recommended whether to continue enrollment without protocol change in Phase Ia and begin enrollment in the Phase Ib portion of the study with tiragolumab in combination with atezolizumab to review safety data in the safety exploratory cohort; , continue enrollment in the Phase Ib chemotherapy expansion cohort, non-chemotherapy expansion cohort, and Q4W dosing expansion cohort, modifying safety monitoring and/or eligibility criteria to add additional safety reviews to address new safety issues, or end the study recommend whether to If there are no safety issues to rule out, proceed with study subject development in the Phase Ia portion of the study while the safety analysis proceeds.

To further mitigate potential unexpected adverse events, the IMC also periodically reviews the safety data of patients entered into the expansion cohorts of the Phase Ia and Phase Ib portions of the study, particularly based on new trial safety data, to conduct studies. Ensure patient safety while receiving study treatment by providing recommendations on The interim analysis of futility by the IMC also occurs in the phase Ia and phase Ib expansion cohorts. In addition, the Medical Monitor may request additional safety reports and may request an ad hoc meeting of the IMC at any time during the study to review ongoing safety data on risk-benefit balances.

During the dose escalation phase, at least 3 patients at each tiragoluumab dose level are treated according to the dose escalation rules described below to determine the MTD or MAD of tiragolumab as a single agent or in combination with atezolizumab. Staggered enrollment of the first 3 patients into each new dose escalation cohort investigating a new dose level of tyragolumab in Phase Ia or Ib ensures that each Cycle 1 and Day 1 treatment is administered ₃7 days apart . All patients will be closely monitored for adverse events during the DLT evaluation period, which is defined as Day 21 (Days 1-21 of Cycle 1).

Any dose escalation patient who does not complete the DLT assessment period for reasons other than DLT will be considered not eligible for assessment for dose escalation decisions and MTD assessments and may be replaced by an additional patient at that same dose level. Patients receiving supportive care during the DLT assessment period that would confound the assessment of DLT (not including supportive care as described below) may be substituted at the discretion of the Medical Monitor. A patient with any component of the study treatment maintained during the DLT evaluation period for reasons other than DLT to the extent that administration of the next scheduled dose is delayed by more than 7 days is considered not evaluable for dose escalation decisions and MTD or MAD evaluation. considered and may be replaced by additional patients at that same dose level.

Patients receiving treatment in the Phase Ia portion of the study and developing disease progression with tyragolumab alone may be eligible for treatment in the Phase Ib portion of the study ( FIG. 8 ). However, in this case, certain qualification criteria for conversion must be met.

Definition of dose limiting toxicity

In both the Phase Ia and Phase Ib portions of the study, any one of the following reactions is considered a DLT if it occurs during the DLT assessment period and is assessed by the investigator as related to the study treatment:

　3 등급의 비혈액성, 간 외 이상 반응으로서, 하기의 예외를 갖는 경우:

Grade 3 nonhematologic, extrahepatic adverse event with the following exceptions:

- Grade 3 nausea, vomiting or diarrhea returning to Grade ≤2 on ≤3 days with standard of care therapy within ≤3 days

- Grade 3 fatigue recovering to Grade ≤ 2 in ≤ 3 days

≤ Grade 3 fever (defined as >40°C for ≤ 24 hours)

- Grade 3 adverse reactions (defined as localized pain, irritation, or rash localized to the site of known or suspected tumor) with tumor redness that returns to Grade ≤2 within ≤ 7 days

- Grade 3 or higher laboratory values considered by the investigator to be asymptomatic and not clinically significant

- Grade 3 rash reversing to ≤ Grade 2 within ≤ 7 days with therapy equivalent to prednisone 10 mg/day or less

- Grade 3 arthralgia that can be adequately managed with supportive care or returns to ≤ Grade 2 within ≤ 7 days

- Grade 3 autoimmune thyroiditis or other endocrine abnormalities manageable with endocrine therapy that does not require initiation of systemic corticosteroids (excluding alternative steroids for adrenal insufficiency)

≥ Grade 4 neutropenia (> 500/μL absolute neutrophil count (ANC) lasting 7 days)

≥ Grade 3 febrile neutropenia <

≥ Grade 4 anemia

≥ Grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with clinically significant bleeding

> Grade 3 elevation of serum liver aminotransferase (ALT or AST) lasting >7 days

In patients with a grade 1 ALT or AST elevation at baseline due to liver metastasis, only ≥ 3 x baseline ≥ grade 3 elevations lasting > 7 days are considered DLTs.

≥ Grade 3 elevation of serum total bilirubin

ALT or AST > 3 × upper limit of normal (ULN) and total bilirubin > 2 × ULN

Capacity escalation rules

Enrollment begins first in the Phase Ia portion of the study. The starting dose of tiragolumab is 2 mg, administered IV every 21 days. The dose of tiragolumab is increased by a factor of 4 between successive dose levels, and the suggested approximate dose levels for evaluation for tiragolumab are 2 mg, 8 mg, 30 mg, 100 mg, 400 mg and 1200 mg. . The maximum dose increment between successive dose levels may be reduced. Based on new nonclinical efficacy, clinical safety, and/or clinical PK data, additional intermediate dose levels of tiragoluumab may be evaluated.

In addition to any DLTs, other available relevant demographic, adverse event, laboratory, dose administration, PK (if available), and pharmacodynamic (if available) data are reviewed prior to dose escalation decisions, which are reviewed by medical monitor personnel to ensure safety Conducted in consultation with a committee and investigator head comprising, but not limited to, professional scientists, statisticians, PK scientists, and/or clinical trial administrators.

Dose escalation is done according to the rules listed below.

A minimum of 3 patients are enrolled at each dose level (cohort).

If none of the first 3 DLT evaluable patients experienced a DLT during the DLT evaluation period, enrollment into the next cohort may proceed at the escalated dose level determined as described above.

If 1 of the first 3 DLT evaluable patients in a given cohort experiences a DLT, at least 3 additional patients at the same dose level are enrolled (eg, the cohort is expanded to 6 patients). If less than one-third of evaluable patients experience a DLT (eg, less than two out of six patients), the dose escalation may continue and enrollment into the next cohort may proceed at the increased dose level.

DLT per dose level in a cohort (eg, 2 or more of 6 patients) If a DLT is observed in at least 1/3 of evaluable patients, the MTD is exceeded and dose escalation is discontinued. The previous cohort is expanded to a minimum of 6 patients unless 6 patients have already been assessed at that level. However, if the dose level at which the MTD is exceeded is at least 2-fold higher than the previous dose level, patients on page 6 may be evaluated at the intermediate dose level.

If the MTD is exceeded at any dose level, the highest dose at which less than one third of DLT evaluable patients (ie, less than 2 out of 6 patients) experience a DLT is declared MTD.

If the MTD is not exceeded at any dose level, the highest dose administered in this study is declared MAD.

Any dose level that does not appear to exceed the MTD may be extended if warranted based on the investigator's assessment of non-DLT adverse events, including those occurring after Cycle 1 and those observed in the expansion cohort. .

Based on a review of available preliminary real-time safety data and available preliminary PK data (collected in Phase Ia and/or Ib studies), dose escalation in Phase Ia and/or Ib may be discontinued, limited, or appropriate. can be considered

After the DLT evaluation for the first two dosing cohorts in the Phase Ia portion of the study is completed, the Investigator and IMC review the safety data and recommend whether to activate the Phase Ib portion of the study. If it is deemed appropriate to activate phase Ib, registration may proceed simultaneously in both parts of the study. The starting dose of tiragolumab in combination with atezolizumab is 2 mg, and atezolizumab is administered as a fixed dose of 1200 mg IV, with both drugs administered every 21 days. The dose of tiragolumab in the Phase Ib portion of the study never exceeds the highest dose shown not to exceed the MTD in the Phase Ia portion of the study. If the combination MTD is exceeded in Cohort 1 of the Phase Ib portion of the study, a lower dose of tiragolumab in combination with atezolizumab may be considered.

To obtain additional safety and pharmacodynamic data to more fully inform dose selection for the expansion cohort, the Phase Ia and/or Ib portion of the study that was shown not to exceed the MTD or MAD based on the dose escalation criteria described above. Additional patients may be enrolled at the dose level. For the purposes of dose escalation decisions, the patient is not considered part of the DLT evaluable population. The patient must have a safely accessible tumor and consent to a biopsy. To inform evaluation of pharmacodynamics, patients with tumors expressing PD-L1 and/or TIGIT based on prospective examination of tumor tissue during screening or prescreening are enrolled. In addition, up to about 12 additional patients may be enrolled at the selected dose level in the Phase Ia or Ib study at MTD or MAD or below to provide additional safety data prior to initiating the dose expansion phase.

Patients who have developed radiographic disease progression only in the Phase Ia portion of the study or who no longer derive clinical benefit from the single agent tyragolumab have safely accessible tumors, consent to biopsy, and meet the specified criteria for conversion. may be eligible for treatment in the Phase Ib portion of the study.

Phase Ia and Phase Ib expansion phase

have locally advanced, recurrent, or metastatic refractory malignancies that have progressed following available standard therapy; for which standard therapies do not exist, have proven ineffective or intolerable, or have been deemed inadequate; Alternatively, patients for whom a clinical trial of an investigational product is the accepted standard of care will be enrolled in the study's expansion cohort. In only the Phase Ib portion of the study, patients with or without chemotherapy for which clinical trials of investigational agents in combination with anti-PD-L1/PD-1 antibodies or anti-VEGF antibodies are considered acceptable treatment options are expanded. may be enrolled in a cohort.

The expansion phase may include: atezolizumab, atezolizumab with chemotherapy, atezolizumab with bevacizumab, with or without chemotherapy, either as a single agent (Phase Ia) or with or without chemotherapy in certain cancer settings; or in combination with pembrolizumab (Phase Ib) to better characterize the safety, tolerability, PK variability, pharmacodynamic activity, and prospective anti-tumor activity of tiragolumab. Enrollment of the expansion cohort was based on assessment of accumulated safety, tolerability, PK, pharmacodynamics, and antitumor activity data as a single agent (Phase Ia) or as: atezolizumab, atezolizumab with chemotherapy; At a selected dose level below the MAD or MTD of atezolizumab with bevacizumab, or tiragolumab in combination with pembrolizumab (Phase Ib).

In the Phase Ia portion of the study, up to about 40 patients were diagnosed with PD-, including NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC, UBC, and CRC (including CRCs with low MSS or MSI) GEJ cancers. Enroll in the planned expansion cohort of L1 selected and/or TIGIT selected multiple tumor indications.

In the Phase Ib portion of the study (no chemotherapy), approximately 20-40 patients may be enrolled in multiple tumor indications, including the following planned indication-specific expansion cohorts:

NSCLC: 암 면역요법(CIT) 경험이 없음(예컨대, 항 PD-L1/PD-1의 선행 치료를 받지 않았음)

NSCLC: no cancer immunotherapy (CIT) experience (eg, no prior treatment with anti-PD-L1/PD-1)

NSCLC: CIT 치료됨(예컨대, 항 PD-L1/PD-1을 이용한 선행 치료를 포함)

NSCLC: CIT treated (including prior treatment with e.g. anti-PD-L1/PD-1)

RCC

RCC

TNBC

TNBC

흑색종

melanoma

HNSCC

HNSCC

OC

OC

GEJ 암을 포함한 GC

GC including GEJ cancer

UBC

UBC

CRC(MSS 또는 MSI이 낮은 CRC 포함)

CRC (including MSS or CRC with low MSI)

흑색종, OC, RCC 및 UBC를 포함한 특정 종양 징후의 생검 코호트

Biopsy cohort of specific tumor indications including melanoma, OC, RCC, and UBC

In the Phase Ib chemotherapy expansion portion of the study, approximately 20-40 patients may be enrolled in each of the following planned chemotherapy expansion cohorts ( FIG. 5 );

코호트 A:

Cohort A:

- induction phase - atezolizumab and tiragolumab in combination with cisplatin or carboplatin and pemetrexed

- Maintenance phase - Atezolizumab and Tiragolumab in combination with pemetrexed

코호트 B:

Cohort B:

- Induction phase - Atezolizumab and Tiragolumab in combination with carboplatin or paclitaxel

- Maintenance phase - Atezolizumab and Tiragolumab

코호트 C:

Cohort C:

- induction phase - atezolizumab and tiragolumab in combination with cisplatin or carboplatin and etoposide

- Maintenance phase - Atezolizumab and Tiragolumab

코호트 D:

Cohort D:

- Atezolizumab and Tiragolumab in combination with Capecitabine

In the Phase Ib Q4W expansion portion of the study, approximately 20-40 patients can be enrolled in the planned cohort (Figure 4).

In the Phase Ib non-chemotherapy expansion portion of the study, approximately 20-40 patients may be enrolled in each of the following planned non-chemotherapy expansion cohorts (Figure 6).

코호트 NC1:

Cohort NC1:

- Tiragolumab and atezolizumab in combination with bevacizumab

코호트 NC2:

Cohort NC2:

- Tiragolumab and Pembrolizumab

Only CIT-naive patients for whom clinical trials of an investigational agent in combination with its anti-PD-L1 antibody are considered an acceptable treatment option are considered eligible for enrollment in the relevant expansion cohort of the Phase Ib portion of the study. Otherwise, the patient will be assigned an available expansion slot in either the Phase Ia or Phase Ib portion of the study at the discretion of the Investigator.

Given that the safety profile of tiragolumab as a single agent (Phase Ia) or tiragolumab in combination with atezolizumab (Phase Ib) may not be fully characterized after patient evaluation in the dose escalation phase, upon enrollment in the expansion cohort Not all potential adverse events or their likelihood of occurrence are known. All available safety data are continuously evaluated to assess tolerability of the dose level studied. To further mitigate potential unexpected adverse events, the IMC also periodically reviews the safety data of all patients entered into the expansion cohorts of the Phase Ia and Ib portions of the study and makes recommendations regarding study conduct related to patient safety. provides If the frequency of Grade 3 or 4 toxicity or other unacceptable toxicity observed in the expansion phase cohort suggests that the MTD was exceeded at that dose level in Phase Ia or Ib, discontinue occurrence of study subjects at that dose level. . Then, resumption of registration is considered in the expansion phase of the lower capacity level. In addition, accumulating safety, tolerability, PK, or pharmacodynamic data suggest that the dose level in the expansion cohort is not relevant for the preliminary antitumor activity evaluation of tiragolumab as a single agent (Phase Ia) or tyragolumab in combination with atezolizumab (Phase Ib). Enrollment of new patients in that cohort at a different dose level should be considered if suggesting suboptimal liability for suboptimal treatment. The dose level studied in the phase Ia or phase expansion phase never exceeds the highest dose level shown not to exceed the MTD at each dose escalation phase in phase Ia or Ib.

In the Phase Ib Chemotherapy Expansion Cohort, the Phase Ib Q4W Dosing Expansion Cohort, and the Phase Ib Non-chemotherapy Expansion Cohort, the IMC also assessed initial safety after all the first 3 patients in each cohort completed Cycle 1 of study treatment during the safety exploration. monitor (see FIG. 7). The IMC will review all safety data from the first three patients for that cohort to determine if the study treatment is acceptable, where the IMC and investigator will conduct an acceptable risk assessment to allow the patient to continue medication. If the study treatment is considered acceptable in each cohort's safety exploration, enrollment may continue with the same dose of tiragolumab in each cohort until an interim analysis of safety. This is done after approximately 20 patients, including those participating in the safety investigation, are enrolled.

The IMC also monitors the effectiveness of the expansion cohort in the Phase Ia and Phase Ib portions of the study by conducting an interim analysis after approximately 20 patients in each cohort have completed their first tumor assessment. If no investigator-dependent antitumor activity and/or clinical benefit is detected in that expansion cohort, enrollment may be discontinued as determined by the IMC in consultation with the study investigator. If an investigator-dependent antitumor activity and/or clinical benefit is detected in patients in that expansion cohort, the IMC may continue to enroll approximately 40 patients. The sample size of any expansion cohort beyond 40 evaluable patients does not increase. Patients who have consented to serial biopsies but do not have evaluable samples may be replaced with a subset of up to 40 evaluable patients to be enrolled in each expansion cohort.

Phase Ia Expansion Cohort

The goals of the Phase Ia expansion cohort were to better characterize safety, tolerability, PK and preliminary efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity in patients treated with tiragolumab at dose levels below the single agent MTD or MAD. will do The cohort consists of approximately 20-40 patients with PD-L1-selected and/or TIGIT-selected tumors. Enrollment is initially limited to patients with the following tumor types: NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC including GEJ cancer, UBC and CRC including low MSS and MSI. If investigator-dependent antitumor activity and/or clinical benefit is observed in the study in patients with other tumor types, the enrollment may be expanded and/or modified to include other indications.

Up to about half of patients enrolled in this cohort on Phase Ia must have safely accessible tumor lesions and consent to pre- and intra-treatment biopsies (core needle, punch, forceps, or excision/amputation). Additional patients may be enrolled so that approximately half of the patients in this cohort receive evaluable serial biopsies with sufficient viable tumor content.

Patients who have developed radiographic disease progression in the Phase Ia expansion cohort or who no longer derive clinical benefit from the single agent tyragolumab may be eligible for transition and treatment to the Phase Ib portion of the study ( FIG. 8 ). . However, in this case, the patient must have a safely accessible tumor, consent to a biopsy, and meet the specified criteria for conversion.

Expansion Cohort by Phase Ib Indication

The goal of the Phase Ib indication-specific expansion cohort is to better characterize safety, tolerability, PK, and preliminary efficacy data, and patients with specific cancer types treated with tyragolumab at dose levels below its MTD or MAD in combination with atezolizumab. to explore potential tumor biomarkers of pharmacodynamic activity in Expansion cohorts for each indication were selected for PD-L1 and/or TIGIT based on prospective examination of tumor tissue during screening or prescreening, and the maximum with tumors covering multiple tumor indications, including the following tumor types: About 20 patients are first enrolled.

NSCLC: CIT 미경험

NSCLC: CIT inexperienced

상기 환자들은 항 PD-L1/PD-1 및/또는 항 CTLA-4를 포함하여 선행 CIT(조사 또는 승인)를 받은 적이 없으며, 항 PD-L1 항체와 병용한 임상 시험이 허용 가능한 치료 선택사항으로 간주되는 경우에만 등록할 수 있다.

These patients have not received any prior CITs (investigation or approval), including anti-PD-L1/PD-1 and/or anti-CTLA-4, and clinical trials with anti-PD-L1 antibodies are considered acceptable treatment options. You can only register if it is considered.

NSCLC: CIT 치료됨

NSCLC: CIT treated

These patients have had prior CIT (investigation or approval) with anti-PD-L1/PD-1.

TNBC

TNBC

RCC

RCC

CRC

CRC

위식도 접합부(GEJ) 암을 포함한 위암(GC)

Gastric cancer (GC), including gastroesophageal junction (GEJ) cancer

HNSCC

HNSCC

UBC

UBC

흑색종

melanoma

OC

OC

After enrolling 20 patients, the IMC will also conduct an interim analysis to determine if there is evidence of investigator-assessed antitumor activity and/or clinical benefit to continue enrolling approximately 40 patients.

Up to about half of patients enrolled in the above indication-specific expansion cohort on phase Ib must have safely accessible tumor lesions and consent to pre- and intra-treatment biopsies (e.g., core needle, punch, forceps, or excision/amputation biopsies) do. Additional patients may be enrolled so that approximately half of the patients in this cohort receive evaluable serial biopsies with sufficient viable tumor content.

Phase Ib Serial Biopsy Expansion Cohort

The purpose of the Phase Ib serial biopsy expansion cohort was to explore potential tumor biomarkers of pharmacodynamic activity and safety, safety, and safety in patients with certain cancer types treated with tyragolumab at dose levels below the MTD or MAD in combination with atezolizumab; To better characterize tolerability, PK and preliminary efficacy data. The cohort consists of approximately 20-40 patients selected for PD-L1 and/or TIGIT based on prospective examination of tumor tissue during screening or prescreening, and may include the following tumor types.

흑색종

melanoma

RCC

RCC

OC

OC

UBC

UBC

Patients enrolled in the continuous biopsy expansion cohort must have two tumor biopsies and therefore must have safely accessible tumor lesions: 1) Pre-treatment biopsy: After all eligibility criteria (except the requirement for available storage tissue) have been met and at baseline prior to dosing of study drug, and 2) on-treatment biopsy: approximately 2 weeks after the first dose of tiragoluumab in combination with atezolipzumab (days 15-21 of Cycle 1 or in between). RECIST target lesions are not biopsied.

Tissue biopsy methods may include core needle, punch, forceps, or excision/incision biopsy. Patients providing the necessary fresh biopsies should also submit archival tumor specimens, if available.

In this serial biopsy cohort, a recent archived specimen may be used instead of an up-to-date baseline biopsy in the following circumstances:

표본이 샘플 기준(예컨대, 코어 수 또는 펀치 크기)을 충족한다.

The specimen meets sample criteria (eg number of cores or punch size).

표본이 제안된 주기 1, 1일의 3개월 이내에 또는 의학 모니터가 승인한 간격 내에서 수집되었다.

Specimens were collected within 3 months of the proposed cycle 1, day 1, or within intervals approved by the medical monitor.

표본이 가장 최근의 전신 요법 및/또는 관련 해부학적 부위에 투여된 임의의 방사선 요법 이후에 수집되었다.

Specimens were collected following the most recent systemic therapy and/or any radiation therapy administered to the relevant anatomical site.

표본이 치료 중 생검의 제안된 부위와 동일한 병변 또는 기관에서 유래한다.

The specimen is from the same lesion or organ as the proposed site of the biopsy during treatment.

Patients whose baseline biopsy has been found not to be evaluable (ie, due to insufficient material or insufficient tumor cells in the sample) will still receive study treatment and be considered for an on-treatment biopsy. Such patients, and those whose biopsies have been found not to be evaluable on treatment, or those whose biopsies do not have sufficient viable tumor content, may be replaced for purposes of continuous biopsy evaluation. Additional optional biopsies may be collected at the discretion of the investigator, preferably at the time of the radiation response or progression.

Selective biopsy of expansion cohorts

Patients enrolled in the expansion cohort should consider elective biopsies (e.g., core needle, punch, forceps, or excision/incision biopsy) to explore pharmacodynamic changes associated with the activity of tiragolumab as a single agent or in combination with atezolizumab. are asked to do Enrollment in each expansion cohort is administered so that up to about half of the patients who develop as study subjects have safely accessible tumor lesions and agree to undergo such elective biopsies. The recommended biopsy time point in this scenario is the same as described above: at baseline after all eligibility criteria (except for the requirement for available storage tissue) have been met, and at approximately 2 weeks after the first dose of tiragolumab. (Day 15-21 of Cycle 1 and in between).

If baseline samples are not evaluable and no comparable recent archival specimens are available, an on-treatment biopsy is not required. Patients with non-evaluable baseline or on-treatment biopsies (ie, biopsies that do not have sufficient viable tumor content) may be replaced for purposes of continuous biopsy evaluation.

Patients offering elective biopsies should also submit archival tumor specimens, if available.

Phase Ib Chemotherapy Expansion Cohort

The purpose of the Phase Ib chemotherapy expansion cohort is to better characterize safety, tolerability, pharmacokinetics, and preliminary efficacy data in patients treated with atezolizumab and tiragolumab in combination with chemotherapy, and to better characterize potential pharmacodynamic activity Searching for tumor biomarkers.

Each cohort consists of approximately 20-40 patients with tumors capable of PD L1 selection and/or TIGIT selection based on prospective examination of tumor tissue during screening or prescreening. Patients with insufficient or unavailable archival tissue may be eligible for enrollment in this cohort if permitted by the Medical Monitor based on discussion with the investigator. Patients with tumor types for which clinical trials of investigational agents in combination with chemotherapy and anti-PD-L1 antibodies are considered acceptable treatment options may be enrolled in this expansion cohort. The number of patients with a specific tumor type (eg, NSCLC, SCLC, TNBC) or with a specific treatment history (eg, CIT naive) may be limited in each study cohort.

Treatment combinations for each cohort are shown in Table 29.

treatment cohort induction period
(4 or 6 times in a 21-day cycle) retainer
(21-day cycle ^a or 28-day cycle ^b ) A Atezolizumab + Tiragolumab + Pemetrexed + Cisplatin or Carboplatin Atezolizumab +
Tiragolumab + Pemetrexed B Atezolizumab + Tiragolumab + Paclitaxel + Carboplatin Atezolizumab +
Tiragolumab C Atezolizumab + Tiragolumab + Cisplatin or Carboplatin + Etoposide Atezolizumab +
Tiragolumab
D Atezolizumab + Tiragolumab + Pemetrexed ^a For patients in cohort A, cohort B (enrolled according to protocol GO30103 version 4) and cohort D with Q3W maintenance period.
^a For patients in cohort B (enrolled according to protocol GO30103 version 5 or later) and cohort C with Q4W maintenance phase.

Treatment regimens in the chemotherapy expansion cohort

Each cohort has an initial safety search for 3 patients (see Figure 5). After the first 3 patients in a cohort have completed 21 days of study treatment (i.e., Days 1 to 21 of Cycle 1), the IMC will review the first 3 patients in that cohort to determine whether the study treatment is tolerated. All safety data are reviewed, where the IMC and investigators perform an acceptable risk assessment to allow the patient to continue on atezolizumab and tiragolumab. Patients who do not complete the first 21 days of treatment for reasons other than treatment-related toxicity may be replaced with additional patients at the same dose level. If, after at least 3 patients have enrolled and completed 21 days of study treatment, if the study treatment is deemed acceptable in a safety investigation for a cohort by the IMC, then enrollment in that cohort will continue until a total of approximately 20 patients have been enrolled. can continue The IMC reviews efficacy data for the first approximately 20 patients in each cohort to evaluate safety and efficacy. If the IMC determines that there is a favorable benefit-risk, enrollment in that cohort may continue until a total of approximately 40 patients.

If the 600 mg dose of tiragolumab is not tolerated during the safety investigation in any cohort, the safety investigation may be initiated at the lower dose of tiragoluumab for 3 additional patients enrolled in that cohort. Safety data for the low-dose group will be assessed after the first 3 patients in this cohort have completed 21 days of study treatment (Days 1-21 of Cycle 1). About 3 additional patients will then be enrolled in the safety expedition to further evaluate the safety and tolerability of tiragolumab at this lower dose. Only the dose of tiragolumab can be reduced; The dose of atezolizumab does not change. Dosage adjustment of chemotherapy, if necessary, follows the guidelines below. If the lower dose of the study treatment is well tolerated, continue enrollment at the lower dose until a total of about 20 patients have been enrolled in each cohort, including those undergoing safety exploration of the lower dose. The IMC evaluates safety and efficacy by reviewing data from 20 patients in each cohort. If the IMC determines that there is a favorable benefit-risk, then enrollment in that cohort may continue until a total of about 40 patients at the lower dose.

Tiragolumab at a dose of 600 mg is well tolerated during the safety exploration period and new clinical PK data (e.g., PK data differs from chemotherapy) and/or pharmacodynamic data (e.g., receptor occupancy) at higher doses of tyra If the use of golumab is implied, a safety investigation is initiated at the higher dose of tiragolumab for the next three patients enrolled in each cohort. This higher dose does not exceed 1200 mg every 3 weeks, which is the highest evaluated dose for MTG7192A in both the Phase Ia and Ib portions of this study, observed to be greater than that observed at the 1200 mg dose level every 3 weeks. There is no maximum concentration (C _max ). If the study treatment at the high-dose tiragolumab is well tolerated, enrollment continues in the high-dose safety expedition until a minimum of 6 patients have been enrolled and complete 21 days of study treatment. If the high-dose study treatment is judged to be well tolerated in a safety investigation by the IMC, enrollment with the high-dose tiragolumab may continue until a total of approximately 20 patients have been enrolled in each cohort. The IMC reviews data from the first 20 patients in each cohort to evaluate safety and efficacy. If the IMC determines that there is a favorable benefit-risk profile, then enrollment in that cohort may continue until a total of about 40 patients at that higher dose.

Phase Ib Chemotherapy Expansion Cohort: Dose and Dosing

Patients in Cohort A, Cohort B, and Cohort C may receive treatment in two phases: the induction phase and the maintenance phase. In the induction phase, patients in certain chemotherapy expansion cohorts receive the following doses and administrations:

코호트 A는 21일 주기의 제 1일마다 아테졸리주맙 1200　mg IV 후에 티라골루맙 600 mg IV에 이어서 페메트렉시드 500　mg/m² IV에 이어서 시스플라틴 75　mg/m² IV 또는 카보플라틴 AUC 6　mg/mL·min IV를 투여 받는다. 질병 진행이나 허용할 수 없는 독성이 없는 경우, 4 내지 6회 주기의 유도기 치료가 실시된다.

Cohort A was atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV followed by pemetrexed 500 mg/m ² IV followed by cisplatin 75 mg/m ² IV or carboplatin AUC 6 every day 1 of a 21-day cycle. mg/mL·min IV is administered. In the absence of disease progression or unacceptable toxicity, 4 to 6 cycles of induction phase treatment are administered.

코호트 B는 21일 주기의 제 1일마다 아테졸리주맙 1200　mg IV 후에 티라골루맙 600 mg IV에 이어서 파클리탁셀 200　mg/m² IV에 이어서 카보플라틴 AUC 6 mg/mL·min IV를 투여 받는다. 질병 진행이나 허용할 수 없는 독성이 없는 경우, 4 내지 6회 주기의 유도기 치료가 실시된다.

Cohort B receives atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV followed by paclitaxel 200 mg/m ² IV followed by carboplatin AUC 6 mg/mL min IV on Day 1 of a 21-day cycle. In the absence of disease progression or unacceptable toxicity, 4 to 6 cycles of induction phase treatment are administered.

코호트 C는 매 21일 주기의 제 1일에 아테졸리주맙 1200　mg IV 후에 티라골루맙 600 mg IV에 이어서 시스플라틴 75　mg/m² IV 또는 카보플라틴 AUC 5　mg/mL·min IV 다음으로 매 21일 주기의 제 1일 내지 3일에 에토포시드 100　mg/m² IV를 투여 받는다. 질병 진행이나 허용할 수 없는 독성이 없는 경우, 4회 주기의 유도기 치료가 실시된다.

Cohort C was atezolizumab 1200 mg IV followed by tiragolumab 600 mg IV on day 1 of every 21-day cycle followed by cisplatin 75 mg/m ² IV or carboplatin AUC 5 mg/mL min IV then every 21 Etoposide 100 mg/m ² IV is administered on days 1 to 3 of the cycle. In the absence of disease progression or unacceptable toxicity, 4 cycles of induction treatment are administered.

For Cohort A and Cohort C, the choice of cisplatin or carboplatin is at the discretion of the investigator, although the number of patients receiving certain platinum-based chemotherapeutic agents may be limited. For Cohort A and Cohort B, the number of cycles administered in the induction phase (4-6) is at the discretion of the investigator.

After the induction phase, if there is no unacceptable toxicity, clinically serious disease progression, and/or loss of clinical benefit, at the discretion of the investigator after careful evaluation and thorough discussion of potential risks and benefits with the patient, the maintenance phase continue treatment at

In the maintenance phase, study treatment continues every Q3W for Cohort A, Cohort B enrolled according to protocol version 4, and Cohort D, or continues every Q4W for Cohort B enrolled according to protocol version 5 or later and Cohort C .

In the maintenance phase, patients in certain chemotherapy expansion cohorts receive the following doses and administrations:

코호트 A는 매 21일 주기의 제 1일에 아테졸리주맙 1200 mg IV, 티라골루맙 600 mg IV, 페메트렉시드 500 mg/m² IV를 받는다.

Cohort A receives atezolizumab 1200 mg IV, tiragolumab 600 mg IV, pemetrexed 500 mg/m ² IV on Day 1 of every 21-day cycle.

코호트 B는 매 28일 주기의 제 1일에 아테졸리주맙 1680 mg IV를 받은 다음 티라골루맙 840 mg IV를 받는다. 환자가 GO30103 버전 4에 등록된 경우, 코호트 B의 환자는 매 21일 주기의 제 1일에 아테졸리주맙 1200 mg IV 및 티라골루맙 600 mg IV를 계속 투여받는다.

Cohort B receives atezolizumab 1680 mg IV followed by tyragolumab 840 mg IV on Day 1 of every 28-day cycle. If patients are enrolled in GO30103 version 4, patients in Cohort B continue to receive atezolizumab 1200 mg IV and tiragolumab 600 mg IV on Day 1 of every 21-day cycle.

코호트 C는 매 28일 주기의 제 1일에 아테졸리주맙 1680 mg IV를 받은 다음 티라골루맙 840 mg IV를 투여 받는다.

Cohort C receives atezolizumab 1680 mg IV followed by tiragolumab 840 mg IV on Day 1 of every 28-day cycle.

Patients in Cohort D are treated with capecitabine, atezolizumab, and tiragolumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Patients receive orally capecitabine at a dose of 1250 mg/m ² BID from Days 1 to 14 of each 21-day cycle. The first dose of capecitabine on Day 1 of Cycle 1 is administered at the hospital prior to the atezolizumab and tiragolumab infusions. The combination of atezolizumab and tiragolumab is administered as an IV infusion with a 21-day cycle.

Individual chemotherapy or immunotherapeutic agents may be independently discontinued if toxic and without disease progression or loss of clinical benefit. However, treatment with atezolizumab alone or tiragolumab alone (with or without chemotherapy) may be considered with no contraindications and only after discussion with a medical monitor.

Phase Ib Q4W Dosing Expansion Cohort

The objective of the Phase Ib Q4W Dosing Expansion Cohort was to evaluate safety, tolerability, PK, and to better characterize preliminary efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity.

The Phase Ib Q4W cohort consists of approximately 20-40 patients with tumors capable of PD L1 selection and/or TIGIT selection based on prospective examination of tumor tissue during screening or prescreening. Patients with insufficient or unavailable archival tissue may be eligible for enrollment in this cohort if permitted by the Medical Monitor based on discussion with the investigator. Patients with tumor types for which clinical trials of investigational agents in combination with anti-PD-L1 antibodies are considered acceptable treatment options may be enrolled in this expansion cohort. The number of patients with a specific tumor type (eg, NSCLC, SCLC) or with a specific treatment history (eg, CIT naive) may be limited in each study cohort.

In each cohort there is an initial safety exploration of 3 patients (see Figure 4). After the first 3 patients in a cohort have completed 28 days of study treatment (i.e., Days 1-28 of Cycle 1), the IMC will review the first 3 patients in that cohort to determine whether the study treatment is tolerated. All safety data are reviewed, where the IMC and investigators conduct an acceptable risk assessment to allow the patient to continue treatment with tiragolumab in combination with atezolizumab. Patients who do not complete the first 28 days of treatment for reasons other than treatment-related toxicity may be replaced with additional patients at the same dose level. If, after at least 3 patients have enrolled and the study treatment has been completed for 28 days, if the study treatment is deemed acceptable in a safety investigation for a cohort by the IMC, then enrollment in that cohort will continue until a total of approximately 20 patients have been enrolled. can continue The IMC reviews efficacy data for the first approximately 20 patients in each cohort to evaluate safety and efficacy. If the IMC determines that there is a favorable benefit-risk, enrollment in that cohort may continue until a total of approximately 40 patients.

If the 840 mg dose of tiragolumab is not tolerated during the safety investigation in any cohort, the safety investigation may be initiated at the lower dose of tiragoluumab for 3 additional patients enrolled in that cohort. Safety data for the low-dose group will be assessed after the first 3 patients in this cohort have completed 28 days of study treatment (Days 1-28 of Cycle 1). About 3 additional patients will be enrolled in the safety expedition to further evaluate the safety and tolerability of tiragolumab at this lower dose. Only the dose of tiragolumab can be reduced; The dose of atezolizumab does not change. If the lower dose of the study treatment is well tolerated, continue enrollment at the lower dose until a total of about 20 patients have been enrolled in each cohort, including those undergoing safety exploration of the lower dose. The IMC evaluates safety and efficacy by reviewing data from 20 patients in each cohort. If the IMC determines that there is a favorable benefit-risk, then enrollment in that cohort may continue until a total of about 40 patients at the lower dose.

If the 840 mg dose of tiragolumab is well tolerated during the safety exploration period, and new clinical PK data and/or pharmacodynamic data (e.g., receptor occupancy) suggest the use of a higher dose of tiragolumab, each cohort Initiate a safety investigation at higher doses of tiragolumab in the next three patients enrolled. This higher dose does not exceed 1200 mg, which is the maximum evaluated dose for MTG7192A in both the Phase Ia and Ib portions of this study, and the maximum observed concentration greater than that observed at the 1200 mg dose level every 3 weeks. (C _max ) is absent. If the study treatment at the high-dose tiragolumab is well tolerated, enrollment continues in the high-dose safety expedition until a minimum of 6 patients have been enrolled and complete 28 days of study treatment. If the high-dose study treatment is judged to be well tolerated in a safety investigation by the IMC, enrollment with the high-dose tiragolumab may continue until a total of approximately 20 patients have been enrolled in each cohort. The IMC reviews data from the first 20 patients in each cohort to evaluate safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, then enrollment in that cohort continues until a total of about 40 patients at the higher dose.

Phase Ib Non-chemotherapy Expansion Cohort

The purpose of the Phase Ib non-chemotherapy expansion cohort was to provide further safety, tolerability, and preliminary efficacy data in patients treated with tiragolumab and atezolizumab in combination with bevacizumab and tiragolumab in combination with pembrolizumab. The goal is to explore well-characterized and potential tumor biomarkers of pharmacodynamic activity.

Each cohort consists of approximately 20-40 patients with tumors that can be selected for PD-L1 and/or TIGIT based on prospective examination of tumor tissue during screening or prescreening. Patients with insufficient or unavailable archival tissue may be eligible for enrollment in this cohort if permitted by the Medical Monitor based on discussion with the investigator. Patients with tumor types for which clinical trials of investigational agents with or without bevacizumab in combination with anti-PD-L1/PD-1 are considered acceptable treatment options at the discretion of the investigator are included in the expansion cohort. can be registered in The number of patients with a specific tumor type (eg, HCC, melanoma) or with a specific treatment history (eg, CIT naive) may be limited in each study cohort.

Treatment combinations for each cohort are shown in Table 30.

treatment cohort treatment regimen ^a
(21 day cycle) Cohort NC1 Tiragolumab + Atezolizumab + Bevacizumab Cohort NC2 Tiragolumab + Pembrolizumab ^a Drug administration sequence

Treatment Combinations by Cohort

There is an initial safety search for approximately 3 patients in each cohort ( FIG. 6 ). After the first 3 patients in a cohort have completed 3 weeks (Day 21) of study treatment (i.e., Days 1 to 21 of Cycle 1), the IMC will review the study treatment for that cohort to determine whether the study treatment is tolerated. All safety data from the first three patients are reviewed, where the IMC and investigator administer tiragolumab and atezolizumab (Cohort NC1) or tiragolumab and pembrolizumab (Cohort NC2) with bevacizumab to patients. Conduct an acceptable risk assessment to continue. Patients who do not complete the first 3 weeks of treatment for reasons other than treatment-related toxicity may be replaced with additional patients at the same dose level. If, after at least 3 patients have enrolled and the study treatment has been completed for 3 weeks, if the study treatment is deemed acceptable in a safety investigation for a cohort by the IMC, enrollment in that cohort will continue until a total of approximately 20 patients have been enrolled. can continue The IMC reviews efficacy data for the first approximately 20 patients in each cohort to evaluate safety and efficacy. If the IMC determines that there is a favorable benefit-risk, enrollment in that cohort may continue until a total of approximately 40 patients.

If a 600 mg dose of tiragolumab is not tolerated during a safety investigation in any cohort, a safety investigation at a lower dose of tiragoluumab may be initiated for approximately 3 additional patients enrolled in that cohort. Safety data for the low-dose group will be assessed after the first 3 patients in this cohort have completed 3 weeks of study treatment (Days 1-21 of Cycle 1). About 3 additional patients will then be enrolled in the safety expedition to further evaluate the safety and tolerability of tiragolumab at this lower dose. Only the dose of tiragolumab can be reduced; The dose of pembrolizumab or atezolizumab with bevacizumab does not change. If the lower dose of the study treatment is well tolerated, continue enrollment at the lower dose until a total of about 20 patients have been enrolled in each cohort, including those undergoing safety exploration of the lower dose. The IMC evaluates safety and efficacy by reviewing data from 20 patients in each cohort. If the IMC determines that there is a favorable benefit-risk, then enrollment in that cohort may continue until a total of about 40 patients at the lower dose.

If the 600 mg dose of tiragolumab is not tolerated during the safety investigation, a safety investigation may be initiated at the higher dose of tiragolumab for the next approximately 3 patients enrolled in each cohort. This higher dose does not exceed 1200 mg every 3 weeks, which is the maximum evaluated dose for tiragolumab in both the Phase Ia and Ib portions of this study, and the maximum concentration observed (C _max ) is 1200 every 3 weeks no greater than that observed at the mg dose level. If the study treatment at the high-dose tiragolumab is well tolerated, enrollment continues in the high-dose safety expedition until a minimum of 6 patients have been enrolled and have completed 3 weeks of study treatment. If the high-dose study treatment is judged to be well tolerated in a safety investigation by the IMC, enrollment with the high-dose tiragolumab may continue until a total of approximately 20 patients have been enrolled in each cohort. The IMC reviews data from the first 20 patients in each cohort to evaluate safety and efficacy. If the IMC determines that there is a favorable benefit-risk profile, then enrollment in that cohort may continue until a total of about 40 patients at that higher dose.

Decrease the dose of tiragolumab and atezolizumab and other non-chemotherapeutic agents

In general, there is no dose reduction of tiragolumab in this study. However, based on available cumulative safety data, if the dose level of tiragolumab initially selected as a single agent (Phase Ia) or in combination with atezolizumab (Phase Ib) exceeds the MTD or MAD, the dose level at that dose level Study subject development may be discontinued and further dose escalation will be discontinued, if applicable.

In this situation, the individual patient may reduce the dose to a new dose level of tiragoluumab if the following criteria are met:

환자의 초기 할당 용량이 추가 등록을 위해 마감된 용량 수준과 동일(또는 그 이상)함

The patient's initial allocated dose is equal to (or higher than) the dose level closed for further enrollment

시험자의 의견으로 전반적인 이익/위험 균형이 Ia상 또는 Ib상에서 계속 치료를 선호하게 함

The overall benefit/risk balance, in the opinion of the investigator, favors continued treatment in either Phase Ia or Ib

For atezolizumab, there is no intra-patient dose reduction; For atezolizumab, it is administered as a fixed dose of 1200 mg every 21 days or 1680 mg every 28 days (Q4W dose expansion cohort).

For bevacizumab, there is no intra-patient dose reduction; Bevacizumab is administered at a fixed dose of 15 mg/kg every 3 weeks.

For pembrolizumab, there is no intra-patient dose reduction; Pembrolizumab is administered as a fixed dose of 200 mg every 3 weeks.

Treatment after disease progression

Patients may receive study treatment in the Phase Ia or Ib portion of the study after standard RECIST v1.1 criteria for advanced disease have been met at the investigator's discretion after discussion with the medical monitor and if the patient meets all of the following criteria: We can continue (Fig. 7):

질병의 명백한 진행을 나타내는 증상 및 징후의 부재(실험실 값의 악화, 예컨대, 신규 또는 악화되는 고칼슘혈증을 포함)

Absence of symptoms and signs indicative of apparent progression of disease (including worsening laboratory values, e.g., new or worsening hypercalcemia)

이스턴 코퍼레이티브 종양학 그룹(ECOG) 전신 활동도의 저하 없음

Eastern Corporate Oncology Group (ECOG) No decline in systemic activity

반복 투약 전에 프로토콜이 허용하는 의학적 중재에 의해 쉽게 관리 및 안정화될 수 없는 중요한 해부학적 부위에서 종양 진행의 부재 중요한 해부학적 부위는 CNS, 중심 기도, 대혈관, 및 종양 진행에 부차적인 기능의 약화가 중증 및/또는 비가역적 장애 또는 사망을 급성으로 유발하는 것으로 예상되는 다른 기관 또는 조직을 포함한다.

Absence of tumor progression in critical anatomical sites that cannot be easily managed and stabilized by medical interventions permitted by the protocol prior to repeat dosing other organs or tissues expected to acutely cause severe and/or irreversible disability or death.

Patients must agree to accept on-treatment investigator discussions about the benefit-risk balance of continuing study treatment beyond radiological progression.

If radiological disease progression is confirmed at subsequent tumor assessments in Phase Ia or Ib, patients, after discussion with medical monitor personnel, if they continue to meet the above criteria and continue clinical benefit as evidenced by at least one of the following: may be considered for continued study treatment at the discretion of:

하나 이상의 평가 가능한 병변의 종양 수축(기준선에서 직경의 최소 30% 감소)

Tumor shrinkage of one or more evaluable lesions (minimum 30% reduction in diameter from baseline)

시험자가 평가한 기저 암으로 인한 하나 이상의 증상 또는 징후의 개선(예컨대, 통증에 대한 마약 요구량 감소, 흉수와 관련된 호흡곤란 감소, 체중 증가)

Improvement in one or more symptoms or signs due to the underlying cancer as assessed by the investigator (e.g., decreased drug demand for pain, decreased dyspnea associated with pleural effusion, weight gain)

Only in the Phase Ia portion of the study, patients treated with single agent tyragolumab, developing progressive disease, and/or no longer eliciting clinical benefit as outlined above, have safely accessible tumors, biopsy may be eligible to receive treatment in the Phase Ib portion of the study for tiragolumab in combination with atezolizumab if they consent to and meet the specified criteria for conversion.

In chemotherapy expansion cohorts A, B, C and D, treatment after disease progression must include immunotherapy with or without chemotherapy (atezolizumab and/or tiragolumab) and not chemotherapy alone do.

Conversion from single agent tiragolumab treatment to tiragolumab in combination with atezolizumab during progression

Patients who were treated with tyragolumab as a single agent in the Phase Ia portion of the study, develop progressive disease, and/or no longer induce clinical benefit, were treated with Tyra in combination with Atezolizumab in the Phase Ib portion of the study. may be eligible for treatment with goluumab ( FIG. 8 ). However, the following conditions must be met:

환자는 흉부, 복부 및 골반의 CT 스캔을 포함하여 연구의 Ia상 부분에서 방사선학적으로 문서화된 질병 진행이 있어야 한다.

Patients must have radiologically documented disease progression in the Phase Ia portion of the study, including CT scans of the chest, abdomen and pelvis.

환자는 티라골루맙 치료의 중단을 요구하는 독성을 경험한 적이 없어야 하며, Ib상 연구에서 티라골루맙 및 아테졸리주맙의 병용 치료를 배제하는 연구 치료제의 마지막 용량 동안 독성을 경험하지 않았어야 한다.

The patient must not have experienced any toxicity that would require discontinuation of tiragolumab treatment and should not have experienced toxicity during the last dose of study treatment that precludes combination therapy of tiragolumab and atezolizumab in a phase Ib study.

환자는 모든 선정 및 배제 기준을 충족해야 한다.

Patients must meet all inclusion and exclusion criteria.

임의의 티라골루맙 관련 이상 반응은 연구의 Ib상 부분에서 치료 첫날 또는 그 전에 1 이하의 등급 또는 기준선 등급으로 회복되었어야 한다. 시험자(들)가 환자와 이익-위험 균형에 대한 신중한 평가 및 논의를 한 후 그리고 의료 모니터 요원의 승인을 받아 예외가 허용될 수 있다.

Any tyragolumab-related adverse events must have resolved to a grade ≤ 1 or baseline grade on or before the first day of treatment in the Phase Ib portion of the study. Exceptions may be permitted after careful evaluation and discussion of the benefit-risk balance with the patient by the investigator(s) and with the approval of the medical monitor.

단일 제제 티라골루맙에 의한 진행 후 티라골루맙 및 아테졸리주맙을 이용한 치료는 시험자(들)가 환자와 이익-위험 균형에 대한 신중한 평가 및 논의를 한 후 그리고 의료 모니터 요원의 승인을 받아 결정한 대로 허용 가능한 것으로 간주되어야 한다.

Treatment with tiragolumab and atezolizumab following progression with single agent tiragolumab as determined by the investigator(s) after careful evaluation and discussion of the benefit-risk balance with the patient and with the approval of the medical monitor staff should be considered acceptable.

For patients with safely accessible disease site(s), a tumor biopsy is required. The biopsy may be performed at any time prior to dosing of tiragolumab and atezolizumab in a phase Ib study. Optional on-treatment biopsies may also be collected on or between days 15-21 of Cycle 1 following dosing of tiragolumab and atezolizumab. RECIST target lesions are not biopsied.

Doses and schedules for treatment conversion of tiragolumab in combination with atezolizumab in phase Ib studies require approval from medical monitor personnel. In general, patients transitioning to the Phase Ib portion of the study receive the highest dose of tyragolumab that has already been shown not to exceed its MTD in combination with atezolizumab ( FIG. 7 ). Thus, the dose level of tiragolumab evaluated in the Phase Ib study may be different from the dose level evaluated in the same patient in the Phase Ia study. Patients who have modified their dose and/or schedule of tiragolumab as a single agent in a Phase Ia study, unless previously shown that the corresponding dose of tiragolumab does not exceed the MTD for tiragolumab in combination with atezolizumab , continue to receive tiragolumab at the same dose and/or schedule in phase Ib.

Patients transitioning from the Phase Ia portion of the study to the Phase Ib portion of the study are treated as follows:

Ia상의 연구 치료 중단 방문에서 수득한 평가는 연구의 Ib상 부분에서 병용 치료에 대한 선별검사 평가로서 사용될 수 있다. 병용 요법에 대한 치료를 시작한 첫날에 앞서 2주 이내에 하기의 재선별 평가를 반복/수득함으로써, 기준선 치료 전 임상 및 질병 상태를 재확립한다: 표적 신체 검사, ECOG 상태, 혈액학 및 혈청 화학 실험실 검사, 응고 패널, 아밀라아제, 리파아제, 갑상선 기능 검사 및 소변 분석.

Assessments obtained at the Phase Ia study discontinuation visit can be used as screening assessments for combination therapy in the Phase Ib portion of the study. Re-establish baseline pre-treatment clinical and disease status by repeating/obtaining the following rescreening assessments within 2 weeks prior to the first day of treatment for combination therapy: target physical examination, ECOG status, hematology and serum chemistry laboratory tests; Coagulation panel, amylase, lipase, thyroid function test and urine analysis.

B형 간염, C형 간염, HIV, 거대세포바이러스(CMV) 및 EBV에 대한 선별 검사는 Ia상 연구를 위한 선별검사 중에 마지막으로 실시되었 때문에 이러한 검사 결과의 양성에 대한 임상적 의심이 없는 한 반복할 필요가 없다.

Screening for hepatitis B, hepatitis C, HIV, cytomegalovirus (CMV) and EBV was last performed during screening for a phase Ia study, so repeat unless there is clinical suspicion that these test results are positive. no need to do

흉부, 복부 및 골반의 CT 스캔을 포함한 방사선학적 종양 평가는, 질병 진행을 문서화하기 위해 이미 실시된 것이 아닌 한, 상기 평가가 Ib상 연구에 등록하는 환자에 대한 새로운 기준선 스캔이 되기 때문에, 병용 치료를 시작하는 첫날에 앞서 6주 이내에 실시해야 한다.

Radiological oncology assessments, including CT scans of the chest, abdomen, and pelvis, are a new baseline scan for patients enrolling in a Phase Ib study, unless they have already been done to document disease progression. It should be done within 6 weeks prior to the first day of initiation.

환자는, 초기 연구 치료에서 진행성 질병, 임상 악화, 병용 치료에 대한 불내성 및/또는 병용 치료로부터의 임상적 이익의 상실을 기록한 종양 평가와 관련된 제2 질병 진행 반응이 있을 때까지, Ib상 연구에서 티라골루맙 및 아테졸리주맙의 병용 요법으로 치료된다. 앞서 기재된 바와 같이, 환자는 의료 모니터 요원과 논의한 후 시험자의 재량에 따라 진행성 질병에 대한 표준 RECIST v1.1 기준이 Ib상 연구에서 충족되고 지정된 모든 기준을 충족하는 경우 연구 치료를 계속할 수 있다.

Patients in the Phase Ib study until a second disease progression response associated with tumor evaluation documenting progressive disease, clinical deterioration, intolerance to combination therapy, and/or loss of clinical benefit from combination therapy from initial study treatment It is treated with combination therapy of tiragolumab and atezolizumab. As previously described, patients may continue on study treatment if, at the investigator's discretion, after discussion with the medical monitor staff, standard RECIST v1.1 criteria for advanced disease are met in the Phase Ib study and all specified criteria are met.

전환되는 환자는 안전성 및 유효성에 대해 평가된다.

Patients who are converted are evaluated for safety and efficacy.

Clinical and exploratory data derived from tumor biopsies obtained prior to phase Ia transition treatment to phase Ib are continuously monitored.

Enrollment for transition from the Phase Ia portion to the Phase Ib study may be restricted or discontinued at any time. Reasons may include safety, unsatisfactory patient enrollment, and/or incomplete data records.

C. research treatment

Dosage and administration

Administration of tiragolumab as a single agent (Phase Ia) or tiragolumab in combination with atezolizumab (Phase Ib) should be administered by emergency medical facilities with access to the intensive care unit and staff trained to monitor and respond to medical emergencies. carried out in an environment where

For treatment in the Phase Ib portion of the study (cohort without chemotherapy), tiragolumab is administered prior to atezolizumab on the day of the scheduled study treatment infusion with an interim observation period.

For treatment in the Phase Ib chemotherapy expansion cohort, on the scheduled study treatment infusion day, atezolizumab is administered prior to tiragolumab with an intervening observation period. Chemotherapy is administered after atezolizumab and tiragolumab, with an interim observation period for tiragolumab.

For treatment in the Phase Ib non-chemotherapy expansion cohort, on the day of the scheduled study treatment infusion, tiragolumab was administered between bevacizumab (Cohort NC1) or interim observation period prior to atezolizumab in combination with pembrolizumab (Cohort Nc2). placed in and administered Bevacizumab is administered after tiragolumab and atezolizumab, with an interim observation period for bevacizumab.

For details on dosage preparation and administration instructions for tiragolumab, atezolizumab or bevacizumab, refer to the respective investigator's brochure and GO30103 Pharmacy Manual.

See the package insert or SmPC for details on dosage preparation and administration instructions for cisplatin, carboplatin, pemetrexed, paclitaxel, capecitabine, etoposide and pembrolizumab.

Tiragolumab in Phase Ia and Ib

Approximate dose levels of tiragolumab to be evaluated in the Phase Ia and Phase Ib portions of this study are 2 mg, 8 mg, 30 mg, 100 mg, 400 mg and 1200 mg administered every 3 weeks by IV infusion. Other dose levels not exceeding the MTD in phase Ia or Ib, or new dosing schedules for tiragolumab in phases Ia and/or Ib will be evaluated based on new nonclinical efficacy, clinical safety, and clinical PK data after consultation with the participating investigators. can Evaluation of dose levels above tiragoluumab 1200 mg will require protocol modifications with supporting evidence. For the Phase Ib chemotherapy and non-chemotherapy expansion cohorts, tiragolumab 600 mg is the initial dose administered every 3 weeks by IV infusion. For Phase Ib chemotherapy cohorts B and C with Q4W maintenance, the tiragolumab dose is changed to 840 mg on maintenance. For the Phase Ib Q4W dosing cohort, 840 mg tyragolumab is the initial dose administered as Q4W by IV infusion. Dosage does not depend on body weight.

The 840 mg Q4W dosing regimen is supported by the results of PK modeling and simulation and exposure safety analysis. The mean concentrations after the 840 mg Q4W dosing regimen are similar to those of the 600 mg every 3 weeks dosing regimen evaluated in studies GO30103 and GO40290 studies. The Cmax of the 840 mg Q4W dosing regimen is 28% higher at steady state compared to the Cmax of the 600 mg every 3 weeks, but falls within the observed exposure range of the highest administered dose in the hospital (1200 mg every 3 weeks in study GO30103). . Preliminary analysis of tiragoluumab exposure-safety relationship based on data from study GO30103 (tiragoluumab dose of 2-1200 mg administered as monotherapy every 3 weeks or in combination with atezolizumab 1200 mg every 3 weeks) suggest that tiragolumab exhibits a uniform exposure-safety relationship. In summary, the 840 mg Q4W dosing regimen was similar in safety and efficacy to the 600 mg every 3 weeks dosing regimen given that exposures were within the observed effective exposure range and tiragoluumab appeared to have a uniform exposure-safety relationship. can provide

The initial dose of tiragolumab in Phase Ia of the study can be delivered for 90 (±10 minutes), followed by a 240 minute observation period (although the infusion may be blunted or obstructed for patients experiencing infusion-related symptoms). In Phase Ib of the study, an initial dose of tiragolumab is delivered over 60 minutes (10 minutes) followed by a 60 minute observation period. If the initial infusion is well tolerated without infusion-related side effects, the second infusion in Phase Ia can be delivered over 60 (10) minutes followed by a 60 minute observation period, and the second infusion in Phase Ib is 30 (10) minutes. can be delivered over a period of time, followed by an observation time of 30 min. If the 60 min infusion is well tolerated, a third infusion on Phase Ia can be delivered for 30 (±10) min followed by a 30 min observation period. If the third infusion in Phase Ia or the second infusion in Phase Ib is well tolerated, all subsequent infusions in Phase Ia can be delivered for 30 (±10) minutes, followed by a 30 minute observation period. Patients previously receiving single agent tiragolumab in phase Ia and currently receiving tiragolumab in combination with atezolizumab in phase Ib may receive the initial dose in phase Ib at the fastest rate the patient has previously tolerated.

There are no dose reductions for tiragolumab in this study (Phase Ia or Phase Ib) except as noted. Guidance is provided for dose changes and discontinuation or discontinuation of treatment for tiragolumab. Guidance for study drug administration in the context of managing specific adverse events is provided.

Adverse events related to overdose or incorrect administration of study drug are recorded.

Phase Ib Atezolizumab

The dose of atezolizumab administered in combination with tiragolumab in the Phase Ib portion of this study is 1200 mg IV every 3 weeks. For Phase Ib chemotherapy cohorts B and C with Q4W maintenance, the atezolizumab dose is changed to 1680 mg on maintenance. The Phase Ib Q4W dosing cohort is administered atezolizumab 1680 mg IV Q4W. The dose is fixed and does not depend on body weight.

In all Phase Ib cohorts that did not include chemotherapy, atezolizumab is administered after the tiragolumab infusion and subsequent observation period. In the Phase Ib chemotherapy expansion cohort, atezolizumab is administered prior to tiragolumab.

The initial dose of atezolizumab is delivered over 60 (±10) minutes. If the first infusion is well tolerated without infusion-related adverse events, the second infusion may be delivered over 30 (±10) minutes. If a 30 minute infusion is well tolerated, all subsequent infusions can be delivered over 30 (±10) minutes. For Cycle 1, atezolizumab dosing is followed by an observation period of 60 minutes. A 30-minute observation period may follow after all subsequent atezolizumab infusions. Patients who have previously received atezolizumab in other clinical trials may receive the initial dose at the fastest rate previously permitted.

There is no dose reduction for atezolizumab in this study. Guidance for dose changes and treatment discontinuation or discontinuation is provided. Guidance for study drug administration in the context of managing specific adverse events is provided.

Adverse events related to overdose or incorrect administration of study drug EW are recorded.

Non-chemotherapy cohort in phase lb expansion cohort

Cohort NC1: Tiragolumab and Atezolizumab with Bevacizumab

Patients in the tiragolumab and atezolizumab and bevacizumab cohorts receive treatment as outlined in Table 31 after pooled evaluation until there is unacceptable toxicity or loss of clinical benefit as determined by the investigator. It is recommended to start treatment within 7 days of enrollment. However, the first dose should not be administered within 7 days of a core biopsy or other surgical procedure.

cycle length Dose, route, and regimen ^a 3 weeks 1. Tiragolumab: 600 mg IV infusion per day
2. Atezolizumab: 1200 mg IV infusion per day
3. Bevacizumab: 15 mg/kg IV infusion per day ^b IV = intravenous
^a Drugs listed in order of administration. All drugs are administered by IV infusion on Day 1 of each 21-day cycle.
^b On Day 1 of Cycle 1, bevacizumab is administered 60 minutes after completion of the atezolizumab infusion. If the patient experienced an infusion-related reaction during a previous drug infusion, the interval between subsequent infusions is 60 minutes. If the previous drug infusion was well tolerated without infusion-related reactions, the interval may be reduced to 30 minutes.

Treatment regimen for cohort NC1

Cohort NC2: Tiragolumab and Pembrolizumab

Patients in the tiragolumab and pembrolizumab cohorts receive treatment as outlined in Table 32 after pooled evaluation until there is unacceptable toxicity or loss of clinical benefit as determined by the investigator. It is recommended to start treatment within 7 days of enrollment. However, the first dose should not be administered within 7 days of a core biopsy or other surgical procedure.

cycle length Dose, route, and regimen ^a 3 weeks 1. Tiragolumab: 600 mg IV infusion per day ^b
2. Pembrolizumab 200 mg IV infusion per day ^b IV = intravenous
^a Drugs listed in order of administration. All drugs are administered by IV infusion on Day 1 of each 21-day cycle.
^b On Day 1 of Cycle 1, pembrolizumab is administered 60 minutes after completion of the tyragolumab infusion. If the patient has experienced an infusion-related reaction during a previous infusion of tyragolumab, the interval between subsequent infusions is 60 minutes. If the previous infusion of tiragolumab was administered without premedication and was well tolerated without infusion-related reactions, the interval may be reduced to 30 minutes.

Treatment regimen for cohort NC2

Phase Ib Non-chemotherapy Expansion Cohort: Dose and Dosing

Patients in cohort NC1 receive tiragolumab 600 mg IV followed by atezolizumab 1200 mg IV followed by bevacizumab 15 mg/kg IV on Day 1 of every 3-week cycle. Treatment is continued until there is unacceptable toxicity or loss of clinical benefit, as determined by the investigator.

Patients in cohort NC2 receive tiragolumab 600 mg IV followed by pembrolizumab 200 mg IV on Day 1 of every 3-week cycle. Treatment is continued until there is unacceptable toxicity or loss of clinical benefit, as determined by the investigator.

In the event of toxicity and loss of clinical benefit, individual immunotherapeutic agents may be independently discontinued. However, treatment with pembrolizumab or bevacizumab or atezolizumab or tiragoluzumab alone may be considered with no contraindications and only after discussion with a medical monitor.

Bevacizumab in Phase Ib Expansion Cohort

Bevacizumab is administered as an IV infusion at a fixed dose of 15 mg/kg on Day 1 of each 21-day cycle. Administration of bevacizumab is performed in a monitored environment with immediate access to trained personnel and appropriate equipment and medications to manage potentially severe reactions. Guidance for dose changes and treatment discontinuation or discontinuation is provided.

Premedication prior to the first infusion of bevacizumab is not permitted. If the patient has previously experienced an IRR with drug infusion, an antihistamine, antipyretic and/or analgesic may be pre-administered at the investigator's discretion. Vital signs (pulse rate, respiration rate, blood pressure, and body temperature) are measured within 60 minutes prior to the infusion. The initial dose of bevacizumab is delivered over 90 (±10) minutes. If the first infusion is well tolerated without infusion-related adverse events, the second infusion may be delivered over 60 (±10) minutes. If a 60 minute infusion is well tolerated, all subsequent infusions can be delivered over 30 (±10) minutes. For Cycle 1, bevacizumab dosing is followed by an observation period of 60 minutes. A 30-minute observation period may follow after all subsequent bevacizumab infusions. Patients previously receiving bevacizumab may receive the initial dose at the fastest rate that was previously well tolerated. Inform the patient of the potential for post-infusion symptom delay and instruct the study physician to contact if these symptoms develop. Guidance for measuring vital signs is provided.

Pembrolizumab in Phase Ib Expansion Cohort

The dose of pembrolizumab administered in combination with tiragolumab in the Phase Ib non-chemotherapy expansion cohort of this study is 200 mg IV every 3 weeks. The dose is fixed and does not depend on body weight.

See Pembrolizumab Prescribing Information for guidance on dose preparation, storage, administration, and instructions for discontinuing or discontinuing treatment for pembrolizumab.

Chemotherapy in the Phase Ib Expansion Cohort

Chemotherapy (except capecitabine) is administered following an infusion of atezolizumab and tiragolumab followed by an observation period.

During the induction phase, chemotherapy cycles are included in the predetermined number of induction chemotherapy cycles when at least one chemotherapy component is administered at least once during a 21-day cycle. Cycles for which no chemotherapy component was given are not included in the total number of induction chemotherapy cycles.

Patients presenting evidence of clinical benefit during treatment (induction or maintenance) may continue treatment after the RECIST v1.1 criteria for PD have been met.

Patients receive antiemetics and IV hydration for chemotherapeutic agents according to local standards of care and manufacturer's guidelines. However, due to the immunomodulatory effect of steroids, steroid premedication is minimized to the extent clinically feasible.

Guidance is provided for changing the dose of chemotherapy and stopping or discontinuing treatment.

Cohort A: atezolizumab + tiragolumab + carboplatin/cisplatin + pemetrexed

On Day 1 of each 21-day cycle, all eligible patients will receive drug infusions in the following order:

Induction: atezolizumab ® tyragolumab ® pemetrexed ® carboplatin or cisplatin

After 4 to 6 cycles in the induction phase, the patient initiates maintenance therapy in the following order of administration:

Maintenance: Atezolizumab ® Tiragolumab ® Pemetrexed

Table 33 lists the proposed premedication for pemetrexed. Table 7 lists the recommended infusion times for therapeutic administration of pemetrexed and carboplatin or cisplatin and pemetrexed during the maintenance phase during the induction phase.

pre-medication capacity and route hour folic acid 350-1000 νg PO Start at least 5-7 days prior to Day 1 of Cycle 1 and continue once daily until 3 weeks after discontinuation of pemetrexed vitamin B12 1000 vg IM Q9W starting before Day 1 of Cycle 1 and continuing until 3 weeks after discontinuation of pemetrexed Dexamethasone (recommended) 4 mg PO BID, pemetrexed the day before, day and day after administration BID　=　2 times a day; IM　=　intravenous; PO　=　Oral; Q9W　=　every 9 weeks.

Premedication of pemetrexed

Cohort B: Atezolizumab + Tiragolumab + Carboplatin + Paclitaxel

On Day 1 of each 21-day cycle, all eligible patients will receive drug infusions in the following order:

Induction: Atezolizumab ® Tiragolumab® Paclitaxel® Carboplatin

After 4 to 6 cycles in the induction phase, patients receive maintenance therapy on Day 1 of each 21-day cycle when enrolled in protocol version 4 and on Day 1 of each 28-day cycle when enrolled in protocol version 5 or later. Start. All eligible patients will receive drug infusions in the following order of administration:

Maintenance: Atezolizumab ® Tiragolumab

Table 8 lists the proposed pre-dosing for induction treatment for patients in Cohort B. Table 9 lists the suggested infusion times for therapeutic administration of paclitaxel and carboplatin during the induction phase.

Cohort C: Atezolizumab + Tiragolumab + Carboplatin + Cisplatin

On Day 1 of each 21-day cycle, all eligible patients are infused with study drug in the following order:

Induction: atezolizumab → tyragolumab → cisplatin or carboplatin → etoposide

Following the induction phase, patients begin maintenance therapy on Day 1 of each 28-day cycle in the following dosing sequence:

Maintenance: Atezolizumab → Tiragolumab

Table 10 lists the suggested infusion times for therapeutic administration of carboplatin or cisplatin and etoposide during the induction phase.

Cohort D: Capecitabine + Atezolizumab + Tiragolumab

On Day 1 of each 21-day cycle, all eligible patients received study drug in the following order:

Capecitabine → Atezolizumab → Tiragolumab

Table 34 lists the suggested duration, dose route, and regimen for therapeutic administration of capecitabine.

cycle length Dose, route, and regimen ^a 3 weeks 1. Capecitamine: 1250 mg/m ² PO BID on days 1-14 followed by a 7-day resting period
2. Atezolizumab: 1200 mg IV infusion per day
3. Tiragolumab: 600 mg IV infusion per day BID = twice a day; PO = oral.
^a Drugs listed in order of administration.

Treatment regimens for cohorts with capecitabine and tiragolumab and atezolizumab

cisplatin

Guidance for cisplatin administration in different cohorts is presented in Table 11.

carboplatin

Guidelines for carboplatin administration in different cohorts are presented in Table 12.

Pemetrexed

Guidelines for administration of pemetrexed in Cohort A are presented in Table 13.

paclitaxel

Guidelines for administration of paclitaxel in Cohort B are presented in Table 14.

etoposide

Guidelines for administration of etoposide in Cohort C are presented in Table 15.

cape citamine

Capecitabine is available in 150 mg and 500 mg tablets. Patients receive the treatment outlined in Table 35 until there is unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Chemotherapy Expansion Cohort hour capacity and route duration D Day 1 of Cycle 1: Administer the first dose of capecitabine at the hospital prior to the infusion of tiragolumab and atezolizumab. 7 days rest after 1250 mg/m2 PO BID on days 1-14 Not applicable BID　=　2 times a day; PO　=　Oral.

Capecitabine should be taken within 30 minutes after a meal with water. Patients are instructed to return used and unused medications to the study site.

D. combination therapy

Combination therapy includes any medications (eg, prescription drugs, over-the-counter medications, herbal or homeopathic remedies, and/or nutritional supplements) used by the patient from day 7 prior to screening until the treatment discontinuation visit.

accepted therapy

Patients experiencing infusion-related symptoms in this study (Phase Ia or Ib) may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or ranitidine or other H2 receptor antagonists according to standard practice. (In institutions outside the United States, equivalent drugs may be substituted according to local practice). Severe infusion-related reactions, such as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation or dyspnea, are managed with supportive care as clinically indicated (e.g., oxygen supplementation and β2 adrenergic agonists). An antihistamine premedication may be administered for Cycle 2 in Phase Ia or Ib at the discretion of the treating physician.

Systemic corticosteroids, immunosuppressive drugs, and TNFα antagonists may attenuate the potentially beneficial immunological effects of treatment with tiragolumab alone or in combination with anti-PD-L1/PD-1. It may be administered at the discretion of the treating physician or after consultation with a medical monitor. If possible, alternatives to corticosteroids, immunosuppressants or TNF-antagonists are considered. Premedication of tiragolumab, atezolizumab, bevacizumab, and pembrolizumab may be administered at the discretion of the treating physician after consultation with a medical monitor in Cycle 2 or higher. The use of inhaled corticosteroids and mineralocorticosteroids (eg, fludrocortisone for patients with orthostatic hypotension or adrenocortical insufficiency) is permitted. Physiological doses of corticosteroids for adrenal insufficiency are acceptable. Megestrol administered as an appetite stimulant is also acceptable. Consult with your medical monitor for plans to use other medications.

For patients in the Phase Ib chemotherapy expansion cohort, antiemetics and systemic steroids may also be given in the following circumstances:

적절한 항구토 예방이 실시된다. 가능한 경우 5?HT3 수용체 및 NK1R 길항제로 구성된 비스테로이드성 항구토 요법의 사용이 권장된다(Hesketh et al. J Clin Oncol 2017;35:3240-3261).

Adequate antiemetic prophylaxis is practiced. The use of nonsteroidal antiemetic therapy consisting of a 5?HT3 receptor and NK1R antagonist is recommended when possible (Hesketh et al. J Clin Oncol 2017;35:3240-3261).

덱사메타손(또는 이의 등가물)을 사용한 전처리는 피부 반응의 발생률 및 중증도를 줄이기 위해 페메트렉시드를 투여받는 코호트 A의 모든 환자에게 제공될 수 있다. 임상 시험에서, 덱사메타손 4 mg은 페메트렉시드 투여 전날, 당일 및 다음날 경구로 BID 투여되었다.

Pretreatment with dexamethasone (or its equivalent) may be given to all patients in Cohort A receiving pemetrexed to reduce the incidence and severity of skin reactions. In a clinical trial, 4 mg of dexamethasone was administered orally BID the day before, on the same day and on the following day, pemetrexed.

파클리탁셀을 투여받는 코호트 B의 모든 환자에게 덱사메타손(또는 이의 등가물)을 이용한 전처리가 제공될 수 있다. 임상 시험에서, 파클리탁셀 투여 12시간 및 6시간 전에 덱사메타손 20 mg을 경구 투여하였다.

All patients in Cohort B receiving paclitaxel may receive pretreatment with dexamethasone (or its equivalent). In a clinical trial, 20 mg of dexamethasone was orally administered 12 hours and 6 hours before administration of paclitaxel.

The planned use of prophylactic antibiotics (eg, after surgical intervention) is discussed with the medical monitor. Study medication is maintained until the end of the antibiotic course.

Patients using oral contraceptives, hormone replacement therapy, prophylactic or therapeutic anticoagulant therapy (eg, stable dose levels of low molecular weight heparin or warfarin) or other maintenance therapy for non-malignant indications should continue their use. Men and women of reproductive potential should use highly effective contraceptives.

For patients in the chemotherapy expansion cohort, caution should be exercised when using the following drugs:

페메트렉시드(코호트 A)를 투여받는 경증에서 중등도의 신부전증(크레아티닌 청소율[CrCl] 45~79 mL/분) 환자에게 비스테로이드성 항염증제(NSAID)를 투여할 때는 주의해야 한다. 소실 반감기가 짧은 NSAID(예컨대, 디클로페낙, 인도메타신)는 페메트렉시드 투여 전 2일, 투여 당일 및 투여 후 2일 동안 사용하지 않는다. 페메트렉시드 및 반감기가 더 긴 NSAID(예컨대, 멜록시캄, 나부메톤) 간의 잠재적 상호작용에 관한 데이터가 없는 경우, 상기 NSAID를 복용하는 환자는 페메트렉시드 투여 전 적어도 5일 동안, 투여 당일, 및 투여 후 2일 동안 투약을 중단해야 한다. NSAID의 병용 투여가 필요한 경우, 독성, 특히 골수억제, 신장 및 위장 독성에 대해 환자를 면밀히 모니터링한다.

Caution should be exercised when administering nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with mild to moderate renal insufficiency (creatinine clearance [CrCl] 45 to 79 mL/min) receiving pemetrexed (Cohort A). NSAIDs with a short elimination half-life (eg, diclofenac, indomethacin) should not be used for 2 days before, on the day of, and for 2 days after administration of pemetrexed. In the absence of data regarding potential interactions between pemetrexed and longer half-life NSAIDs (e.g., meloxicam, nabumetone), patients taking these NSAIDs should be treated for at least 5 days prior to administration of pemetrexed, on the day of administration, and dosing should be stopped for 2 days after dosing. If concomitant administration of an NSAID is required, closely monitor the patient for toxicity, particularly myelosuppression, renal and gastrointestinal toxicity.

아미노글리코시드 및 루프 이뇨제와 같은 내이독성 약물은 시스플라틴 또는 카보플라틴을 투여받는 환자에서 내이독성을 강화할 수 있다. 시스플라틴과 함께 항히스타민제의 사용은 현기증 및 이명과 같은 내이독성 증상을 가릴 수 있으므로 면밀히 검토한다. 시스플라틴 또는 카보플라틴을 투여받는 환자에게서 리튬 및 항경련제(페니토인을 포함) 수치를 면밀히 모니터링한다. INR은 경구 항응고제 및 시스플라틴을 복용하는 환자에게서 면밀히 모니터링한다.

Ototoxic drugs such as aminoglycosides and loop diuretics may enhance ototoxicity in patients receiving cisplatin or carboplatin. The use of antihistamines with cisplatin should be carefully considered as it may mask ototoxic symptoms such as vertigo and tinnitus. Closely monitor lithium and anticonvulsant (including phenytoin) levels in patients receiving cisplatin or carboplatin. INR is closely monitored in patients taking oral anticoagulants and cisplatin.

와파린을 에토포시드와 병용으로 복용하는 환자(코호트 C)에게서 기준선 INR을 초과하는 증가를 보이는 바와 같이 응고 시간이 증가하는 것으로 보고되었다. 에토포시드와 함께 와파린을 투여받는 환자는 빈번한 INR로 면밀히 모니터링한다.

An increase in clotting time as seen with an increase above baseline INR was reported in patients taking warfarin in combination with etoposide (Cohort C). Patients receiving warfarin in combination with etoposide are closely monitored for frequent INR.

카페시타빈(코호트 D) 및 경구 쿠마린 유래 항응고제 치료를 동시에 받고 있는 환자는 항응고제 용량을 적절하게 조정하기 위해 이의 항응고제 반응(INR 또는 프로트롬빈 시간)을 자주 모니터링해야 한다. 와파린 및 펜프로쿠몬과 같은 쿠마린 유래 항응고제와 병용으로 카페시타빈을 복용하는 환자에게서 응고 매개변수의 변화 및/또는 출혈 및 사망이 보고되었다. CYP2C9 기질인 류코보린 및 페니토인을 복용하는 카페시타빈(코호트 D)을 복용하는 환자의 경우 추가 예방 조치가 필요하다.

Patients receiving concomitant treatment with capecitabine (Cohort D) and oral coumarin-derived anticoagulants should frequently monitor their anticoagulant response (INR or prothrombin time) to adjust the anticoagulant dose appropriately. Changes in coagulation parameters and/or bleeding and death have been reported in patients taking capecitabine in combination with coumarin-derived anticoagulants such as warfarin and fenprocumone. Additional precautions are required in patients taking capecitabine (Cohort D) taking the CYP2C9 substrates leucovorin and phenytoin.

For patients in the non-chemotherapy expansion cohort, caution should be exercised when using the following drugs:

주로 비스포스포네이트와 병용하여 베바시주맙을 투여받은 환자에게서 턱의 골괴사가 보고되었다. 따라서, 비스포스포네이트를 병용 투여하는 환자에게 베바시주맙을 사용할 때는 주의를 기울여야 한다.

Osteonecrosis of the jaw has been reported mainly in patients receiving bevacizumab in combination with bisphosphonates. Therefore, caution should be exercised when using bevacizumab in patients receiving concomitant bisphosphonates.

forbidden therapy

The use of the following therapies is contraindicated during the study period:

하기의 화학요법, 호르몬 요법, 면역요법, 방사선 요법, 임상시험용 제제, 또는 한약 요법 포함하지만 이제 제한되지는 않는 보건 기관의 승인을 받았거나 실험 단계에 있는지 여부와 상관없이 암 치료를 위한 모든 병용 요법

Any combination therapy for the treatment of cancer, whether or not approved by a health agency or in an experimental phase, including, but not limited to, chemotherapy, hormone therapy, immunotherapy, radiation therapy, investigational agents, or herbal therapy:

Radiation therapy may be considered for temporary relief of pain (eg, treatment of known bone metastases) if the patient is otherwise benefiting. For patients in the Phase Ia or Phase Ib dose escalation cohort, palliative radiation therapy is deferred until the completion of the DLT evaluation period. Administration of study treatment may be deferred during radiotherapy with consent from the medical monitor.

Patients experiencing mixed reactions may receive local therapy (eg, surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) to control 3 or fewer lesions upon approval of the medical monitor.

Patients who have undergone radiation therapy or resection for a target lesion will not be able to subsequently evaluate that target lesion for response determination according to RECIST v1.1.

독성약화 생백신(예컨대, 플루미스트 인플루엔자 백신)은 연구 중 언제라도, 및 연구 치료제의 마지막 투여 후 5개월 동안 금지된다.

Live attenuated vaccines (eg, flumist influenza vaccine) are contraindicated at any time during the study and for 5 months after the last dose of study treatment.

환자는 전체 연구 동안 IFN-, IFN-, 또는 IL-2를 포함하지만 이에 제한되지는 않는 면역자극제를 투여받을 수 없다. 상기 제제는 아테졸리주맙과 병용하여 자가면역 질환의 위험을 잠재적으로 증가시킬 수 있다.

Patients cannot receive immunostimulatory agents including, but not limited to, IFN-, IFN-, or IL-2 during the entire study. Such agents may potentially increase the risk of autoimmune diseases in combination with atezolizumab.

전통적인 한약은 일반적으로 특성이 불완전하게 특성화되고 독성을 유발하거나 독성 평가를 혼란스럽게 할 수 있는 예상치 못한 약물-약물 상호작용을 초래할 수 있기 때문이다.

This is because traditional herbal medicines are usually incompletely characterized and can lead to unexpected drug-drug interactions that can lead to toxicity or confound toxicity assessment.

Contraindicated regimens specifically for HCC patients considered for cohort NC1:

· The use of full dose anticoagulants, therapeutic doses of thrombolytic therapy, and antiplatelet therapy is currently contraindicated.

Local label recommended doses for prophylactic use of anticoagulants or thrombolytic therapy are acceptable.

Low-dose aspirin (less than 325 mg/day) is acceptable. Co-administration of proton pump inhibitors is strongly recommended to reduce potential gastrointestinal damage.

If a patient experiences a venous thromboembolism while receiving study drug treatment, it may still be possible for the patient to continue taking the study drug despite anticoagulant treatment.

와파린 또는 쿠마딘 유사 제품(예방용 포함)의 사용은 현재 금지되어 있다.

The use of warfarin or coumadin-like products (including prophylactic) is currently prohibited.

The prophylactic use of low-dose anticoagulants, unfractionated heparin or LMWH is permitted. The preferred choice for anticoagulant treatment is LMWH according to ASCO guidelines (Lyman GH et al. J Clin Oncol 2015;33:654-6).

With the exception of chronic low-dose aspirin (<325 mg/day) use, chronic concomitant use of NSAIDs while receiving study drug is contraindicated. However, intermittent or short-term ingestion of oral NSAIDs is permitted when co-administered with proton pump inhibitors to reduce potential gastrointestinal damage for symptom relief of medical conditions (eg headache, fever).

D. Selection Criteria

Patients must meet the following criteria for study entry:

general standard

서명한 사전 동의서(ICF)

Signed Informed Consent Form (ICF)

연령 ≥ 18 세

Age ≥ 18 years

시험자의 판단으로, 연구 프로토콜을 준수할 수 있는 능력

ability to comply with the study protocol, at the discretion of the investigator

0 또는 1의 ECOG 전신 활동도

ECOG systemic activity of 0 or 1

기대 수명 ₃12주

Life expectancy ₃12 weeks

제1 연구 치료(주기 1의 1일) 전 14일 이내에 수득한 이하의 실험실 결과로 정의되는 적절한 혈액 및 말단 기관 기능:

Adequate blood and end organ function as defined by the following laboratory results obtained within 14 days prior to the first study treatment (Day 1 of Cycle 1):

절대적인 중성구 카운트(ANC) ≥ 1500 세포/μL

Absolute neutrophil count (ANC) ≥ 1500 cells/μL

백혈구(WBC) 수 ≥ 2,500/μL

White blood cell (WBC) count ≥ 2,500/μL

림프구 수 ₃　500/mL

Lymphocyte count ₃ 500/mL

혈소판 수 ₃　100,000/mL(주기　1의 1일 이전 14일 이내에 수혈 없음)

Platelet count ₃ 100,000/mL (no transfusion within 14 days prior to Day 1 of Cycle 1)

헤모글로빈 ₃　9 g/dL

Hemoglobin ₃ 9 g/dL

환자는 현지 치료의 표준에 따라 수혈을 받거나 적혈구 생성 치료를 받을 수 있음.

Patients may receive transfusions or receive erythropoiesis according to local standards of care.

총 빌리루빈 ≤ 1.5 x 정상치 상한 (ULN)

Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

파클리탁셀을 투여받는 환자(코호트 B)는 총 빌리루빈이 1.25 ULN 이어야 한다.

Patients receiving paclitaxel (Cohort B) must have a total bilirubin of 1.25 ULN.

AST 및 ALT 3 ULN

AST and ALT 3 ULN

하기의 예외를 갖는 알칼리성 포스파타아제 ≤ 2.5 × ULN:

Alkaline phosphatase ≤ 2.5 x ULN with the following exceptions:

간 또는 뼈 전이가 보고된 환자들은 알칼리성 포스파타아제 5 ULN을 가질 수 있음.

Patients with reported liver or bone metastases may have alkaline phosphatase 5 ULN.

혈청 알부민 2.5 g/dL

Serum albumin 2.5 g/dL

PT 및 활성화된 부분 트롬보플라스틴 시간(aPTT) 1.5 ULN

PT and activated partial thromboplastin time (aPTT) 1.5 ULN

This applies only to patients not receiving therapeutic anticoagulants.

Patients receiving therapeutic anticoagulants are maintained at stable doses.

콕크로프트-가울트 사구체 여과율 추정치를 바탕으로 측정 또는 계산된 크레아티닌 CL 50　mL/분:

Creatinine CL 50 mL/min, measured or calculated based on the Cockcroft-Gault glomerular filtration rate estimate:

(140 years old) (weight kg) (0.85 for women)

72 (serum creatinine mg/dL)

Patients receiving cisplatin (Cohort A or Cohort C) should have measured or calculated a creatinine clearance ≥ 60 mL/min based on the Cockcroft-Gault estimate.

(난관 결찰을 한 여성을 포함한)출산 잠재력을 가진 여성에 대한 혈청 임신 검사를 실시하고 주기 1의 1일에 앞서 14일 이내 음성으로 기록해야 한다.

Serum pregnancy tests for women of childbearing potential (including those with tubal ligation) should be performed and recorded as negative within 14 days prior to Day 1 of Cycle 1.

가임 여성의 경우: 금욕 유지(이성간 성교 금지) 또는 하기에 정의된 바와 같이 피임법 사용에 대한 동의 및 난자 기증 자제에 대한 동의

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods as defined below and to refrain from egg donation

여성은 치료 기간 중 및 티라골루맙 최종 투여 후 90일, 아테졸리주맙 최종 투여 후 5개월, 펨브롤리주맙 최종 투여 후 4개월, 베바시주맙 및 화학요법(페메트렉시드, 시스플라틴, 카보플라틴, 파클리탁셀, 에토포시드 및 카페시타빈) 최종 투여 후 6개월 동안 금욕을 유지하거나 또는 연간 실패율이 1% 미만인 피임법을 사용하여야 한다. 여성은 상기 동일한 기간 동안 난자 기증을 자제해야 한다.

During treatment and 90 days after the last dose of tiragolumab, 5 months after the last dose of atezolizumab, 4 months after the last dose of pembrolizumab, bevacizumab and chemotherapy (pemetrexed, cisplatin, carboplatin, Paclitaxel, etoposide, and capecitabine) should either maintain abstinence for 6 months after the last administration or use a contraceptive method with an annual failure rate of less than 1%. Women should refrain from donating eggs during the same period as above.

여성이 초경 이후이고, 폐경 후 상태(폐경 이외의 확인된 원인 없이 계속해서 12개월 이상 동안 무월경이 지속됨)에 도달하지 않았으며, 외과적 불임 수술(난소, 나팔관 및/또는 자궁 제거) 또는 시험자가 결정한 대로 다른 원인(예컨대, 뮐러관 무발생)으로 인한 경우, 가임기인 것으로 간주된다. 가임기의 정의는 지역 지침 또는 규정에 맞게 조정될 수 있다.

The woman is postmenopausal, has not reached postmenopausal status (amenorrhea continues for more than 12 consecutive months without an identified cause other than menopause), has not undergone surgical sterilization (removal of the ovaries, fallopian tubes and/or uterus) or If due to other causes (eg, absence of Muller's canal), as determined, it is considered to be of childbearing age. The definition of childbearing age may be adapted to local guidelines or regulations.

연간 실패율이 1% 미만인 피임법의 예로는 양측 난관 결찰, 남성 불임술, 배란을 억제하는 호르몬 피임약, 호르몬 방출 자궁 내 장치 및 구리 자궁 내 장치가 있다.

Examples of contraceptive methods with an annual failure rate of less than 1% include bilateral tubal ligation, male sterilization, hormonal contraceptives that suppress ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

호르몬 피임법은 장벽법으로 보완되어야 한다.

Hormonal contraception should be supplemented with barrier methods.

성적 금욕의 신뢰성은 임상 시험 기간 및 환자가 선호하는 일상적인 생활 방식과 관련하여 평가한다. 주기적 금욕(예컨대, 달력, 배란, 증상체온, 또는 배란후 방법) 및 회수는 피임의 허용가능한 방법이 아니다.

The reliability of sexual abstinence is assessed with respect to the duration of the clinical trial and the patient's preferred daily lifestyle. Periodic abstinence (eg, calendar, ovulation, symptomatic body temperature, or postovulatory methods) and withdrawal are not acceptable methods of contraception.

남성의 경우: 하기에 규정된 바와 같이, 금욕을 유지하거나(이성간 성교를 자제하거나) 또는 피임법을 이용하는 데 동의, 및 정자 기증의 자제하는 데 동의:

For Men: Consent to maintain abstinence (abstain from heterosexual intercourse) or use contraceptive methods, and to refrain from donating sperm, as provided below:

임신하지 않은 가임기 여성 파트너와 함께, 수술로 인한 불임이 아닌 남성은 치료 기간 동안 그리고 티라골루맙의 마지막 용량 투여 후 90일 동안, 카페시타빈의 마지막 용량 투여 후 3개월, 임의의 다른 모든 화학요법 약물의 마지막 용량 투여 후 6개월 동안 금욕을 유지하거나, 또는 실패율이 연간 1% 미만인 추가적인 피임법을 사용해야 한다. 남성은 상기 동일한 기간 동안 정자 기증을 삼가야 한다.

With a non-pregnant female partner of childbearing potential, men who are not surgically infertile during treatment and for 90 days after the last dose of tiragolumab, 3 months after the last dose of capecitabine, and any other chemotherapy Abstinence must be maintained for 6 months after administration of the last dose of the drug, or an additional method of contraception with a failure rate of less than 1% per year should be used. Men should refrain from donating sperm during the same period.

With female partners of childbearing potential, males maintain abstinence during treatment and for 90 days after the last dose of tiragolumab, 3 months after the last dose of capecitabine, and 6 months after the last dose of chemotherapy to avoid embryo exposure or use a condom.

성적 금욕의 신뢰성은 임상 시험 기간 및 환자가 선호하는 일상적인 생활 방식과 관련하여 평가한다. 주기적 금욕(예컨대, 달력, 배란, 증상체온, 또는 배란후 방법) 및 회수는 피임의 허용가능한 방법이 아니다.

The reliability of sexual abstinence is assessed with respect to the duration of the clinical trial and the patient's preferred daily lifestyle. Periodic abstinence (eg, calendar, ovulation, symptomatic body temperature, or postovulatory methods) and withdrawal are not acceptable methods of contraception.

E. Criteria for selection by cancer

입수 가능한 적어도 1회의 표준 요법 후 진행된 국소 진행성, 재발성 또는 전이성 난치성 악성 종양에 대한 조직학적 기록이 있거나; 이에 대해 표준 요법이 존재하지 않거나, 비효과적이거나 견딜 수 없는 것으로 입증되었거나, 부적절하다고 간주되거나; 또는 이에 대해 임상 시험용 제제의 임상 시험이 인정된 치료의 표준인 환자.

There is a histological record of locally advanced, recurrent, or metastatic refractory malignancies that have progressed after at least one available standard therapy; for which standard therapies do not exist, have proven ineffective or intolerable, or have been deemed inadequate; or patients for whom clinical trials of an investigational product are the accepted standard of care.

적어도 1회의 입수 가능한 표준 요법 후에 진행된 환자가 입수 가능한 추가 승인된 치료 표준 선택사항이 있는 경우, 연구 담당의는 본 연구에 참여하기 위한 사전 동의서를 수득하기 전에 해당 치료의 위험 및 이점에 대해 논의해야 한다. 상기 논의는 환자 기록에 문서화해야 한다.

If there are additional approved standard of care options available for patients who have progressed after at least one available standard of care, the study physician should discuss the risks and benefits of that treatment before obtaining informed consent to participate in the study. do. The above discussion should be documented in the patient record.

Ib상 연구의 확장 코호트에 대해서만, 이에 대해 화학요법을 포함하거나 포함하지 않는 항 PD-L1 항체 병용한 임상시험용 제제의 임상 시험이 허용가능한 치료 선택사항으로 고려되는 국소 진행성, 재발성 또는 전이성 난치성 악성 종양의 조직학적 문서가 있는 환자는 또한 적격일 수 있다.

For the expansion cohort of Phase Ib studies only, locally advanced, recurrent, or metastatic refractory malignancies for which clinical trials of investigational agents in combination with anti-PD-L1 antibody, with or without chemotherapy, are considered acceptable treatment options. Patients with histological documentation of the tumor may also be eligible.

관련 병리 보고서와 함께 포르말린 고정, 파라핀 포매(FFPE) 블록(바람직한) 또는 15개의 비염색 슬라이드에서 대표적인 종양 표본의 입수 가능성이 확인된 환자.

Patients with confirmed availability of representative tumor specimens on formalin-fixed, paraffin-embedded (FFPE) blocks (preferred) or 15 unstained slides with relevant pathology reports.

허용 가능한 샘플에는 심부 종양 조직에 대한 코어 바늘 생검(최소 5개 코어), 피부, 피하 또는 점막 병변에 대한 절제, 절개, 펀치 또는 겸자 생검이 포함될 수 있다.

Acceptable samples may include core needle biopsies (minimum of 5 cores) for deep tumor tissue, and excision, incision, punch or forceps biopsies for skin, subcutaneous or mucosal lesions.

미세 바늘 흡인(FNA) 샘플, 칫솔질, 삼출액이나 복수의 세포 펠릿들, 세척 샘플은 허용되지 않는다.

Fine needle aspiration (FNA) samples, brushing, exudates or multiple cell pellets, and washing samples are not permitted.

골 전이로부터의 종양 조직은 PD-L1 및/또는 TIGIT(Ig 및 ITIM 도메인이 있는 T 세포 면역 수용체) 발현에 대해 평가할 수 없으므로 허용되지 않는다.

Tumor tissue from bone metastases is not acceptable as it cannot be evaluated for PD-L1 and/or TIGIT (T cell immune receptor with Ig and ITIM domains) expression.

별개의 시점(예컨대, 초기 진단 시점 및 질병 재발 시점)에서 수득한 적절한 조직 및/또는 다중 전이성 종양이 입수 가능할 경우, 가장 최근에 수집된(이상적으로는 가장 최근의 전신 보조 요법 이후) 조직에 우선순위를 부여해야 한다. 다중 샘플은, 입수 가능성을 기준으로, 소정의 환자에 대하여 수집될 수 있지만; 블록 또는 15개 이상의 염색되지 않은 슬라이드에 대한 요건은 단일 생검 또는 절제 시료에 의해 충족되어야 한다.

If appropriate tissue and/or multiple metastatic tumors obtained at separate time points (e.g., time of initial diagnosis and time of disease recurrence) are available, preference is given to the most recently collected (ideally after the most recent systemic adjuvant therapy). should be ranked. Multiple samples may be collected for a given patient, based on availability; The requirement for blocks or more than 15 unstained slides must be met by a single biopsy or excision sample.

주요 사전 동의서(ICF)에 서명하기 전에, 환자는 보관 또는 새로운 종양 표본의 수집 및 시험을 특별히 허용하기 위해 사전 선별검사 ICF에 서명할 수 있다.

Prior to signing the Primary Informed Consent Form (ICF), the patient may sign the Prior Screening ICF to specifically allow storage or collection and testing of new tumor specimens.

환자가 하기의 요건들 중 임의의 것을 충족하는 경우, 불충분한 또는 입수 가능하지 않은 보관 조직을 가진 환자는, 의료 모니터 요원과의 논의시, 적격이 될 수 있다:

Patients with insufficient or not available storage tissue may be eligible, upon discussion with medical monitor personnel, if the patient meets any of the following requirements:

적어도 10개의 염색되지 않은 연속 슬라이드를 제공할 수 있음

Can provide at least 10 unstained serial slides

종양의 전처리 코어, 펀치 또는 절제/절개 생검 샘플 수집에 동의하고 이를 받을 의향이 있음(허용 가능한 샘플은 상기를 참조).

Consent and willing to receive a pretreatment core, punch or excision/incision biopsy sample of the tumor (see above for acceptable samples).

용량 증량 코호트에 등록할 예정임

Will be enrolled in a dose escalation cohort

화학요법 확장 코호트(Ib상)에 등록할 예정임

To be enrolled in the Chemotherapy Expansion Cohort (Phase Ib)

Q4W 투약 확장 코호트(Ib상)에 등록할 예정임

To be enrolled in the Q4W Dosing Expansion Cohort (Phase Ib)

보충 코호트 또는 확장 코호트에 속한 환자의 경우, 제출된 보관 종양 조직은 등록 전에 PD-L1 및/또는 TIGIT 발현에 대해 평가해야 한다.

For patients in the supplemental or expansion cohorts, the submitted archival tumor tissue should be evaluated for PD-L1 and/or TIGIT expression prior to enrollment.

RECIST v1.1에 따라 측정 가능한 질병을 가진 환자

Patients with measurable disease according to RECIST v1.1

이전에 조사된 병변은 표적 병변으로 계산된다.

A previously irradiated lesion is counted as a target lesion.

생검을 목적으로 하는 병변은 표적 병변으로 간주하지 않는다.

Lesions intended for biopsy are not considered target lesions.

F. Additional Inclusion Criteria for Patients Withdrawal of Phase Ia and Ib Cohort Replenishment

보충 코호트 등록은 이의 종양에 PD-L1 및/또는 TIGIT 발현이 있는 환자로 제한한다. 따라서, 보관 종양 조직을 제출하고 등록 전에 PD-L1 및/또는 TIGIT 발현에 대해 평가해야 한다. 이의 종양 조직이 PD-L1 발현에 대해 평가할 수 없는 환자는 적격이 아니다. PD-L1 및/또는 TIGIT 발현은 면역 침윤성 세포 또는 종양 세포에서 평가될 수 있다. 여러 종양 표본이 제출된 경우(예컨대, 보관 표본 및 재발된 질병의 조직), PD-L1 및/또는 TIGIT에 대해 적어도 1개의 표본을 평가할 수 있는 경우 환자는 적격일 수 있다. 상기 환자의 PD-L1 및/또는 TIGIT 점수는 각각 샘플 중 최대 PD-L1 및/또는 TIGIT 점수이다.

Enrollment in the supplemental cohort is limited to patients with PD-L1 and/or TIGIT expression in their tumors. Therefore, archival tumor tissues should be submitted and evaluated for PD-L1 and/or TIGIT expression prior to enrollment. Patients whose tumor tissue cannot be assessed for PD-L1 expression are not eligible. PD-L1 and/or TIGIT expression can be assessed in immune invasive cells or tumor cells. If multiple tumor specimens are submitted (eg, archival specimens and tissue of relapsed disease), a patient may be eligible if at least one specimen can be evaluated for PD-L1 and/or TIGIT. The patient's PD-L1 and/or TIGIT score is the maximum PD-L1 and/or TIGIT score in the sample, respectively.

환자는 하기의 종양 유형 중 하나의 PD-L1 선택 및/또는 TIGIT 선택된 종양이 있어야 한다: 비소세포폐암(NSCLC), 신세포암(RCC), 삼중음성 유방암(TNBC), 흑색종, 두경부 편평세포 암종(HNSCC), 난소암(OC), 위식도 접합부(GEJ) 암을 포함한 위암(GC), 요로상피 방광암(UBC), 미세위성 안정(MSS) 및 낮은 미세위성 불안정성(MSI 낮음)을 포함한 결장직장암(CRC).

Patients must have a PD-L1-selected and/or TIGIT-selected tumor of one of the following tumor types: non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), triple negative breast cancer (TNBC), melanoma, head and neck squamous cell Colon including carcinoma (HNSCC), ovarian cancer (OC), gastric cancer (GC) including gastroesophageal junction (GEJ) cancer, urothelial bladder cancer (UBC), microsatellite stable (MSS) and low microsatellite instability (low MSI) rectal cancer (CRC).

환자는 유의적인 절차상의 합병증의 허용할 수 없는 위험 없이 총 1 내지 2회의 생검(치료 전 및 치료 중) 또는 1회의 생검(치료 전 생검 대신 보관 조직을 제출할 수 있는 경우)을 허용하는 접근 가능한 병변이 있어야 한다.

Patients with accessible lesions that allow a total of 1 to 2 biopsies (pre-treatment and on-treatment) or 1 biopsy (if archival tissue can be submitted in lieu of pre-treatment biopsies) without an unacceptable risk of significant procedural complications. there should be

허용가능한 샘플은 깊은 종양 조직 또는 림프절용 코어 바늘 생검 또는 피부, 피하, 또는 점막 병변용 절제, 절개, 펀치, 또는 겸자 생검을 포함한다. FNA, 삼출물 또는 복수의 세포 펠릿, 세척 샘플 및 뼈 생검은 허용하지 않는다. 코어 바늘 생검을 위해 고려되는 표적 병변은 주어진 시점(최소 직경 18 게이지)에서 최소 3개, 이상적으로는 5개의 코어를 탐색하는 데 적합한 것으로 간주된다.

Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excision, incision, punch, or forceps biopsies for skin, subcutaneous, or mucosal lesions. FNA, exudate or ascites cell pellets, wash samples and bone biopsies are not permitted. Target lesions considered for core needle biopsy are considered suitable to explore at least 3, ideally 5 cores at a given time point (minimum diameter 18 gauge).

여러 병변이 있는 경우, 종양 또는 전이 부위와 관련된 이질성의 도입을 피하기 위해 가능한 경우 모든 시점에서 동일한 종양 병변을 생검해야 한다.

In the presence of multiple lesions, the same tumor lesion should be biopsied at all time points whenever possible to avoid the introduction of heterogeneity associated with tumor or metastasis sites.

G. Additional Inclusion Criteria for Patients in the Expansion Cohort

확장 코호트의 등록은 이의 종양이 PD-L1 및/또는 TIGIT 선택된 환자로 제한된다. 따라서, 보관 종양 조직을 제출하고 등록 전에 PD-L1 및/또는 TIGIT 발현에 대해 평가해야 한다. 이의 종양 조직이 PD-L1 발현에 대해 평가할 수 없는 환자는 적격이 아니다. PD-L1 및/또는 TIGIT 발현은 면역 침윤성 세포 또는 종양 세포에서 평가될 수 있다. 여러 종양 표본이 제출된 경우(예컨대, 보관 표본 및 재발된 질병의 조직), PD-L1 및/또는 TIGIT 발현에 대해 적어도 1개의 표본을 평가할 수 있는 경우 환자는 적격일 수 있다. 상기 환자의 PD-L1 및/또는 TIGIT 점수는 각각 샘플 중 최대 PD-L1 및/또는 TIGIT 점수이다.

Enrollment in the expansion cohort is limited to patients whose tumors are selected for PD-L1 and/or TIGIT. Therefore, archival tumor tissues should be submitted and evaluated for PD-L1 and/or TIGIT expression prior to enrollment. Patients whose tumor tissue cannot be assessed for PD-L1 expression are not eligible. PD-L1 and/or TIGIT expression can be assessed in immune invasive cells or tumor cells. If multiple tumor specimens are submitted (eg, archival specimens and tissues of relapsed disease), a patient may be eligible if at least one specimen can be evaluated for PD-L1 and/or TIGIT expression. The patient's PD-L1 and/or TIGIT score is the maximum PD-L1 and/or TIGIT score in the sample, respectively.

각 확장 코호트에서 발생한 환자의 약 절반이 선택적 생검을 받는 데 동의한 환자가 되도록 등록을 관리하다.

Manage enrollment so that approximately half of the patients occurring in each expansion cohort are those who have consented to undergo an elective biopsy.

Ib상의 연속 생검 확장 코호트에 등록된 환자의 경우, 생검이 필요하다.

For patients enrolled in the Phase Ib serial biopsy expansion cohort, a biopsy is required.

H. Additional Inclusion Criteria for Patients in the Phase Ia Expansion Cohort

환자는 하기의 종양 유형을 포함하는 PD-L1 선택 및/또는 TIGIT 선택된 종양이 있어야 한다: NSCLC, RCC, TNBC, 흑생종, HNSCC, OC, GEJ 암을 포함한 GC, UBC, 및 CRC

Patients must have PD-L1 selected and/or TIGIT selected tumors comprising the following tumor types: NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC, UBC, and CRC including GEJ cancers

I. Additional inclusion criteria for patients in the expanded cohort for each indication in Phase Ib

NSCLC 코호트(CIT 미경험): CIT(항 PD-L1/PD-1 제제를 포함)가 현지 규제 당국에 의해 NSCLC 치료제로 승인된 경우, 항 PD-L1/PD-1 및/또는 항 CTLA-4(세포독성 T 림프구 관련 단백질 4)를 포함하여 이전에 CIT(조사 또는 승인)로 치료한 적이 없는 조직학적으로 확인된 난치성, 진행성 NSCLC를 가지고, 항 PD-L1 항체와 병용한 임상 시험용 제제에 대한 임상 시험이 허용 가능한 치료 선택 사항으로 간주되는 환자를 포함한다.

NSCLC cohort (CIT naive) : Anti-PD-L1/PD-1 and/or anti-CTLA-4 (anti-PD-L1/PD-1 and/or anti-CTLA-4) if CIT (including anti-PD-L1/PD-1 agents) has been approved as a treatment for NSCLC by local regulatory authorities. Clinical trials for investigational agents in combination with anti-PD-L1 antibodies with histologically confirmed refractory, advanced NSCLC not previously treated with CIT (investigation or approval), including cytotoxic T lymphocyte-associated protein 4). Include patients for whom the trial is considered an acceptable treatment option.

종양이 공지된 감작성 EGFR 돌연변이 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 EGFR 티로신 키나아제 억제제(들)를 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have a known sensitizing EGFR mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with the EGFR tyrosine kinase inhibitor(s).

종양이 공지된 역형성 림프종 키나아제(ALK) 재배열을 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 ALK 티로신 키나아제 억제제(들)을 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have known anaplastic lymphoma kinase (ALK) rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ALK tyrosine kinase inhibitor(s).

종양이 공지된 ROS1 재배열을 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 ROS1 티로신 키나아제 억제제(들)을 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have known ROS1 rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ROS1 tyrosine kinase inhibitor(s).

종양이 BRAF^V600E 돌연변이를 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 트라메티닙과 병용한 다브라페닙을 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have the BRAF ^V600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib.

NSCLC 코호트(CIT 치료됨): 항 L1/PD-1을 포함하여 이전에 CIT(조사 또는 승인)로 치료된 적이 있는 조직학적으로 확인된 난치성, 진행성 NSCLC를 가진 환자.

NSCLC Cohort (CIT Treated) : Patients with histologically confirmed refractory, advanced NSCLC who have previously been treated with CIT (investigation or approval), including anti-L1/PD-1.

종양이 공지된 감작성 EGFR 돌연변이 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 EGFR 티로신 키나아제 억제제(들)를 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have a known sensitizing EGFR mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with the EGFR tyrosine kinase inhibitor(s).

종양이 공지된 ALK 재배열을 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 ALK 티로신 키나아제 억제제(들)을 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have known ALK rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ALK tyrosine kinase inhibitor(s).

종양이 공지된 ROS1 재배열을 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 ROS1 티로신 키나아제 억제제(들)을 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have known ROS1 rearrangements must also have experienced disease progression (during or after treatment) or intolerance to treatment with the ROS1 tyrosine kinase inhibitor(s).

종양이 BRAF^V600E 돌연변이를 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 트라메티닙과 병용한 다브라페닙을 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors have the BRAF ^V600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib.

환자는 이전에 항 PD-L1/PD-1을 포함해야 하는 CIT 단독요법 및/또는 병용요법(조사 또는 승인)에서 문서화된 질병 진행을 경험했어야 한다.

The patient must have previously experienced documented disease progression on CIT monotherapy and/or combination therapy (research or approval) that should include anti-PD-L1/PD-1.

단독요법 및/또는 병용요법으로서의 이전의 항 PD-L1/PD-1은 상기 확장 코호트에 등록하기 전에 투여된 가장 최근의 전신 항암 요법을 나타내야 한다.

Previous anti-PD-L1/PD-1 as monotherapy and/or combination therapy should represent the most recent systemic anticancer therapy administered prior to enrollment in the expansion cohort.

단독요법 또는 병용요법으로 이전의 항 L1/PD-1을 투여받는 동안 임의의 시간에 RECIST v1.1에 따라 시험자가 평가한 확인된 부분 반응(PR) 또는 완전 반응(CR)에 대한 문서화된 최상의 반응을 경험한 약 10명 이상의 환자가 등록될 수 있다.

Documented best-practice for confirmed partial response (PR) or complete response (CR) assessed by investigator per RECIST v1.1 at any time while receiving prior anti-L1/PD-1 as monotherapy or combination therapy About 10 or more patients experiencing a reaction may be enrolled.

단독요법 및/또는 병용요법으로 이전의 항 L1/PD-1을 투여받는 동안 임의의 시간에 RECIST v1.1에 따라 시험자가 평가한 안정한 질병(SD)에 대한 문서화된 최상의 반응을 경험한 약 10명 이상의 환자가 등록될 수 있다.

About 10 who experienced the best documented response for stable disease (SD) assessed by investigator according to RECIST v1.1 at any time while receiving prior anti-L1/PD-1 as monotherapy and/or combination therapy More than one patient may be enrolled.

단독요법 및/또는 병용요법으로 이전의 항 PD-L1/PD-1을 투여받는 동안 임의의 시간에 RECIST v1.1에 따라 시험자가 평가한 진행성 질병(PD)에 대한 문서화된 최상의 반응을 경험한 약 10명 이상의 환자가 등록될 수 있다.

Experienced best documented response to investigator-assessed progressive disease (PD) according to RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or combination therapy More than about 10 patients may be enrolled.

단독요법 및/또는 병용요법으로서의 이전의 항 PD-L1/PD-1은 상기 확장 코호트에 등록하기 전에 투여된 가장 최근의 전신 항암 요법을 나타내야 한다.

Previous anti-PD-L1/PD-1 as monotherapy and/or combination therapy should represent the most recent systemic anticancer therapy administered prior to enrollment in the expansion cohort.

주로 독성 또는 불내성을 이유로 이전의 항 PD-L1/PD-1 단일요법 및/또는 병용요법을 중단한 환자는 상기 확장 코호트 등록에 적격이지 않다.

Patients who discontinue previous anti-PD-L1/PD-1 monotherapy and/or combination therapy, primarily for toxicity or intolerance, are not eligible for this expansion cohort enrollment.

TNBC 코호트: 조직학적으로 난치성, 진행성 에스트로겐 수용체(ER) 음성, 프로게스테론 수용체 음성, 및 인간 표피 성장 인자 수용체 2(HER2) 음성 유방 선암종(삼중 음성)이 확인된 환자

TNBC Cohort : Histologically confirmed refractory, advanced estrogen receptor (ER) negative, progesterone receptor negative, and human epidermal growth factor receptor 2 (HER2) negative breast adenocarcinoma (triple negative).

삼중 음성 상태는 미국임상종양학회 미국병리학회(ASCO-CAP) 지침에 정의된 바와 같이 문서화해야 한다:

Triple negative status should be documented as defined in the American Society of Clinical Oncology (ASCO-CAP) guidelines:

(i) 종양 세포 핵의 < 1%는 ER에 대하여 면역반응성이고 종양 세포 핵의 < 1%는 프로게스테론 수용체에 대하여 면역반응성이며

(i) <1% of tumor cell nuclei are immunoreactive to ER and <1% of tumor cell nuclei are immunoreactive to progesterone receptor;

and

HER2 시험은 면역조직화학 (IHC) 1+, IHC 0, 또는 동일계내 혼성화(ISH) 음성을 나타낸다

HER2 test is immunohistochemistry (IHC) 1+, IHC 0, or in situ hybridization (ISH) negative

CRC 코호트t: 결장 또는 직장의 난치성 진행성 선암종이 조직학적으로 확인된 환자

CRC cohort t : Patients with histologically confirmed refractory advanced adenocarcinoma of the colon or rectum

맹장 기원의 종양을 가진 환자는 적격이지 않다.

Patients with tumors of cecal origin are not eligible.

GC 코호트: 조직학적으로 확인된 수술이 불가능한, 국소 진행성 또는 전이성 또는 재발성 위 또는 GEJ 선암종(완치 요법에 적합하지 않음)을 가진 환자

GC Cohort : Patients with histologically confirmed inoperable, locally advanced or metastatic or recurrent gastric or GEJ adenocarcinoma (not suitable for curative therapy)

해부학적 식도위 접합부 위 1 내지 5 cm 이내에 종양 중심이 위치하는 말단 식도의 선암종으로서 정의된 유형 1 GEJ 종양을 가진 환자는 상기 연구에 적격이다.

Patients with a type 1 GEJ tumor, defined as adenocarcinoma of the distal esophagus, with a tumor center located within 1 to 5 cm above the anatomical gastroesophageal junction, are eligible for this study.

식도암(편평세포 암종 또는 선암종)을 가진 환자는 의료 모니터와의 논의 후에 적격이 될 수 있다.

Patients with esophageal cancer (squamous cell carcinoma or adenocarcinoma) may be eligible after discussion with a medical monitor.

종양이 HER2 양성인 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 HER2 표적화 항체/HER2 억제제(들)을 이용한 치료에 불내성을 경험했어야 한다.

Patients whose tumors are HER2 positive must also have experienced disease progression (during or after treatment) or intolerance to treatment with the HER2 targeting antibody/HER2 inhibitor(s).

HER2 양성은, 원발성 종양 또는 전이성 병변에 대한 국소 실험실 검사에 의해 평가된 바와 같이, IHC 3+ 또는 IHC 2+/ISH+(여기서, ISH 양성은 ₃2의 HER2:CEP17 비율로 정의됨)로 정의된다.

HER2 positivity is defined as IHC 3+ or IHC 2+/ISH+, where ISH positivity is defined as a HER2:CEP17 ratio of ₃2, as assessed by local laboratory tests for primary tumors or metastatic lesions.

불충분하거나 입수 불가능한 조직(예컨대, 보관 및/또는 생검)으로 인해 HER2 검사를 받지 않아 종양의 HER2 상태를 알 수 없는 환자는 의료 모니터와 논의 후 여전히 적격일 수 있다.

Patients whose tumor's HER2 status is unknown because they have not undergone HER2 testing due to insufficient or unavailable tissue (eg, storage and/or biopsies) may still be eligible after discussion with a medical monitor.

HNSCC 코호트: 조직학적으로 확인된 수술 불가능한, 국소 진행성 또는 전이성, 재발성, 또는 지속성 두경부 편평세포 암종(구강, 구인두, 하인두, 또는 후두)(근치 요법이 적합하지 않음)을 가진 환자

HNSCC Cohort : Patients with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent squamous cell carcinoma of the head and neck (oral, oropharyngeal, hypopharyngeal, or larynx) for which curative therapy is not suitable.

머리 및 목의 다른 원발성 해부학적 위치에 HNSCC를 가진 환자, 원발성이 알려지지 않은 HNSCC를 가진 환자, 또는 비편평 조직학적 종양을 가진 환자는 적격이지 않다.

Patients with HNSCC in other primary anatomical locations of the head and neck, patients with HNSCC of unknown primary, or patients with nonsquamous histological tumors are not eligible.

비인두의 HNSCC가 있는 환자는 의료 모니터요원(Medical Monitor)과 논의한 후 적격이 될 수 있다.

Patients with HNSCC of the nasopharynx may be eligible after discussion with a Medical Monitor.

HNSCC에 대한 HPV 상태는 공지되어 있어야 한다.

The HPV status for HNSCC should be known.

UBC 코호트: 조직학적으로 확인된 요로상피(신우, 요관, 방광, 및 요도를 포함)의 난치성 진행성 이행 세포 암종을 가진 환자

UBC Cohort : Patients with histologically confirmed refractory advanced transitional cell carcinoma of the urothelium (including renal pelvis, ureter, bladder, and urethra)

혼합 조직을 가진 환자는 지배적인 이행 세포 패턴을 가져야 한다.

Patients with mixed tissue should have a dominant transitional cell pattern.

흑색종 코호트: 조직학적으로 확인된 난치성 진행성 전이성 흑색종을 가진 환자

Melanoma Cohort : Patients with histologically confirmed refractory advanced metastatic melanoma

CIT(항 PD-L1/PD-1 제제 및/또는 항 CTLA-4 제제를 포함)가 현지 규제 당국에 의해 흑색종 치료제로 승인된 경우, 이의 항 PD-L1/PD-1 항체와 병용한 임상 시험용 제제에 대한 임상 시험이 허용 가능한 치료 선택 사항으로 간주되는 흑생종을 가진 환자를 포함한다.

Clinical trials in combination with its anti-PD-L1/PD-1 antibody when CIT (including anti-PD-L1/PD-1 agents and/or anti-CTLA-4 agents) has been approved for the treatment of melanoma by local regulatory authorities Clinical trials of investigational agents include patients with melanoma who are considered an acceptable treatment option.

종양이 공지된 BRAFV600 돌연변이를 갖는 환자는 또한 (치료 동안 또는 이후) 질병 진행 또는 BRAF 억제제(들) 및/또는 미토겐 활성화 단백질 키나아제(MEK) 억제제(들)에 대한 불내성을 경험했어야 한다.

Patients whose tumors have a known BRAFV600 mutation must also have experienced disease progression (during or after treatment) or intolerance to BRAF inhibitor(s) and/or mitogen activated protein kinase (MEK) inhibitor(s).

상기 코호트의 환자 중 약 20% 이하가 안구(포도막) 흑색종을 가진 환자가 되도록 등록을 관리한다.

Enrollment is managed so that no more than about 20% of patients in this cohort have ocular (uveal) melanoma.

OC 코호트: 조직학적으로 확인된 난치성, 진행성 상피성 난소암, 나팔관암 또는 원발성 복막암을 가진 환자

OC Cohort : Patients with histologically confirmed refractory, advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer

경계성 난소 상피 신생물(예컨대, 악성 가능성이 낮은 종양, 비정형 증식성 종양)은 제외한다.

Borderline ovarian epithelial neoplasms (eg, low malignant tumors, atypical proliferative tumors) are excluded.

RCC 코호트: 투명 세포 조직학의 성분 및/또는 육종양 조직학의 성분을 가진 조직학적으로 확인된 불치성, 진전된 RCC를 가진 환자

RCC Cohort : Patients with histologically confirmed incurable, advanced RCC with a component of clear cell histology and/or a component of sarcoma histology

CIT(항 PD-L1/PD-1 제제를 포함)가 현지 규제 당국에 의해 RCC 치료제로 승인된 경우, 이의 항 PD-L1 항체와 병용한 임상 시험용 제제에 대한 임상 시험이 허용 가능한 치료 선택 사항으로 간주되는 RCC를 가진 환자를 포함한다.

When CITs (including anti-PD-L1/PD-1 agents) have been approved by local regulatory authorities for the treatment of RCC, clinical trials of their investigational agents in combination with their anti-PD-L1 antibodies are considered acceptable treatment options. Include patients with RCC considered.

J. Additional Inclusion Criteria for Patients in the Phase Ib Serial Biopsy Expansion Cohort

환자는 하기의 종양 유형을 포함할 수 있는 PD-L1 선택 및/또는 TIGIT 선택된 종양이 있어야 한다: 흑색종, OC, RCC, 및 UBC.

The patient must have a PD-L1 selected and/or TIGIT selected tumor, which may include the following tumor types: melanoma, OC, RCC, and UBC.

CIT(항 PD-L1/PD-1 제제를 포함)가 현지 규제 당국에 의해 상기 적응증(들)의 치료제로 승인된 경우, 이의 항 PD-L1 항체와 병용한 임상 시험용 제제에 대한 임상 시험이 허용 가능한 치료 선택 사항으로 간주되는 흑색종 또는 RCC를 가진 환자

If CIT (including anti-PD-L1/PD-1 agents) has been approved as a treatment for the above indication(s) by the local regulatory authority, clinical trials for clinical investigational agents in combination with its anti-PD-L1 antibody are permitted. Patients with melanoma or RCC considered a possible treatment option

환자는 유의적인 절차상의 합병증의 허용 불가능한 위험 없이 총 1 내지 2회의 생검(치료 전 및 치료 중) 또는 1회의 생검(치료 전 생검 대신 보관 조직을 제출할 수 있는 경우)을 허용하는 접근 가능한 병변이 있어야 한다.

Patients must have an accessible lesion that allows for a total of 1-2 biopsies (pre-treatment and on-treatment) or 1 biopsy (if archival tissue can be submitted in lieu of a pre-treatment biopsy) without an unacceptable risk of significant procedural complications. do.

허용가능한 샘플은 깊은 종양 조직 또는 림프절용 코어 바늘 생검 또는 피부, 피하, 또는 점막 병변용 절제, 절개, 펀치, 또는 겸자 생검을 포함한다. FNA, 삼출물 또는 복수의 세포 펠릿, 세척 샘플 및 뼈 생검은 허용하지 않는다. 코어 바늘 생검을 위해 고려되는 표적 병변은 주어진 시점(최소 직경 18 게이지)에서 최소 3개, 이상적으로는 5개의 코어를 탐색하는 데 적합한 것으로 간주된다.

Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excision, incision, punch, or forceps biopsies for skin, subcutaneous, or mucosal lesions. FNA, exudate or ascites cell pellets, wash samples and bone biopsies are not permitted. Target lesions considered for core needle biopsy are considered suitable to explore at least 3, ideally 5 cores at a given time point (minimum diameter 18 gauge).

In the presence of multiple lesions, the same tumor lesion should be biopsied at all time points whenever possible to avoid the introduction of heterogeneity associated with tumor or metastasis sites.

K. Exclusion Criteria

Patients meeting any of the following criteria are excluded from study enrollment:

General exclusion criteria

연구 및 추적 조사 절차를 준수할 능력이 없음

Inability to comply with study and follow-up procedures

임신, 젖분비, 또는 수유

Pregnant, lactating, or lactating

뉴욕 심장학회 분류 심장병 (분류 II 이상), 지난 3개월 이내의 심근경색, 불안정성 부정맥 및/또는 불안정형 협심증과 같은 심각한 심혈관 질병.

New York Heart Association Classification Heart disease (class II or higher), serious cardiovascular disease such as myocardial infarction within the past 3 months, unstable arrhythmias and/or unstable angina.

활동성 바이러스, 알코올성 또는 기타 간염, 간경변, 유전성 간 질병 또는 현재 알코올 남용을 포함하여 임상적으로 유의미한 것으로 알려진 간 질병.

Liver disease known to be clinically significant, including active virus, alcoholic or other hepatitis, cirrhosis, hereditary liver disease, or current alcohol abuse.

선별검사 헤모글로빈 A1_C　₃　8% 또는 공복 혈당 ₃ 160 mg/dL(또는 8.8 mmol/L)로 정의되는 제대로 조절되지 않는 제2형 당뇨병

Poorly controlled type 2 diabetes, defined as screening hemoglobin A1 _C ₃ 8% or fasting blood sugar ₃ 160 mg/dL (or 8.8 mmol/L)

주기 1, 1일에 이전 28일 이내의 주요 수술 절차 또는 연구 과정 중 주요 수술 절차 필요성이 예상되는 경우

On Cycle 1, Day 1, major surgical procedures within the previous 28 days or the need for major surgical procedures during the course of the study are anticipated.

임상시험용 약물의 사용을 금하거나 결과 해석에 영향을 미칠 수 있거나 환자를 치료 합병증으로 인한 고위험에 빠뜨릴 수 있는 질병 또는 병태에 대한 합리적인 의심을 제공하는 기타 질병, 대사 기능장애, 신체 검사 소견, 및/또는 임상 실험실 소견

Other diseases, metabolic dysfunctions, physical examination findings, and/or which give rise to a reasonable suspicion of a disease or condition that may contraindicate the use of investigational drugs or may affect the interpretation of results or place the patient at high risk for complications of treatment; or clinical laboratory findings

L. Criteria for exclusion by cancer

하기의 경우를 제외하고, 연구 치료제의 개시에 앞서 3주 이내에 조사 또는 승인에 상관없이 화학요법, 호르몬 요법, 및/또는 방사선요법을 포함한, 임의의 항암 요법:

Any anti-cancer therapy, including chemotherapy, hormonal therapy, and/or radiotherapy, regardless of irradiation or approval, within 3 weeks prior to initiation of study therapy, except as follows:

전립선 암에 대하여 성선자극호르몬 방출 호르몬(GnRH) 작용제 또는 길항제를 이용한 호르몬 요법

Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for prostate cancer

호르몬 대체 요법 또는 경구 피임약

Hormone replacement therapy or oral contraceptives

주기 1의 1일에 앞서 7일을 초과하여 중단된 암 치료를 위해 지역 규제 당국에서 승인한 티로신 키나아제 억제제(TKI)의 경우; 기준선 스캔은 선행 TKI 중단 후 수득해야 하고, 선행 암 치료로 인한 이상 반응과 관련된 기준을 충족해야 한다.

For tyrosine kinase inhibitors (TKIs) approved by local regulatory authorities for cancer treatment discontinued more than 7 days prior to Day 1 of Cycle 1; Baseline scans must be obtained after discontinuation of prior TKI and must meet criteria related to adverse events due to prior cancer treatment.

주기　1의 1일에 앞서 1주일 초과의 한방 요법

More than 1 week of herbal therapy prior to Day 1 of Cycle 1.

주기 1의 1일에 앞서 2주를 초과한 통증성 전이 또는 잠재적으로 민감한 위치(예컨대, 경막외강)의 전이에 대한 완화 방사선요법

Palliative radiotherapy for painful metastases greater than 2 weeks prior to Day 1 of Cycle 1 or metastases to potentially sensitive locations (eg, epidural space)

본 연구의 Ia상 부분에서 티라골루맙 및 아테졸리주맙을 사용한 2b상 연구로 전환하는 환자는 Ib상 연구에 들어가기 전에 단일 제제로서 티라골루맙으로 치료받을 수 있다.

Patients transitioning from the Phase Ia portion of this study to a Phase 2b study with tiragolumab and atezolizumab may be treated with tyragolumab as a single agent prior to entering the Phase Ib study.

CIT를 이용한 선행 치료에 기반된 적격성은 약물의 기계론적인 부류 및 하기에 기재된 바와 같이 환자가 고려되는 코호트에 따라 좌우된다: 또한, 선행 암 요법으로 인한 이상 반응과 관련된 모든 기준을 충족해야 한다.

Eligibility based on prior treatment with CIT depends on the mechanistic class of drug and the cohort into which patients are considered, as described below: In addition, all criteria related to adverse events due to prior cancer therapy must be met.

All cohorts in Phase Ia and Ib (Dose Escalation, Supplementation, and Expansion) :

하기의 경우를 제외하고, 선행 항 TIGIT 제제는 허용되지 않는다:

Prior anti-TIGIT agents are not permitted, except in the following cases:

Ia상 연구에서 티라골루맙으로 치료받은 환자는 지정된 기준이 충족되는 경우 Ib상 연구에 등록하는 것이 허용될 수 있다.

Patients treated with tiragolumab in a Phase Ia study may be accepted to enroll in a Phase Ib study if the specified criteria are met.

암 백신 및/또는 사이토카인을 이용한 선행 치료는 적어도 6주 또는 약물의 5회 반감기 중 더 짧은 기간이 마지막 용량 투여 내지 제안된 주기 1의 1일 사이를 경과한 경우 허용된다.

Prior treatment with cancer vaccines and/or cytokines is permitted provided that at least 6 weeks or 5 half-lives of the drug, whichever is shorter, has elapsed between the last dose administration and Day 1 of the proposed cycle 1.

최소 휴약 기간은 임의의 선행 전신 암 요법의 경우 3주이다.

The minimum washout period is 3 weeks for any prior systemic cancer therapy.

이러한 프로토콜에 명시적으로 기재되지 않은 선행 암 면역요법은 잠재적 적격성을 결정하기 위해 의료 모니터 요원과 논의해야 한다.

Prior cancer immunotherapy not expressly described in these protocols should be discussed with the medical monitor to determine potential eligibility.

Phase Ia and Ib Dose Escalation and Supplemental Cohorts (Enrollment During Dose Escalation):

면역 관문 억제제(예컨대, 항 PD-L1/PD-1), 면역조절 MAb, 및/또는 MAb 유래 요법을 사용한 선행 치료는 마지막 용량 투여 내지 제안된 주기 1의 1일 사이에 약물의 적어도 5회의 제거 반감기가 경과한 경우 허용된다.

Prior treatment with an immune checkpoint inhibitor (eg, anti-PD-L1/PD-1), immunomodulatory MAb, and/or MAb-derived therapy includes at least 5 eliminations of drug between the last dose administration and day 1 of the proposed cycle 1. Allowed if half-life has elapsed.

톨 유사 수용체(TLR) 작용제, 인돌아민 2,3-디옥시게나제 또는 트립토판-2,3-디옥시게나제(IDO/TDO) 억제제, 또는 OX40 작용제를 포함한 면역조절제를 이용한 선행 치료는 마지막 용량 투여 내지 제안된 주기 1의 1일 사이에 적어도 6주가 경과한 경우 허용된다.

Prior treatment with immunomodulators including Toll-like receptor (TLR) agonists, indoleamine 2,3-dioxygenase or tryptophan-2,3-dioxygenase (IDO/TDO) inhibitors, or OX40 agonists Acceptable if at least 6 weeks have elapsed between Day 1 of the proposed cycle 1.

Capacity Expansion and Supplemental Cohorts in Phase Ia and Ib (Enrollment During Dose Expansion):

면역 관문 억제제, 면역조절 MAb, 및/또는 MAb 유래 요법을 사용한 선행 치료는, 하기의 경우를 제외하고, 마지막 용량 투여 내지 제안된 주기 1의 1일 사이에 적어도 6주가 경과한 경우 허용된다:

Prior treatment with an immune checkpoint inhibitor, immunomodulatory MAb, and/or MAb-derived therapy is permitted provided that at least 6 weeks have elapsed between the last dose administration and Day 1 of the proposed Cycle 1, except as follows:

The preceding anti-PD-L1/PD-1 must undergo a washout period of at least 3 weeks

Antecedent CTLA-4 must undergo a 6-week washout period

Ib상 NSCLC CIT 치료 확장 코호트에서, 가장 최근의 전신 치료는 항 PD-L1/PD-1을 단독요법 또는 병용요법으로서 가져야 한다.

In the Phase Ib NSCLC CIT Treatment Expansion Cohort, the most recent systemic treatment should have anti-PD-L1/PD-1 as monotherapy or combination therapy.

Ib상의 NSCLC CIT 미경험 확장 코호트에서, 면역 관문 억제제(예컨대, 항 PD-L1/PD-1), 면역조절 MAb, 및/또는 MAb 유래 요법을 이용한 선행 치료는 허용되지 않는다.

Prior treatment with immune checkpoint inhibitors (eg, anti-PD-L1/PD-1), immunomodulatory MAbs, and/or MAb-derived therapies is not permitted in the Phase Ib NSCLC CIT-naive expansion cohort.

Prior treatment with an immunomodulatory agent, including a TLR agonist, IDO/TDO inhibitor, or OX40 agonist, includes at least 5 half-lives of the drug between administration of the last dose of the prior treatment and Day 1 of the proposed Cycle 1, with the following exceptions: Or if at least 3 weeks result is acceptable:

In the NSCLC CIT-naive Expansion Cohort on Phase Ib, prior treatment with other immunomodulatory agents is not permitted.

선행 암 면역요법으로 인한 면역 관련 4 등급의 이상 반응에 관한 임의의 이력(대체 요법으로 관리되는 내분비병증 또는 혈청 아밀라제 또는 리파아제의 무증상 상승 제외)

Any history of immune-related Grade 4 adverse events from prior cancer immunotherapy (except for endocrinopathy managed with replacement therapy or asymptomatic elevations of serum amylase or lipase)

선행 면역치료제의 영구 중단을 초래하고/하거나 주기 1의 1일에 앞서 적어도 6개월 전에 실시한 선행 암 면역요법(대체 요법으로 관리되는 내분비병증 또는 혈청 아밀라아제 또는 리파아제의 무증상 상승 제외)으로 인한 면역 매개 3 등급의 이상 반응에 관한 임의의 이력

Immune-mediated 3 Any history of graded adverse events

대체 요법으로 관리되는 탈모증, 백반증 또는 내분비병증을 제외하고 등급 1 이하로 회복되지 않았던 선행 항암 요법의 이상 반응

Adverse reactions from prior anticancer therapy that did not return to grade 1 or lower except for alopecia, vitiligo, or endocrineopathy managed by alternative therapy

기준선으로 완전히 회복되지 않았던 선행 암 면역요법과 관련된 면역 매개 이상 반응(대체 요법으로 관리되는 내분비병증 또는 안정 백반증 제외)

Immune-mediated adverse events associated with prior cancer immunotherapy that did not fully recover to baseline (except for endocrinopathy or stable vitiligo managed with alternative therapy)

면역 매개 이상 반응으로 코르티코스테로이드 치료를 받은 환자는 코르티코스테로이드 중단 후 4주 이상 동안 관련 증상이나 징후가 없음을 입증해야 한다.

Patients treated with corticosteroids for immune-mediated adverse events should demonstrate no associated symptoms or signs for at least 4 weeks after discontinuation of corticosteroids.

NSCLC의 폐 림프상피종 유사 암종 아형 환자

Patients with Pulmonary Lymphothelioma-like Carcinoma Subtype of NSCLC

원발성 CNS 악성종양, 치료되지 않은 CNS 전이, 또는 활동성 CNS 전이(증상 통제를 위해 진행 중이거나 코르티코스테로이드가 필요한 경우)

Primary CNS malignancy, untreated CNS metastases, or active CNS metastases (if ongoing or require corticosteroids to control symptoms)

Patients with a history of treated CNS metastases are eligible if they meet all of the following criteria:

CNS 외부의 측정 가능한 질병

measurable disease outside the CNS

코르티코스테로이드가 등록에 앞서 2주 이상 동안 중단된 점을 제외하고, CNS 전이에 대한 요법으로서 코르티코스테로이드에 대한 진행 중인 요건 없음, 그리고 CNS 전이에 기인한 진행 중인 증상 없음

No ongoing requirements for corticosteroids as therapy for CNS metastases, except that corticosteroids were discontinued for at least 2 weeks prior to enrollment, and no ongoing symptoms due to CNS metastases

안정적인 용량의 항경련제를 사용할 수 있다.

Stable doses of anticonvulsants may be used.

CNS 지향된 요법의 완결 시에 향상의 방사선 사진 증거, 및 CNS 지향된 요법의 완결 및 선별검사 방사선투과 연구 사이에 중간 진행의 증거 없음

Radiographic evidence of improvement upon completion of CNS-directed therapy, and no evidence of intermediate progression between completion of CNS-directed therapy and screening radiographic studies.

선별검사 CNS 방사선투과 연구는 방사선요법의 완결 이후로 4주 이상임

Screening CNS radiographic study > 4 weeks after completion of radiotherapy

연수막성 질병

leptomeningeal disease

통제되지 않는 종양 관련 통증

Uncontrolled tumor-related pain

완화 방사선요법으로 치료할 수 있는 증상이 있는 병변(예컨대, 골 전이 또는 신경 충돌을 유발하는 전이)은 등록 전에 치료해야 한다.

Symptomatic lesions that can be treated with palliative radiotherapy (eg, bone metastases or metastases causing nerve impingement) should be treated prior to enrollment.

추가 성장이 기능성 결손 또는 난치성 통증(예컨대, 척수 압축과 현재 관련되지 않은 경막외 전이)을 유발할 수 있는 무증상 전이성 병변은 등록 전에 적절한 경우 국소 영역 요법에 대해 고려한다.

Asymptomatic metastatic lesions in which further growth may result in functional deficits or refractory pain (eg, epidural metastases not currently associated with spinal cord compression) are considered for local area therapy when appropriate prior to enrollment.

조절되지 않는 늑막 삼출, 심장주위 삼출, 또는 재발성 배출 절차를 요구하는 복수(매월 1회 또는 더 자주)

Uncontrolled pleural effusion, pericardiac effusion, or ascites requiring recurrent evacuation procedures (once monthly or more often)

카테터(예컨대, PLEURX®)를 장착한 환자는 허용한다.

Patients with catheters (eg PLEURX®) are permitted.

무시할만한 전이 또는 사망 위험이 있는 경우(예컨대, 적절히 치료된 자궁상피내 암종, 기저 또는 편평 세포 피부암, 국소 전립선암 또는 또는 관상피내암종)를 예외로 한, 주기 1의 1일에 앞서 5년 이내에 연구 중인 질병 이외의 악성 종양

Study within 5 years prior to Day 1 of Cycle 1, with the exception of cases with negligible risk of metastasis or death (e.g., appropriately treated intrauterine carcinoma, basal or squamous cell skin cancer, focal prostate cancer, or ductal carcinoma) Malignant tumors other than the underlying disease

통제되지 않은 고칼슘혈증(1.5 mmol/L 초과의 이온화 칼슘 또는12 mg/dL 초과의 Ca 또는 ULN 이상의 교정된 혈청 칼슘) 또는 지속적 비스포스포네이트 요법 또는 데노수맙의 사용을 요하는 증상성 고칼슘혈증.

Uncontrolled hypercalcemia (ionized calcium >1.5 mmol/L or Ca >12 mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring the use of continuous bisphosphonate therapy or denosumab.

In particular, patients receiving bisphosphonate therapy or denosumab to prevent skeletal events and without a history of clinically significant hypercalcemia are eligible. However, patients receiving denosumab must be willing or eligible to receive bisphosphonates instead of denosumab for the duration of the study.

환자는 수술 및/또는 방사선으로 척수 압박을 확실하게 치료하지 않았거나, 척수 압박에 대한 치료를 받았으나 선별검사에 앞서 2주 이상 질병이 임상적으로 안정적이라는 증거가 없다.

The patient has not reliably treated spinal cord compression with surgery and/or radiation, or has received treatment for spinal cord compression, but there is no evidence that the disease is clinically stable for more than 2 weeks prior to screening.

M. Treatment-specific exclusion criteria

하기의 경고를 수반한, 비제한적으로 전신 홍반성 낭창, 류마티스성 관절염, 염증성 장 질환, 항인지질 증후군과 관련된 혈관 혈전증, 베게너 육아종증, 쇼그렌 증후군, 벨 마비(자가면역 병인학의 경우에만), 길랑-바레 증후군, 다발성 경화증, 혈관염, 또는 사구체신염을 포함하는, 자가면역 질환의 이력:

With the following warnings, without limitation, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy (for autoimmune etiology only), Guillain - History of autoimmune diseases, including Barré's syndrome, multiple sclerosis, vasculitis, or glomerulonephritis:

Patients with a history of autoimmune hypothyroidism on stable doses of thyroid replacement hormone may be eligible.

Patients with eczema, psoriasis, chronic lichen simplex or vitiligo with only dermatological symptoms (eg, no psoriatic arthritis) may be eligible if the following conditions are met:

발진은 체표면적의 10% 미만을 덮어야 한다.

The rash should cover less than 10% of the body surface area.

질병은 기준선에서 잘 제어되며 낮은 역가의 국소 스테로이드만 필요하다.

Disease is well controlled at baseline and requires only low titer topical steroids.

마지막 12개월 이내에 기저 질환의 급성 악화가 없음(예컨대, 소랄렌에 더하여 자외선 A 방사선(PUVA), 메토트렉세이트, 레티노이드, 생물학적 제제, 경구 칼시뉴린 억제제, 고 역가 또는 경구 스테로이드가 필요하지 않음)

No acute exacerbation of underlying disease within the last 12 months (e.g., no need for ultraviolet A radiation (PUVA), methotrexate, retinoids, biologics, oral calcineurin inhibitors, high titers or oral steroids in addition to psoralen)

주기 1의 1일에 앞서 2주 이내에 전신 면역억제제(프레드니손 10 mg/일 초과, 사이클로포스파미드, 아자티오프린, 메토트렉세이트, 탈리도마이드 및 종양괴사인자-[TNF-] 길항제를 포함하지만 이에 제한되지는 않음)를 이용한 치료

Systemic immunosuppressants (prednisone >10 mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide, and tumor necrosis factor-[TNF-] antagonists, including but not limited to, within 2 weeks prior to Day 1 of Cycle 1) treatment with no)

Patients receiving acute, low-dose, systemic immunosuppressants (eg, a single dose of dexamethasone for nausea) may be enrolled in the study after discussion and approval with a medical monitor.

The use of inhaled corticosteroids (eg, fluticasone for chronic obstructive pulmonary disease) is permitted.

The use of oral mineralocorticoids (eg, fludrocortisone in patients with orthostatic hypotension) is permitted.

Physiological doses of corticosteroids for adrenal insufficiency are acceptable.

특발성 폐 섬유증, 폐렴(약물 유발 포함), 조직성 폐렴(즉, 폐쇄성 세기관지염, 잠복성 조직성 폐렴 등)의 병력 또는 선별검사 흉부 CT 스캔에서 활동성 폐렴의 증거

History of idiopathic pulmonary fibrosis, pneumonia (including drug-induced), systemic pneumonia (i.e. bronchiolitis obliterans, latent systemic pneumonia, etc.) or evidence of active pneumonia on a screening chest CT scan

A history of radiation pneumonitis (fibrosis) in the field of radiation is acceptable.

HIV 감염에 대한 양성 테스트

positive test for HIV infection

활동성 B형 간염(선별 검사 시 B형 간염 표면 항원[HBsAg] 검사 양성으로 정의됨)

Active hepatitis B (defined as positive hepatitis B surface antigen [HBsAg] test at screening)

Patients with previous or reversible hepatitis B infection (defined as negative HBsAg test and positive IgG antibody to the hepatitis B core antigen [anti-HBc]) are eligible. Hepatitis B virus (HBV) DNA should be obtained from these patients prior to day 1 of cycle 1 and should not show active infection.

활동성 C형 간염

active hepatitis C

Hepatitis C virus (HCV) antibody positive patients are eligible only if the polymerase chain reaction (PCR) is negative for HCV RNA.

활동성 EBV 감염 및 선별검사 시 만성 활동성 EBV 감염이 공지되거나 의심되는 경우

Active EBV infection and known or suspected chronic active EBV infection at screening

Patients positive for EBV IgG and/or EBNA are eligible only if EBV IgM and/or EBV PCR is negative.

활동성 결핵

active tuberculosis

감염 합병증, 세균혈증, 또는 중증 폐렴으로 인한 입원을 포함하지만 이에 제한되지는 않는 주기 1의 1일에 앞서 4주 이내의 중증 감염

Severe infection within 4 weeks prior to Day 1 of Cycle 1, including but not limited to hospitalization for infectious complications, bacteremia, or severe pneumonia

하기를 포함하여 중증 감염의 상기 기준을 충족하지 않는 최근 감염:

Recent infections that do not meet the above criteria for severe infections, including:

주기 1의 1일에 앞서 2주 이내에 감염 징후 또는 증상

Signs or symptoms of infection within 2 weeks prior to Day 1 of Cycle 1

주기 1의 1일에 앞서 2주 이내에 경구 또는 IV 항생제 투여

Administer oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1.

예방적 항생제를 투여받는 환자(예컨대, 요로 감염 또는 만성 폐쇄성 폐질환 예방)는 적격이다.

Patients receiving prophylactic antibiotics (eg, prevention of urinary tract infections or chronic obstructive pulmonary disease) are eligible.

선행 동종 골수 이식 또는 선행 고형 장기 이식

Prior allogeneic bone marrow transplantation or prior solid organ transplantation

주기 1의 1일에 앞서 4주 이내에 독성약화 생백신을 투여 또는 연구 중에 독성약화 생백신이 필요할 것으로 예상되는 경우

Administered live attenuated vaccine within 4 weeks prior to Day 1 of Cycle 1, or if live attenuated vaccine is expected to be required during the study

인플루엔자 예방접종은 인플루엔자 시즌 동안만 제공되어야 한다. 환자는 주기 1의 1일에 앞서 4주 이내에 또는 연구 중 어느 때라도, 그리고 마지막 연구 치료제 후 5개월 동안 독성약화 인플루엔자 생백신(예컨대, 플루미스트^β)을 접종해서는 안 된다.

Influenza vaccination should be given only during the influenza season. Patients should not receive live attenuated influenza vaccine (eg, flumist ^β ) within 4 weeks prior to Day 1 of Cycle 1 or at any time during the study and for 5 months after the last study treatment.

키메라성 또는 인간화 항체 또는 융합 단백질에 대한 중증 알러지성, 과민성, 또는 다른 과민증 반응의 병력

History of severe allergic, hypersensitivity, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

CHO 세포 제품에 대한 공지된 과민증

Known hypersensitivity to CHO cell products

아테졸리주맙 제제의 성분에 대한 알레르기 또는 과민증

Allergy or hypersensitivity to any component of the atezolizumab formulation

N. Exclusion Criteria Specific to the Chemotherapy Expansion Cohort

백금 또는 백금 함유 화합물에 대한 공지된 심각한 알레르기 또는 과민증

Known severe allergy or hypersensitivity to platinum or platinum-containing compounds

시스플라틴에 특정한 배제 기준

Exclusion Criteria Specific to Cisplatin

공지된 청력 장애가 있는 환자(시스플라틴 치료에만 해당)

Patients with known hearing impairment (cisplatin treatment only)

NCI CTCAE v4.0 기준에 정의된 바에 따른 2 등급 이상의 말초 신경병증(시스플라틴 치료에만 해당)

Grade 2 or greater peripheral neuropathy as defined by the NCI CTCAE v4.0 criteria (cisplatin treatment only)

콕크로프트-가울트 GFR 추정치를 기반으로 측정되거나 계산된 크레아티닌 청소율 60 mL/분(시스플라틴 치료에만 해당):

Creatinine clearance 60 mL/min, measured or calculated based on Cockcroft-Gault GFR estimates (cisplatin treatment only):

(140 - age) x (weight kg) x (0.85 for women)

72　x　 (serum creatidine mg/dL)

O. Exclusion Criteria Specific to Cohort A

페메트렉시드에 대한 공지된 심각한 알레르기 또는 과민증

Known severe allergy or hypersensitivity to pemetrexed

P. Exclusion Criteria Specific to Cohort B

파클리탁셀에 대한 공지된 심각한 알레르기 또는 과민증

Known severe allergy or hypersensitivity to paclitaxel

크레모포어^® EL을 함유한 제품에 대한 심각한 과민 반응의 공지된 이력(예컨대, 주사 농축액을 위한 시클로스포린 및 주사 농축액을 위한 테니포시드)

Known history of severe hypersensitivity reactions to products containing Cremophor ^® EL (eg, cyclosporine for injectable concentrate and teniposide for injectable concentrate)

Q. Exclusion Criteria Specific to Cohort C

에토포시드에 대한 공지된 심각한 알레르기 또는 과민증

Known severe allergy or hypersensitivity to etoposide

R. Exclusion Criteria Specific to Cohort D

카페시타빈 약물 제제의 임의의 성분에 과민증

Hypersensitivity to any component of the capecitabine drug formulation

알약을 삼킬 수 없음

unable to swallow pills

흡수장애 증후군, 위장 기능에 중대한 영향을 미치는 질환, 위 또는 소장 절제, 궤양성 대장염

Malabsorption syndrome, diseases that significantly affect gastrointestinal function, resection of the stomach or small intestine, ulcerative colitis

공지된 디히드로피리미딘 탈수소효소 결핍증 또는 플루오로피리미딘 요법에 대한 심각하고 예상치 못한 반응의 병력

History of known dihydropyrimidine dehydrogenase deficiency or serious and unexpected response to fluoropyrimidine therapy

항바이러스제 소리부딘(항바이러스제) 또는 브리부딘과 같은 화학적 관련 유사체의 동시 사용 요건(카페시타빈을 포함한 연구 치료제 개시 후 4주 이내에 상기 약물의 사용을 허용하지 않음)

Requirements for concomitant use of the antiviral agent sorivudine (an antiviral agent) or chemically related analogs such as bribudine (use of these drugs is not permitted within 4 weeks of initiation of study therapy, including capecitabine)

S. Exclusion criteria specific to cohort NC1

2회 세션에서 평균 3회 이상의 혈압 측정값을 기준으로 한 부적절하게 조절되는 고혈압(수축기 혈압 150 mmHg 초과 및/또는 이완기 혈압 100 mmHg 초과로 정의됨); 이러한 매개변수를 달성하기 위한 항고혈압 요법이 허용된다.

inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg) based on an average of 3 or more blood pressure measurements in 2 sessions; Antihypertensive therapy to achieve these parameters is acceptable.

고혈압 위기 또는 고혈압 뇌병증의 병력

History of hypertensive crisis or hypertensive encephalopathy

연구 치료제 개시 전 6개월 이내에 중대한 혈관 질환(예컨대, 외과적 치료가 필요한 대동맥류 또는 최근 말초 동맥 혈전증)

Serious vascular disease (e.g., aortic aneurysm or recent peripheral arterial thrombosis requiring surgical treatment) within 6 months prior to initiation of study treatment

연구 치료제 개시 전 1개월 이내의 객혈 이력(1회 사건 당 밝은 적혈구 2.5 mL 이상)

History of hemoptysis within 1 month prior to initiation of study treatment (more than 2.5 mL of bright red blood cells per event)

출혈 체질 또는 상당한 응고 장애의 증거(치료적 항응고제가 없는 경우)

Evidence of bleeding constitution or significant clotting disorders (in the absence of therapeutic anticoagulants)

현재 또는 최근(연구 치료제 개시 전 10일 이내) 아스피린(325 mg/일) 또는 클로피도그렐(75 mg/일)의 사용

Current or recent (within 10 days prior to initiation of study treatment) use of aspirin (325 mg/day) or clopidogrel (75 mg/day)

비고: INR 및/또는 aPTT가 연구 치료제 개시 전 7일 이내 치료 한계치(기관 표준에 따라) 내에 있고 환자가 연구 치료제 개시 전 2주 이상 동안 항응고제의 안정 용량을 투여받은 경우 치료 목적으로 전체 용량의 경구 또는 비경구 항응고제의 사용이 허용되고; 항응고제의 예방적 사용이 허용됨

Remarks: For therapeutic purposes, if the INR and/or aPTT are within the limit of treatment (according to institutional standards) within 7 days prior to initiation of study treatment and the patient has received a stable dose of anticoagulant for at least 2 weeks prior to initiation of study treatment, then the full dose of oral or the use of parenteral anticoagulants is permitted; Prophylactic use of anticoagulants is permitted

연구 치료제 개시 전 3일 이내에 혈관 접근 장치의 배치를 제외한 핵심 생검 또는 기타 경미한 수술 절차

Core biopsy or other minor surgical procedures excluding placement of vascular access devices within 3 days prior to initiation of study treatment

연구 치료제 개시 전 6개월 이내에 복부 또는 기관식도 누공, 위장 천공 또는 복강내 농양의 병력

History of abdominal or tracheoesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment

연구 치료제 개시 전 6개월 이내 기저 질환과 관련된 폐색하부 또는 폐쇄성 증후군 또는 연구 치료제 개사 전 6개월 이내에 일상적인 비경구 수분공급, 비경구 영양, 또는 관 영양 공급이 필요한 경우를 포함한 장 폐쇄의 병력 및/또는 위장 폐쇄의 임상 징후 또는 증상

History and/or history of intestinal obstruction, including subobstructive or obstructive syndrome related to underlying disease within 6 months prior to initiation of study treatment, or requiring routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months prior to initiation of study treatment; or clinical signs or symptoms of gastrointestinal obstruction

폐색하부 또는 폐쇄성 증후군의 징후 또는 증상이 있거나 초기 진단 당시 장폐색이 있는 환자는 증상 해결을 위한 최종(외과적) 치료를 받은 경우 등록할 수 있음

Patients with signs or symptoms of subobstructive or obstructive syndrome, or with intestinal obstruction at the time of initial diagnosis, may be enrolled if they have received final (surgical) treatment to resolve their symptoms.

천자 또는 최근 수술 절차로 설명되지 않는 복부 자유 공기의 증거

Evidence of abdominal free air not accounted for by puncture or recent surgical procedures

치유되지 않는 심각한 상처, 활동성 궤양, 또는 치료되지 않은 골절

Severe wounds that do not heal, active ulcers, or untreated fractures

계량봉 소변 검사에서 2+ 이상의 단백질 및 24시간 소변 수집에서 1.0 g 이상의 단백질로 입증된 2 등급 이상의 단백뇨

Grade 2 or higher proteinuria demonstrated with a protein of 2+ or higher in a dipstick urinalysis and 1.0 g or higher at a 24-hour urine collection

선별검사 시 계량봉 소변 검사에서 2 이상의 단백질을 가진 모든 환자는 단백질에 대한 24시간 소변 수집을 받아야 한다.

All patients with a protein 2 or higher on a dipstick urine test at screening should have a 24-hour urine collection for the protein.

계량봉 소변 검사에서 단백질이 2+ 미만인 환자는 연구에 적격이다.

Patients with a protein less than 2+ in the dipstick urine test are eligible for the study.

주요 기도나 혈관, 또는 중앙에 위치한 종격동 종양 덩어리(용골에서 30 mm 미만)에 많은 부피를 침범하는 전이성 질환

Metastatic disease involving large volumes of major airways or blood vessels, or a centrally located mediastinal tumor mass (less than 30 mm from the keel)

소화성 궤양 질환, 게실염 또는 대장염을 포함하지만 이에 제한되지는 않는 연구 치료제 개시 전 6개월 이내의 복강 내 염증 과정의 병력

History of intra-abdominal inflammatory processes within 6 months prior to initiation of study treatment, including but not limited to peptic ulcer disease, diverticulitis, or colitis

연구 치료제 개시 전 28일 이내의 방사선 요법 또는 60일 이내의 복부/골반 방사선 요법

Radiation therapy within 28 days or abdominal/pelvic radiation therapy within 60 days prior to initiation of study treatment

연구 치료제 개시 전 28일 이내의 주요 수술 절차, 개방 생검 또는 심각한 외상성 손상 또는 연구 치료제 개시 전 60일 이내에 복부 수술, 복부 개입 또는 심각한 복부 외상성 손상; 또는 연구 과정 중 주요 수술 절차가 필요하거나 임의의 상기 절차의 부작용으로부터 회복되지 않을 것으로 예상되는 경우

major surgical procedure, open biopsy, or severe traumatic injury within 28 days prior to initiation of study treatment, or abdominal surgery, abdominal intervention, or severe traumatic injury to the abdomen within 60 days prior to initiation of study treatment; or if a major surgical procedure is required during the course of the study or is not expected to recover from the adverse effects of any of the above procedures.

T. evaluation

Tiragolumab as a single agent (Phase Ia) or: Atezolizumab, chemotherapy and atezolizumab, bevacizumab and atezolizumab, or tiragolumab in combination with pembrolizumab (Phase Ib), respectively Closely monitor patient safety and tolerability and evaluate toxicity prior to initiation. Dosing should be done only when clinical evaluation and local laboratory test results allow.

Unless a time period is specified, all assessments will be conducted on the scheduled visit date. Assessments scheduled on study treatment days will be conducted prior to infusion of study drug(s) unless otherwise specified.

Medical history, baseline conditions, concomitant medications, and demographic data

Medical history includes, but is not limited to, history of cancer (including, but not limited to, prior cancer therapy and/or prior CITs and procedures, and tumor characteristics such as hormone receptor status or mutation status), other clinically significant disease, surgery, smoking history , alcohol use and/or abuse, reproductive status, and any medications (eg, prescription, over-the-counter, herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to the screening visit.

For patients transitioning to the Phase Ia portion of the study, the history of rescreening at the time of resumption of treatment at disease progression includes any cancer-related procedures or study treatment that occurred after initial discontinuation of treatment not captured during follow-up as specified in the protocol. Any adverse events involved are included.

Demographic data include age, gender, and self-reported race/ethnicity. Race/ethnicity is recorded as this variable potentially contributes to differences in observed PK, pharmacodynamics, toxicity, and/or treatment response.

vital signs

Vital signs include measurements of body temperature, respiration rate, pulse rate, and systolic and diastolic blood pressure when the patient is seated.

On study treatment days, vital signs are measured within 60 minutes prior to the first study drug infusion of the day.

For the first infusion of tiragolumab in phase la, every 15 (±5) minutes during the infusion, at the end of the infusion (±5 minutes), and at 30 (±10) minutes, 120 (±15) minutes after the end of the infusion, and Measure at 240 (±15) minutes.

For the first infusion of tiragolumab in Phase Ib, vital signs are measured every 15 min (±5 min) during the infusion, at the end of the infusion (±5 min), and at 30 min (±10 min) after the end of the infusion. For all Phase Ib cohorts without chemotherapy, the first infusion of atezolizumab or pembrolizumab is administered 60 minutes after completion of the tiragolumab infusion; The first infusion of bevacizumab is administered 60 minutes after completion of the infusion of atezolizumab.

For the Phase Ib cohort with chemotherapy, the first infusion of tiragolumab is administered 60 minutes after completion of the infusion of atezolizumab.

For the first and subsequent infusions of atezolizumab and pembrolizumab, and for subsequent infusions of tiragolumab, during and 30 (±10) minutes after the infusion, if clinically indicated or if symptoms occurred with the previous infusion Measure vital signs.

For the first infusion of bevacizumab, vital signs are measured during the infusion, at the end of the infusion (±5 min), and at 30 (±10) minutes post-infusion if clinically indicated or if symptoms occurred from a previous infusion.

Between tiragolumab and atezolizumab or pembrolizumab, or between atezolizumab and bevacizumab (for all Phase Ib cohorts not including chemotherapy), or between atezolizumab and tiragolumab (with chemotherapy) for the phase Ib cohort that included), the interval between subsequent infusions is 30 minutes if the previous infusion of tiragolumab or atezolizumab was tolerated without an IRR, or 60 if the patient previously experienced an IRR with a previous infusion of tiragolumab or atezolizumab is a minute

In chemotherapy expansion A, B, and C cohorts, additional vital signs are measured and recorded in cycle 1 within 30 (10) minutes after completion of the last chemotherapy infusion (e.g., cohort A: following carboplatin or cisplatin administration, cohort B: carboplatin after dosing, cohort C: after etoposide). At subsequent cycles, additional vital signs are measured and recorded after chemotherapy infusion, if clinically indicated.

At the screening visit, the collected vital signs are recorded. At each subsequent visit, either obtained prior to the first study drug infusion of the day or an adverse event (e.g., body temperature in case of fever) or major signs of an adverse event (e.g., blood pressure associated with infusion-related reactions or heart rate associated with arrhythmias) Record only constitutive vital signs. All vital signs collected according to the protocol are documented in the patient's medical record.

Blood oxygen saturation is measured at baseline by pulse oximetry.

Physical examination

Full physical examinations performed at screening included assessments of the head, eyes, ears, nose, and throat, and cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, urogenital, and nervous system.

ECOG systemic activity is assessed.

At follow-up visits (or as clinically indicated), a limited, symptom-directed physical examination is performed. Changes from baseline abnormalities are recorded in the patient's medical record. New or worsening clinically significant abnormalities are recorded as adverse events.

As part of the tumor evaluation, the physical examination also includes evaluation for lymphadenopathy, splenomegaly, hepatomegaly, and skin neoplasms or metastases. All patients should be monitored for symptoms of CNS metastasis and any symptoms reported above should be followed by a full neurological examination. Brain magnetic resonance imaging (MRI) or contrast-enhanced CT of the head is performed as clinically indicated to confirm or refute new or worsening brain involvement.

Tumor and Response Assessment

screening test

All known sites of disease should be documented at screening and re-evaluated at each subsequent tumor assessment.

Screening and subsequent tumor evaluation should include CT scans or MRI scans of the chest, abdomen, and pelvis (with IV contrast media and oral contrast where appropriate according to institutional standards unless use is prohibited). If CT scans for tumor evaluation are performed on a positron emission tomography (PET)/CT scanner, the CT acquisition should be consistent with the standard for full-contrast CT scans.

Brain imaging (MRI or contrast-enhanced CT) is required at screening for patients with treated brain metastases and as clinically indicated based on symptoms or signs suggestive of new or worsening CNS metastases. In cases of ambiguous head CT, brain MRI is required to clarify the presence or extent of suspected brain metastases.

Additional investigations, such as bone scans and CT scans of the neck, are also conducted if there is any clinical suspicion of disease at any site that may not be substantiated by the minimum evaluation schedule listed above and as indicated by the underlying disease. (eg, head and neck CT scans indicated for HNSCC patients). At the discretion of the investigator, other methods of assessment of measurable disease according to RECIST v1.1 may be used.

The same radiological procedures used to evaluate diseased sites at screening are used throughout the study (eg, same contrast agent protocol for CT scans). Stable brain metastases should be assessed with each tumor assessment using the same radiographic procedures as the baseline study. Patients without brain metastases do not require brain scans for tumor evaluation unless clinically warranted. Response is assessed by the investigator based on the detailed imaging modality and physical examination above using RECIST v1.1. Investigator's assessment of overall tumor response at all time points is based solely on RECIST v1.1. Assessments are conducted by the same evaluator whenever possible to ensure internal consistency throughout the visit.

A tumor assessment is performed. If PD is suspected, a scan may be performed at any time at the discretion of the investigator.

After cessation of initial study treatment (if discontinuation is for reasons other than disease progression), follow-up tumor evaluations will occur until death, disease progression, initiation of other systemic chemotherapy, loss of follow-up, withdrawal of consent, or termination of study, whichever occurs first Conduct.

Patients continuing treatment beyond radiographic disease progression according to RECIST v1.1 should be considered at 6 (±2) weeks (i.e., at the next planned tumor assessment if the scan frequency is every 2 cycles, or if the scan frequency is every 4 cycles). as an unplanned tumor assessment) as a follow-up scan, or sooner if clinically indicated. Tumor evaluation continues every 2 cycles thereafter until 2 consecutive scans show stability or improvement compared to the first scan showing disease progression on radiography, at which point scan frequency returns or switches to every 4 cycles if possible should be Investigator assessments of overall tumor response at all time points are based solely on RECIST v1.1.

laboratory, biomarkers, and other biological samples

Regional laboratory tests for Phase Ia and Ib

The following laboratory tests are conducted in the local laboratory of the research institution:

혈액학(RBC 수, 헤모글로빈, 헤마토크리트, [호중구, 호산구, 림프구, 단핵구, 호염기구 및 기타 세포]를 갖는 WBC 수, 및 혈소판 수를 포함한 CBC)

Hematology (CBC including RBC count, hemoglobin, hematocrit, WBC count with [neutrophils, eosinophils, lymphocytes, monocytes, basophils and other cells], and platelet count)

혈청/혈장 화학물질(나트륨, 칼륨, 염화물, 중탄산염, BUN 또는 요소, 크레아티닌, 포도당, 칼슘, 마그네슘, 인, 총 빌리루빈, ALT, AST, 알칼리성 인산분해효소, LDH, 총 단백질 및 알부민)

Serum/plasma chemicals (sodium, potassium, chloride, bicarbonate, BUN or urea, creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein and albumin)

혈청 페리틴 및 C 반응성 단백질(CRP)

Serum ferritin and C-reactive protein (CRP)

응고(PT, aPTT 및 INR)

Coagulation (PT, aPTT and INR)

아밀라아제와 리파아제

amylase and lipase

임신 검사: 모든 가임 여성(난관 결찰술을 받은 여성 포함)은 선별검사 시 혈청 임신 검사를 받는다. 소변 임신 검사는 연구 치료 기간 동안 정기적으로 실시한다. 소변 임신 검사 결과가 양성이면, 혈청 임신 검사로 환자의 상태가 판단될 때까지 투약을 연기한다.

Pregnancy Testing: All women of childbearing potential (including those who have had tubal ligation) have a serum pregnancy test at screening. Urine pregnancy tests are performed regularly during study treatment. If the urine pregnancy test result is positive, the drug should be delayed until the patient's condition is determined by a serum pregnancy test.

소변 검사(비중, pH, 포도당, 단백질, 케톤 및 혈액)

Urine tests (specific gravity, pH, glucose, protein, ketones, and blood)

갑상선 기능 검사(갑상선 자극 호르몬[TSH], 유리 T3 및 유리 T4)

Thyroid function tests (thyroid-stimulating hormone [TSH], free T3 and free T4)

EBV 혈청학(EBV IgM, EBV IgG, 및/또는 EBNA]) 및/또는 EBV PCR

EBV serology (EBV IgM, EBV IgG, and/or EBNA]) and/or EBV PCR

An EBV IgM test and/or an EBV PCR test is required prior to Day 1 of Cycle 1 to be considered for eligibility if the patient is serologically positive for EBV IgG and/or EBNA.

CMV 혈청학(CMV IgG)

CMV Serology (CMV IgG)

HBV 혈청학(HBsAg, HBsAg에 대한 항체 및 B형 간염 핵심 항원)

HBV serology (HBsAg, antibodies to HBsAg and hepatitis B core antigen)

An HBV DNA test should be obtained 1 day prior to Cycle 1 if the patient is positive for a serological test for anti-HBc.

HCV 혈청학(항 HCV)

HCV Serology (Anti-HCV)

HCV RNA testing is required before Day 1 of Cycle 1 to be considered for eligibility if a patient is positive for anti-HCV serology.

모든 환자는 연구에 포함되기 전에 HIV 검사를 받고 HIV 양성 환자는 연구에서 제외된다.

All patients are tested for HIV prior to inclusion in the study, and HIV-positive patients are excluded from the study.

CA-125, CA19-9, 암배아 항원(CEA), 전립선 특이적 항원(PSA), 베타-hCG, AFP, CA15-3 및 CA27.29를 포함하지만 이에 제한되지는 않는 종양 표지자(해당되는 경우 정보 제공)

Tumor markers (if applicable) including but not limited to CA-125, CA19-9, carcinoembryonic antigen (CEA), prostate specific antigen (PSA), beta-hCG, AFP, CA15-3 and CA27.29 Provide information)

Phase Ia and Ib Central Laboratory Testing

The tests listed below are conducted in a central laboratory. Samples collected for PK or ADA assays may be required for further immunogenicity characterization, PK, biomarker and/or immunogenicity assay development and validation. Therefore, such samples are discarded within 5 years of completion of the final clinical study report or earlier according to local regulations.

Assessments performed on blood samples

ADA 분석

ADA analysis

A validated assay is used to obtain serum samples for ADA determination for tiragolumab (Phases Ia and Ib).

A validated assay is used to obtain serum samples for ADA determination for atezolizumab (Phase Ib only).

PK 분석

PK analysis

Serum samples are obtained for determination of tyragolumab concentrations using validated assays (Phases Ia and Ib).

Obtain serum samples for determination of atezolizumab concentrations using validated assays (phase Ib only).

Plasma samples are obtained for determination of concentrations of cisplatin, carboplatin, pemetrexed, paclitaxel, capecitabine, and etoposide using validated assays (phase Ib chemotherapy expansion cohort only).

자가 항체 시험

autoantibody test

Serum samples were obtained for autoantibody testing, including, but not limited to, antinuclear antibodies, anti-double-stranded DNA, anti-neutrophil cytoplasmic antibodies, and thyroid peroxidase antibodies, to clinical events during the study period, either for individual patients or across the study population. based on it.

혈액 내 바이오마커 분석

Analysis of biomarkers in blood

Blood samples are obtained for biomarker evaluation from all eligible patients at screening visits and treatment.

전체 유전체 서열분석(WGS)

Whole Genome Sequencing (WGS)

A single blood sample may be collected for WGS and sent to one or more laboratories for analysis. WGS data and related clinical data may be shared with non-researchers or submitted to government or other health research databases for broad sharing with other researchers to conduct research on human health and disease. Study participants are not identified by name or other personally identifiable information.

The WGS is subject to review and approval by the respective institutional IRB/EC and, where applicable, the appropriate regulatory body. If an institution is not accredited for WGS, the above assessment does not apply to that institution.

WGS data can be analyzed in the context of this study and explored in conjunction with other studies to better understand disease pathobiology and guide the development of new therapeutic approaches. Given the complexity and exploratory nature of these analyzes, WGS data and analyzes are used for research purposes only and are not shared with investigators or study participants.

The sample is stored indefinitely until depleted or until the patient requests that the sample be discarded.

Assessments conducted on tumor samples

The status of immune-related and tumor-associated biomarkers (including but not limited to, expression of PD-L1, TIGIT, PVR, and/or CD226 on specific cell types; and prevalence and/or activation of infiltrating T cells) Both archived and fresh tumor samples can be evaluated using methods including, but not limited to, IHC, IF, and qRT-PCR. Tumor RNA and/or DNA can be purified and characterized by RNA sequencing and WGS. Additional exploratory biomarkers may also be evaluated if clinical and non-clinical data guides them.

보관 종양 조직: 연구에 등록된 모든 환자에 대해

Archival tumor tissue: for all patients enrolled in the study

If available, archival tumor tissue samples obtained outside of this study for other purposes are collected from all patients (paraffin blocks are preferred; at least 15 unstained serial slides are acceptable). For all patients with phase Ia or Ib, availability of archived tumor tissue should be confirmed prior to study entry. Fine needle aspirates, exudates or multiple cell pellets, wash samples and bone biopsies do not meet the requirements for storage tissue.

If appropriate tissue and/or multiple metastatic tumors obtained at separate time points (e.g., time of initial diagnosis and time of disease recurrence) are available, preference is given to the most recently collected (ideally after the most recent systemic adjuvant therapy). should be ranked.

Patients with insufficient or not available storage tissue may still be eligible.

Archival tumor tissues are used to evaluate potential predictive biomarkers using specialized assays for protein, RNA and DNA analysis.

필요한 종양 생검: Ib상의 연속 생검 확장 코호트에 등록된 환자의 경우

Tumor biopsies required: For patients enrolled in the Phase Ib serial biopsy expansion cohort

Time points: Serial biopsies are obtained at two time points: 1) pre-treatment biopsies are obtained at baseline after all eligibility criteria have been met, and 2) approximately 2 weeks after the first administration of both tiragolumab and atezolizumab. An on-treatment biopsy is obtained (ie, on or between days 15 and 21 of cycle 1).

Additional selective biopsies may be collected at the discretion of the investigator, preferably at the time of radiological progression (especially when excitation is suspected) or at the time of response.

Serial tumor biopsies are used to evaluate tumor pharmacodynamic biomarkers and potential predictive biomarkers using specialized assays for protein, RNA and DNA analysis.

Ia상에서 Ib상으로의 전환을 위한 진행 중 종양 조직 생검: 시험자가 평가한 방사선학적 질병의 진행 후 연구의 Ia상에서 Ib상 부분으로의 전환에 대해 고려 중인 환자의 경우

On-going tumor tissue biopsy for transition from Phase Ia to Phase Ib: For patients contemplating transition to Phase Ia to Phase Ib portion of the study following investigator-assessed radiologic disease progression

An in-progress biopsy is required if the investigator considers sample collection clinically feasible and the patient has provided written informed consent. A tumor tissue sample is obtained consisting of a core needle biopsy for deep tumor tissue or lymph nodes or an excision, incision, punch, or forceps biopsy for skin, subcutaneous, or mucosal lesions.

On-going biopsies are used to evaluate tumor pharmacodynamic biomarkers and potential predictive biomarkers using specialized assays for protein, RNA and DNA analysis.

선택적 종양 생검: 특히 Ia상 또는 Ib상의 확장 코호트에 등록된 환자의 최대 절반에서 선택적 생검을 받는 데에 특정 정보에 입각한 동의서를 제공한 환자의 경우

Selective tumor biopsy: especially for patients who have given informed consent to undergo elective biopsy in up to half of patients enrolled in Phase Ia or Phase Ib expansion cohorts

Patients who consented to elective biopsy were enrolled at baseline after all eligibility criteria have been met, and at about 2 weeks after the first dose of tiragolumab as a single agent (Phase Ia), or first dose of tiragolumab and atezolizumab Tumor biopsies are given about 2 weeks after (Phase Ib) (ie, days 15-21 of Cycle 1 or in between).

For patients with an accessible residual mass and with confirmed prolonged CR and/or PR (eg, approximately 1 year in duration), a biopsy of that residual mass is performed to obtain viable tumor cells (vs. fibrous or necrotic) organization) is recommended.

Tumor tissue samples can be collected using a core needle, punch, excision biopsy (as specified above) or forceps biopsy. For additional guidance related to the selected biopsy technique, see the sample specifications described above for essential tumor biopsy.

Selective tumor biopsies are used to evaluate tumor pharmacodynamic biomarkers and potential predictive biomarkers using specialized assays for protein, RNA and DNA analysis.

샘플 사양: Ia상 및 Ib상의 모든 환자에 대해, 필수 및 선택적 생검은 하기의 샘플 요건을 충족해야 한다.

Sample Specifications: For all patients with Phase Ia and Phase Ib, mandatory and optional biopsies must meet the following sample requirements.

A tumor tissue sample is obtained consisting of a core needle biopsy of deep tumor tissue or lymph nodes or an excision, incision, punch, or forceps biopsy for skin, subcutaneous, or mucosal lesions. Fine needle aspirates, exudates or ascites cell pellets, wash samples and bone biopsies are not permitted. A target lesion considered for a core needle biopsy is considered suitable for exploring at least three cores at a given time point (minimum diameter 18 gauge). If possible, successive passages through the same lesion should be separated by at least 1 cm.

When multiple lesions are available, it is desirable to obtain an on-treatment biopsy from the same lesion (or organ) as the pre-treatment biopsy, if possible, to avoid the introduction of heterogeneity associated with the site of metastasis.

RECIST target lesions are not biopsied.

Tissue samples and their derivatives (eg, DNA and RNA) are stored indefinitely or until used up or until the patient requests disposal of the sample.

Ia상 및 Ib상의 모든 환자에 대한 나머지 샘플의 사용

Use of Remaining Samples for All Patients in Phase Ia and Ib

Tumor tissue that may signal the patient's activity (anti-tumor or autoimmune) of tiragolumab as a single agent (phase Ia) or in combination with atezolizumab (phase Ib) with or without chemotherapy or any remaining sample or portion of a sample not necessary for a medical diagnosis (body fluids), if at any time during the course of a study that yields other tissue, a medically directed procedure (i.e., bronchoscopy, esophageal gastroduodenoscopy, colonoscopy, etc.) sample or remaining tumor tissue) can be obtained for exploratory analysis. Patients must provide informed consent to collect and evaluate the sample.

The remaining tumor samples are used to evaluate tumor pharmacodynamic biomarkers and potential predictive biomarkers using specialized assays for protein, RNA and DNA analysis.

electrocardiogram

Triple ECG records are obtained for all other patients at the time points designated for the dose escalation cohort and the supplemental cohort of tiragolumab alone (Phase Ia). ECGs obtained on different days of the week are as time-matched as possible. Three interpretable ECG records (eg, excluding artifacts) should be obtained at each time point (5 min). The average of the three readings is used to determine the ECG interval (eg, PR, QRS, QT). Additional ECGs may be obtained at unscheduled time points as clinically indicated.

All ECG recordings should be performed using a standard high-quality, high-fidelity digital electrocardiogram machine equipped with computer-based interval measurement. Lead placement is as consistent as possible. ECG recordings should be performed after the patient has been in the supine position for at least 10 minutes. All ECGs should be obtained prior to other procedures scheduled at the same time (eg, vital signs measurement, blood collection) and should not be obtained within 3 hours after any meal. In cases where it may be difficult for the patient to follow the above guidelines, the time between meal intake and ECG recording may be shortened to 2.5 hours or to institutional standards as long as the same minimum time is maintained at all time points. Circumstances that may induce changes in heart rate, including environmental disturbances (eg television, radio, conversation), should be avoided during the rest period prior to ECG and during ECG recording.

For safety monitoring purposes, the investigator must review, sign and date all ECG traces. An overall assessment of the ECG, normal or abnormal, with or without clinical significance is recorded. A paper or electronic copy of the ECG trace is maintained at the institution as part of the patient's permanent study file.

If, at a specific post-dose time point, the mean QT interval, corrected via the Fredericia formula (QTcF), is >500 ms and/or >60 ms longer than the baseline value, then another ECG would ideally be Records should be made within the next 5 min, and on 2 consecutive ECGs, ECG monitoring is continued until QTcF has stabilized. Treatment according to the standard of the table may be performed at the discretion of the investigator. Even if a PK sample is not reserved at that time, an unreserved PK sample is obtained. The investigator evaluates the patient for potential concomitant risk factors (eg, electrolyte abnormalities, concomitant medications known to prolong the QT interval, severe bradycardia).

Cancer-related procedures

Collection of cancer-related medical, surgical, and radiological procedures begins on Day 1 and is performed during the treatment period and survival follow-up period in both the Phase Ia and Ib portions of the study.

Anti-drug antibody test

Tiragolumab and/or atezolizumab may elicit an immune response against itself. Validated screening tests, confirmations, and assays of potency include pre-, during and post-treatment with tiragolumab as a single agent in phase Ia or treatment with a combination of tiragolumab and atezolizumab with or without chemotherapy in phase Ib. It is then used to detect ADA at multiple time points. ADA response correlates with relevant clinical endpoints to understand clinical significance. Additional ADA assays (eg, neutralizing antibody assays) can be used to further characterize the ADA response.

U. Discontinuation of patient and study treatment

patient discontinuation

Discontinuation of a patient from a study is distinct from discontinuation of study treatment and occurs when the patient dies, fails to follow-up, or withdraws consent to follow-up.

Patients have the right to voluntarily withdraw from the study at any time for any reason. In addition, the investigator has the right to withdraw a patient from the study at any time. Reasons for study withdrawal may include, but are not limited to:

언제든지 환자의 동의 철회

Withdraw patient's consent at any time

시험자가 만약 환자가 연구를 계속하는 경우 이의 안전성이 위험해질 수 있는 것으로 결정한 임의의 의학적 상태

Any medical condition that the investigator has determined that the safety of the patient may be at risk if the patient continues the study.

시험자가 철회가 환자에게 최선의 이익이라고 결정한 경우

If the investigator determines that withdrawal is in the patient's best interest

Every effort is made to obtain information about patients withdrawn from the study. The main reasons for withdrawal from the study or follow-up are documented. However, after the withdrawal of consent, the patient will not be followed for any reason. Patients who withdraw from the study are not replaced.

study treatment discontinuation

Patients should discontinue study treatment if they experience any of the following:

모든 방사선학적 데이터, 생검 결과 및 임상 상태의 통합 평가 후 시험자가 결정한 바와 같이 질병 진행으로 인한 증상 악화(즉, 질병에 부착적으로 통제할 수 없는 통증 또는 관리할 수 없는 복수 등).

Exacerbation of symptoms due to disease progression (i.e., uncontrollable pain attached to disease or unmanageable ascites, etc.) as determined by the investigator after integrated evaluation of all radiological data, biopsy results, and clinical status.

개별 환자의 치료에 대한 잠재적 반응 및 사건의 심각성을 고려할 때 시험자가 허용할 수 없는 것으로 결정된 면역 매개 이상 반응의 발병을 포함하여 연구 치료와 관련된 참을 수 없는 독성

intolerable toxicity associated with the study treatment, including the development of immune-mediated adverse events determined to be unacceptable by the investigator given the severity of the event and potential response to treatment in an individual patient.

시험자가 만약 환자가 연구 치료를 계속하는 경우 이의 안전성이 위험해질 수 있는 것으로 결정한 임의의 의학적 상태

Any medical condition that the investigator has determined that the safety of the patient would be at risk if the patient continued study treatment.

비 프로토콜 전신 항암 요법의 사용

Use of non-protocol systemic chemotherapy

임신

Pregnant

Patients have the right to voluntarily withdraw from study treatment at any time for any reason. In addition, the investigator has the right to withdraw a patient from study treatment at any time. Reasons for withdrawal from study treatment may include, but are not limited to:

시험자가 철회가 환자에게 최선의 이익이라고 결정한 경우

If the investigator determines that withdrawal is in the patient's best interest

환자의 비준수

patient non-compliance

Patients who discontinue study treatment primarily for reasons other than disease progression continue tumor evaluation, and all patients who discontinue study treatment continue follow-up for survival every 3 months unless consent is withdrawn.

Patients who discontinue study treatment must return to the hospital for a treatment discontinuation visit within 30 days of the last dose of study treatment.

Discontinuation of tiragolumab (Phase Ia) or concomitant discontinuation of tiragolumab and atezolizumab, tiragolumab and atezolizumab plus bevacizumab, or tiragolumab and pembrolizumab (Phase Ib) in the evaluation of its response A visit presenting PD that causes

After discontinuation of study treatment, all patients are followed for survival and subsequent anticancer therapy. Survival and follow-up chemotherapy follow-up information is collected through phone calls, patient medical records, and/or hospital visits approximately every 3 months until death, loss of follow-up, or study termination, unless the patient requests discontinuation of follow-up. Information on subsequent anti-cancer therapy includes systemic therapy (eg, chemotherapy, targeted therapy, hormone therapy, or CIT), surgery (eg, resection of metastatic disease), and radiation procedures (eg, radiation therapy for tumor lesions). .

If a patient withdraws from the study, the institution's staff may use public information sources (eg, local records) to obtain information on survival status only.

V. analysis

Purpose and endpoints

The present study investigated the safety, PK, pharmacodynamics, and prospective antibiotics of tiragolumab as a single agent (Phase Ia) or in combination with atezolizumab or other anticancer therapies (Phase Ib) in patients with locally advanced or metastatic tumors. Assess tumor activity. The specific study objectives and corresponding endpoints are summarized in Table 36.

purpose Corresponding evaluation variable Safety Objectives (Primary Study Objectives):

최대 허용 용량(MTD) 및 권장 II상 용량(RP2D)의 추정 및 용량 제한 독성(DLT)의 특성화를 포함하여, 단일 제제(Ia상)로서 또는 아테졸리주맙(Ib상)과 병용으로 투여할 때의 티라골루맙의 안전성 및 내약성을 평가하기.

아테졸리주맙 및 화학요법과 병용한 티라골루맙의 안전성 및 내약성을 평가하기.

아테졸리주맙 및 베바시주맙과 병용한 티라골루맙의 안전성 및 내약성을 평가하기.

펨브롤리주맙과 병용한 티라골루맙의 안전성 및 내약성을 평가하기.

When administered as a single agent (Phase Ia) or in combination with atezolizumab (Phase Ib), including estimation of the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and characterization of dose limiting toxicity (DLT) To evaluate the safety and tolerability of tiragolumab.

To evaluate the safety and tolerability of tiragolumab in combination with atezolizumab and chemotherapy.

To evaluate the safety and tolerability of tiragolumab in combination with atezolizumab and bevacizumab.

To evaluate the safety and tolerability of tiragolumab in combination with pembrolizumab.

Incidence and characteristics of DLT

Incidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0

Changes from baseline in target vital signs

Changes from baseline in targeted clinical laboratory test results, including electrocardiogram (ECG)

Number of cycles received and dose intensity

Incidence of anti-tyragolumab antibody (Phase Ia or Ib) and/or anti-Atesolizumab antibody (Phase Ib) and potential correlation with PK, pharmacodynamics, safety, and preliminary efficacy parameters Pharmacokinetic goals:

To characterize the pharmacokinetic (PK) curves of tiragolumab as a single agent (Phase Ia) or administered in combination with atezolizumab (Phase Ib).

To characterize the PK curve of atezolizumab with or without chemotherapy in combination with tiragolumab (Phase Ib alone).

To characterize the PK profile of capecitabine, cisplatin, carboplatin, pemetrexed, paclitaxel, and etoposide when administered in combination with atezolizumab and tiragolumab (Phase Ib expansion cohort).

Serum concentrations of tiragolumab administered as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) at specific time points for the following parameters:
- Area under the concentration-time curve (AUC)
- Maximum plasma concentration (C _max )
- Minimum plasma concentration (C _minimum )
- Cleaning rate (CL)
- volume of distribution in steady state (V _ss )

Other parameters such as accumulation ratio, half-life, and dose proportionality can also be calculated.

Serum C _max and C _min of atezolizumab

Plasma concentrations of capecitabine, cisplatin, carboplatin, pemetrexed, paclitaxel, and etoposide at specific time points Activity Goals:

To conduct a preliminary evaluation of the antitumor activity of tyragolumab as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) in patients with locally advanced or metastatic tumors

To conduct a preliminary evaluation of the antitumor activity of tiragolumab in combination with atezolizumab and bevacizumab.

To conduct a preliminary evaluation of the antitumor activity of tiragolumab in combination with pembrolizumab.

Objective Response - Defined as complete response (CR) or partial response (PR) according to the Solid Tumor Response Evaluation Criteria (RECIST) v.1.1, determined by the investigator and confirmed by a repeat assessment at least 4 weeks after initial documentation.

Duration of Objective Response (DoR) - defined as the time from the first occurrence of a documented objective response to documented disease progression or death from any cause, whichever occurs first, according to RECIST v1.1 as determined by the investigator

PFS - defined as the time from the first study treatment to the onset of progression or death from any cause, whichever occurs first, per RECIST v.1.1 as determined by the investigator

Overall survival (OS) - defined as time from first study treatment to death from any cause Immunogenicity goals:

To characterize the immunogenic potential (Phase Ia) of tiragolumab administered as a single agent by measuring anti-tiragolumab antibodies and assessing their relationship to other outcome measures, and anti-tyragolumab and/or anti-atezolizumab antibodies To characterize the immunogenic potential (Phase Ib) of tiragolumab in combination with atezolizumab with or without chemotherapy by measuring and evaluating its relationship to other outcome measures.

Prevalence of ADA to tiragolumab at baseline and incidence of ADA to tiragolumab during the study

Prevalence of ADA to atezolizumab at baseline and incidence of ADA to atezolizumab during the study The purpose of exploratory biomarkers:

As a pharmacodynamic marker for the activity of tiragolumab administered as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) in patients with locally advanced or metastatic tumors. Preliminary evaluation of possible biomarkers Changes in immune infiltrates, immune-related gene expression, and/or TIGIT-related gene expression in tumor tissue before and during study treatment

Administered as a single agent (Phase Ia) or in combination with atezolizumab with or without chemotherapy (Phase Ib) or in combination with pembrolizumab or bevacizumab in patients with locally advanced or metastatic tumors Preliminary evaluation of biomarkers that may serve as predictors for the antitumor activity of tiragolumab

Levels of TIGIT, PD-L1 and/or other candidate predictive markers in tumor tissue Changes in blood biomarkers, including cytokines and immune cells, before and during study treatment
Biomarker determination by RNA sequencing and whole genome sequencing (WGS)

Phase Ia and Ib objectives and their endpoints

activity analysis

The analysis described below is based on the definition of objective response according to RECIST v1.1.

Response assessment data, objective duration of response, PFS and OS are listed for all treated patients by dose level or tumor type, where appropriate.

objective response rate

Analysis of ORR includes patients in Phase Ia or Ib studies who have received any amount of study treatment and have measurable disease at baseline. Objective response is defined as a CR or PR determined by investigator assessment and confirmed by repeated assessments at least 4 weeks after initial documentation. Patients with missing baseline or no response assessment are classified as non-responders. Objective response rates are estimated and summarized by tumor type and, if applicable, dose.

duration of response

Among patients with an objective response, the duration of the objective response is defined as the time from the initial complete or partial response to disease progression or death, whichever occurs first. For patients who did not die, did not experience disease progression, or failed follow-up prior to study termination, the duration of objective response is censored on the date of last tumor assessment.

progression-free survival

The PFS analysis includes patients receiving any amount of study treatment. PFS is defined as the time from day 1 of study treatment to documented disease progression or death, whichever occurs first. For patients who have not documented PD or death prior to study termination, or who fail to follow-up, PFS is censored on the day of the last tumor assessment. For patients with no post-baseline tumor assessment, PFS is censored on Day 1 of study treatment.

overall survival

OS analysis included patients who received any amount of study treatment. OS is defined as the time from administration of the first dose of study treatment to death from any cause during the study. For patients who do not die before study termination or fail to follow-up, OS is censored on the last known date of survival.

Safety analysis

Safety includes DLT, adverse events, changes in laboratory test results, changes in vital signs and ECG, and any study treatment (tiragolumab, atezolizumab, bevacizumab, pembrolizumab, carboplatin, cisplatin, pemetrexed). , paclitaxel, capecitabine, and etoposide). All patients who received any amount of study treatment are included in the safety analysis.

Verbose descriptions of adverse events are mapped to synonym terms. Adverse event data are listed by study site, dose cohort or appropriate tumor type, patient number, and study date. All responses that occur during or after treatment on Day 1 are summarized by mapped duration, appropriate synonym level, and NCI CTCAE v4.0 grade. In addition, serious adverse events, including death, are listed and summarized separately.

Adverse events leading to discontinuation of treatment are listed. Patients who withdraw from the study prior to completion of the DLT evaluation period for reasons other than DLT will be considered ineligible for DLT and MTD evaluation.

Relevant laboratory values, vital signs, and ECG data are presented by time point, along with identified NCI CTCAE grade 3 and grade 4 values where appropriate. The incidence of ADA responses (presence of serum anti-tyragolumab or anti-atezolizumab) and potential correlation with PK, pharmacodynamic and safety parameters can be assessed.

Pharmacokinetic analysis

In the Phase Ia study, individual and mean serum tyragolumab concentration versus time data are tabulated and plotted by dose level. The pharmacokinetics of tiragolumab are summarized by estimating total AUC, C _max , C _min , total CL , V _ss , and terminal half-life (fitted to collected data). Estimates for these parameters are tabulated and summarized (mean, standard deviation, and coefficient of variation). Inter-patient variability and drug accumulation are assessed.

In the Phase Ib study, serum tyragolumab and atezolizumab concentration data (C _max and C _min ) were tabulated and summarized with each cycle dose level collected. Descriptive statistics include mean, median, standard deviation and range as appropriate. Other PK parameters can be determined and summarized as data assurance. Because these results provide preliminary information on whether tiragolumab or atezolizumab Pk is altered by concomitant administration of other agents, the data can be compared with historical data.

In the Phase Ib chemotherapy expansion cohort, serum concentrations of tiragolumab and atezolizumab and plasma concentrations of carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine and etoposide are collected. Concentrations of tiragolumab, atezolizumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine and etoposide are summarized using the descriptive statistics described above. Because these results provide preliminary information on whether tiragolumab, atezolizumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine and etoposide PK are altered by the simultaneous administration of other agents. Compare the data with historical data.

Pharmacodynamic analyzes include evaluation of pharmacodynamic biomarkers in both tumor tissue and blood, where possible. Additional PK and pharmacodynamic analyzes are performed as appropriate. If necessary, a potential adjustment of the biomarker sampling time may be applied based on the observed biomarker response in the initial patient.

Immunogenicity assay

A patient is considered to have a treatment-evoked ADA response if it is ADA negative at baseline and an ADA response occurs following study drug administration. A patient is considered to have a treatment-enhancing ADA response if the patient is ADA positive at baseline and the titer of one or more post-baseline samples is greater than or equal to 4 times the titer of the baseline sample (i.e., greater than or equal to 0.60 titer units). A patient is considered negative for ADA if it is ADA negative at all time points. A patient is considered unaffected by treatment if a patient is ADA positive at baseline but has no post-baseline sample with a titer at least 4 times greater than that of the baseline sample.

ADA outcomes for tiragolumab and atezolizumab are summarized and listed by patient and cycle for the Phase Ia and Phase Ib portions of the study.

Interim Analysis of Phase Ia and Phase Ib Expansion Cohorts

The IMC will conduct an interim analysis for each expansion cohort in Phases Ia and Ib to guide the possibility of early termination of enrollment in the absence of evidence of activity. After approximately 20 patients enrolled in the expansion cohort have completed one or two tumor assessments, the IMC meets to conduct interim analyses. Tiragolumab in combination with atezolizumab (Phase Ia) or with or without chemotherapy in interim analysis, or tiragolumab in combination with atezolizumab and bevacizumab, or in combination with pembrolizumab If the activity presented by the objective tumor response to one tiragolumab (Phase Ib) is below the threshold of interest for that patient group (e.g., no response was observed in the first 20 patients), the IMC will be evaluated for the expansion cohort. You may be advised to discontinue registration.

For example, if the actual ORR is 5%, the probability that no response will be observed in the first 20 patients is approximately 35%, and if the true ORR is 10%, the probability that no response will be observed in the first 20 patients is approximately 12%.

The IMC is also responsible for

If there is evidence or sufficient specific patients are not enrolled to permit an appropriate assessment (e.g., patients with specific tumor types, specific tumor PD-L1 and/or TIGIT expression status, and/or specific CIT history), You may be advised to continue your registration.

In all cases, in consultation with the study investigator, the medical monitor staff makes a decision to discontinue expansion cohort enrollment based on futility in accordance with IMC recommendations. Medical monitor personnel may request additional ad hoc meetings of the IMC to review ongoing data from each expansion cohort in Phase Ia or Phase Ib.

W. Summary of Clinical Studies for Tiragolumab

Preliminary clinical data are available from this ongoing study (GO30103) evaluating tiragolumab in patients with locally advanced or metastatic tumors. As of the clinical deadline of December 2, 2019, study GO30103 enrolled 190 patients, of which 42 patients were enrolled in the Phase Ia portion and 171 patients in the Phase Ib portion, which included post-disease Phase Ia. 23 patients converted from

An ongoing phase II study (GO40290, also known as CITYSCAPE) is a chemotherapy-naïve study with locally advanced unresectable or metastatic PD-L1 selected NSCLC, except in patients with sensitizing epidermal growth factor receptor (EGFR) mutations or ALK translocations. To evaluate the efficacy and safety of tiragolumab and atezolizumab compared to placebo plus atezolizumab in patients.

Clinical Pharmacokinetics and Immunogenicity

As of the data deadline of December 2, 2019, available data (2-1200 mg tiragolumab administered every 3 weeks in the phase Ia portion of study GO30103 and 1200 mg administered every 3 weeks in the phase Ib portion of study GO30103) A preliminary PK analysis based on 2-1200 mg tyragolumab administered every 3 weeks in combination with atezolizumab) was performed using standard noncompartmental PK methods. The pharmacokinetics of tiragolumab in combination with atezolizumab were shown to be consistent with those of tiragoluumab administered as a single agent. According to a preliminary population-PK analysis, tiragolumab exposure was approximately dose-proportional after IV administration at doses ranging from 100 mg to 1200 mg as monotherapy every 3 weeks or in combination with 1200 mg atezolizumab every 3 weeks. increased to Pre-population PK analysis estimated a tyragolumab clearance of 0.28 L/day with a linear drug elimination half-life of approximately 15 days. Development of an antidrug antibody (ADA) to tiragolumab was observed in 3 of 154 (1.9%) evaluable patients in the Phase Ib portion of study GO30103. Preliminary data suggest no apparent effect of tiragolumab ADA on PK. However, a small number of patients with positive ADA were not adequate to assess the effect of ADA on the pharmacokinetics of tiragolumab.

clinical safety

As of the December 2, 2019 data deadline, safety data were available for 42 patients in the Phase Ia portion of study GO30103. Adverse events commonly reported in phase Ia (reported in ≥10% of all patients) regardless of relationship to tiragolumab were fatigue, constipation, vomiting, decreased appetite, anemia, cough, dyspnea, headache, and infusion-related reactions. (IRR), malignant neoplasms, nausea and pruritus. Adverse events commonly reported with tiragolumab (reported in >10% of patients) included fatigue and IRR.

Grade 3 or higher adverse events (based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [NCI CTCAE v4.0]) correlated with cause due to study drug was reported in 16 patients (38.1%) in the phase Ia portion of study GO30103 without study GO30103, and 3 patients (7.1%) experienced a treatment-related Grade 3 or greater adverse event. Grade 3 or higher adverse events considered by the investigator with respect to tyragolumab included increased amylase, increased blood creatinine, liver failure (described below), IRR, and rash.

As of the data cut-off date of December 2, 2019, 171 patients were enrolled in the Phase Ib portion of study GO30103, including 23 patients who converted from Phase Ia after disease progression. Of the 171 patients treated in phase Ib, 163 patients (95.9%) experienced at least one adverse event, of which 110 patients (64.7%) experienced treatment-related adverse events. Adverse events commonly reported in phase Ib (reported in ≥10% of all patients) regardless of relationship to tiragolumab include pruritus, fever, anemia, rash, progression of malignant neoplasm, constipation, decreased appetite, diarrhea, and cough. , asthenia, vomiting and fatigue were included. Adverse reactions commonly reported with tiragolumab and/or atezolizumab (reported in more than 10% of patients) included itching and rash.

Grade 3 or greater adverse events (based on NCI CTCAE v4.0) were reported in 91 patients (53.5%) in the Phase Ib portion of study GO30103, irrespective of cause due to study drug, and in 21 patients (12.4%) A treatment-related grade 3 or higher adverse event was experienced. Grade 3 or higher adverse events considered by investigators with tiragolumab and/or atezolizumab include decreased lymphocyte count, increased lipase, lymphopenia, increased amylase, adrenal insufficiency, asthenia, tamponade, headache, hyperglycemia, and lipolysis. Hyperemia, hyperfasting hyperemia, pneumonia, pruritus rash, rhabdomyosarcoma diabetes, diabetic ketoacidosis, and lipase were included.

A fatal event of hepatotoxicity culminating in fulminant liver failure occurred in patients enrolled in the Phase Ia monotherapy expansion cohort of study GO30103. At screening, the patient's transaminases were within the normal range. At pre-dose C1D1, AST and ALT were elevated to Grade 1. During dosing of tiragolumab for C1D1, the patient exhibited an infusion response responsive to dosing discontinuation and tea care standards, and the patient received approximately 733 mg of tiragolumab at a targeted 1200 mg dose. On study day 8, ALT/AST rose to grade 3 associated with grade 3 rash, and the patient was treated with prednisone 60 mg daily. By day 12 of the study, the rash had improved but AST and ALT were Grade 4 (including normal bilirubin and PT International Normalized Ratio (INR)) and a second immunosuppressant (azathioprine) was added. The patient progressively deteriorated despite the use of two immunosuppressants and developed overt liver failure with elevated bilirubin and progressive hepatic encephalopathy and died on day 30 of the study. Several alternative etiologies of hepatitis were excluded, including viruses (HBV, HCV), concomitant medications, or anatomical abnormalities. A liver biopsy performed on day 16 of the study showed confluent submass necrosis with little inflammatory infiltrates interpreted as toxic hepatitis.

After this event, analysis of safety data showed no significant change in the detection of adverse events and no new significant adverse events were observed in subjects administered in the Phase Ia and Ib portions of study GO30103.

As of the data deadline of 30 June 2019, tiragolumab plus atezolizumab (600 mg every 3 weeks) or placebo plus atezolizumab in 135 safety evaluable patients in phase II blinded study GO40290 was administered. The safety profile of tiragolumab and atezolizumab included adverse events of all grades (98.5% vs. 95.6%), AEs ≥ Grade 3 (41.8% vs. 44.1%), serious AEs (34.3% vs. 35.3%), and leading to treatment discontinuation. Similar to placebo and atezolizumab for AEs (7.5% vs. 10.3%). Adverse events of particular interest were reported in 47.8% of patients in the tiragolumab and atezolizumab groups and 32.4% of patients in the placebo plus atezolizumab group. Updated data for December 2019 showed a similar safety profile.

One fatal case of EBV reactivation and possible secondary hemophagocytic lymphohistiocytosis (HLH) was reported in a 69-year-old male from Taiwan with a metastatic lymphothelioma-like carcinoma subtype (PD-L1-positive) of NSCLC, which was reported in an Asian patient. It may be associated with EBV infection. At screening, the patient had a positive serum Epstein-Barr nuclear antigen (EBNA) antibody test, but had no clinical signs of active EBV infection identified by the treating investigator. On Day 1 of Cycle 1, the patient received both study drugs atezolizumab and tiragolumab and was well tolerated on treatment. On day 10, the patient developed a fever suspected of upper respiratory tract infection and was treated with antibiotics. On Day 1 of Cycle 2, the patient received atezolizumab and developed a grade 2 fever 20 minutes post-infusion. Because the fever was presumed to be atezolizumab IRR, no tiragolumab was administered in cycle 2. The patient was hospitalized with a fever, but a close examination for the cause of infection was negative. Once the fever resolved, the patient was discharged on Day 8 of Cycle 2. On Day 15 of Cycle 2, the patient was re-hospitalized for intermittent fever and developed hypotension, metabolic acidosis, acute kidney injury, pancytopenia, coagulopathy, bleeding, changes in mental status, transaminatitis, hyperbilirubinemia, and respiratory failure. The accompanying shock occurred and he was transferred to the intensive care unit. The patient had high blood EBV titers and bone marrow biopsy was consistent with HLH. Cultures for other infectious agents were negative. Despite treatment with steroids and multiple immunosuppressants (tocilizumab, hydroxychloroquine and etanercept), the patient deteriorated and died on day 31 of cycle 2. Overall, the patient received one dose of tiragolumab (cycle 1) and two doses of atezolizumab (cycle 1 and cycle 2). Although the exact cause of the event at the time of this revision is unknown and an investigation is ongoing, available information indicates that the patient had a histologically rare NSCLC subtype and a chronic active EBV infection that was reactivated by administration of tiragolumab and atezolizumab. this was suspected Given the temporal relationship between study drug exposure and the patient's clinical course, the patient appears to have developed secondary HLH. Following this indicator event of EBV reactivation in patients with pulmonary lymphothelioma-like carcinoma, the safety data were carefully reviewed and no other cases of viral reactivation were observed in either the Phase II study (GO40290) or the current Phase 1 study (GO30103).

As of the December 2, 2019 data deadline, 42 patients were treated with tiragolumab as a single agent. Patients receiving single agent tiragolumab experienced an IRR. In phase la, 5 patients (12%) experienced IRR. Signs and symptoms associated with IRR were generally mild and included fever, chills, hot flashes, hypertension, lymphadenopathy, nausea, myalgia, and skin lesions. All IRR cases were successfully dealt with as supportive actions. As IRR occurred during and after infusion of single agent tyragolumab in 12% of patients, the IRR was shifted from potential risk to identified risk. Although there is no additional identified risk for tiragolumab, involvement of the TIGIT co-inhibitory pathway may increase the risk of autoimmune inflammation when tiragolumab is administered as a single agent. Therefore, tiragolumab as a single agent may induce adverse reactions similar to those of atezolizumab. These immune-mediated adverse events have been well characterized for other immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-L1/PD-1.

This is the first clinical evaluation of tiragolumab in combination with an anti-PD-L1/PD-1 agent. Although clinical evaluation of tiragolumab in combination with atezolizumab is limited and not all risks are known, as of December 2, 2019, more than 200 patients were treated with tiragolumab in combination with atezolizumab. received. Although there are currently no identified inherent risks for tiragolumab administered in combination with atezolizumab, the involvement of the TIGIT co-inhibitory pathway when tiragolumab is administered in combination with atezolizumab is implicated in some immune responses, including HLH and MAS. may increase the risk of Therefore, when co-administered with atezolizumab, tiragolumab may exacerbate atezolizumab-related adverse events or may have toxicity that does not overlap with atezolizumab.

The greatest clinical experience to date with combinations of complementary modulators of adaptive immunity comes from trials of ipilimumab in combination with nivolumab. Another anti-TIGIT antibody MK-7684 (vivostolimab) showed an acceptable safety profile and promising antitumor activity in patients with advanced tumors when combined with pembrolizumab. Based on these data, it is expected that the frequency and severity of immune-mediated adverse events may increase with combination compared to single agent inhibitors, but complex immune-mediated adverse events can be monitored and managed in a clinical setting.

clinical effectiveness

As of the December 2, 2019 data cut-off date, no objective responses were reported for patients enrolled in the Phase Ia portion of study GO30103, and the best response in 8 of 42 patients who received oncological evaluation during the study was stable disease ( SD). In the Phase Ib portion of the study, objective responses, including complete response (CR) in 4 of 171 patients and partial response (PR) in 23 of 171 patients, were assessed for multiple tumors, including NSCLC, HNSCC, and triple negative breast cancer. It has been observed in patients who have not experienced cancer immunotherapy (CIT) of the same type.

As of the June 30, 2019 data deadline, data from blinded, randomized, phase II study GO40290 showed that the combination of tiragolumab and atezolizumab improved ORR and PFS compared to placebo and atezolizumab in the ITT population. . The ORR of tiragolumab and atezolizumab was 31.3% (95% CI: 19.5-43.2) compared to placebo and atezolizumab, which was 16.2% (95% CI: 6.7-25.7). The investigator-evaluated PFS of tiragolumab and atezolizumab was HR 0.57 (95% CI: 0.37 to 0.90) = 5.4 months compared to the PFS of placebo and atezolizumab of 3.6 months (95% CI: 2.7 to 4.4) (95% CI: 4.2, below).

Phase Ib of tiragolumab and atezolizumab including chemotherapy

In multiple, large-scale, randomized, phase 3 trials of advanced solid tumors, the addition of anti-PD-L1/PD1 to standard chemotherapy improved OS and PFS in patients compared to chemotherapy alone. In this trial, anti-PD-1 was added to pemetrexed and platinum-based chemotherapy in nonsquamous NSCLC (Gandhi et al. N Engl J Med 2018; 378:2078-92) and carboplatin and paclitaxel or Addition to nap-paclitaxel was studied (Paz-Ares et al. N Engl J Med 2018; 379:204051. This trial also added anti-PD-L1 to carboplatin and etoposide in extended-stage SCLC ( Horn et al. N Engl J Med 2018; 379:2220-9), investigated the addition of nap-paclitaxel in TNBC (Schmid et al. N Engl J Med 2018; 379:2108-21). Thus, anti-PD-L1/PD-1 in combination with chemotherapy has been approved by FDA and EMA for patients with advanced cancer.Preclinical data suggest that the combination of anti-TIGIT and anti-PD-L1/PD-1 is a single The addition of anti-TIGIT to anti-PD-L1/PD-1 in combination with chemotherapy is recommended because it suggests that the anti-tumor immune response is more enhanced than the agent anti-PD-L1/PD-1 alone. Assume that it can be more effective than adding L1/PD-1.

The safety profile of the combination of anti-PD-L1/PD-1 and chemotherapy was generally consistent with the known toxic effects of each agent as observed in several clinical trials for advanced solid tumors (Gandhi et al. N Engl). J Med 2018; 378:2078-92; Horn et al. N Engl J Med 2018; 379:2220-9; Paz-Ares et al. N Engl J Med 2018; 379:2040-51; Schmid et al. N Engl J Med 2018; 379:2108-21). Given the similarity of the mechanism of action between tiragolumab and atezolizumab, the safety profile of tiragolumab co-administered with atezolizumab and chemotherapy may be related to the immune-related toxicity of combined anti-TIGIT and anti-PD-L1 and individual chemotherapy. It is expected to be consistent with the toxicity of the drug. Therefore, the design and safety management plan for the Phase Ib chemotherapy expansion cohort includes the considerations outlined for combining anti-TIGIT with anti-PD-L1 to reduce potential risks to participating patients as well as extensive clinical experience with chemotherapy. This is included.

Phase Ib of tiragolumab and atezolizumab, including bevacizumab

Strong scientific evidence and new clinical data suggest that combined PD-L1, VEGF and TIGIT inhibition may be of clinical benefit in several tumor types.

In chemotherapy-naïve patients with stage IV NSCLC, results from study GO29436 (IMpower150) showed that atezolizumab plus bevacizumab plus chemotherapy resulted in a significantly greater OS compared to bevacizumab and chemotherapy alone. long (Socinski et al. N Engl J Med 2018; 378:2288-301). For patients with inoperable, locally advanced, or metastatic RCC, the results of study WO29637 (IMmotion151) were improved compared to sunitinib after treatment with the combination of atezolizumab and bevacizumab in a treatment-naive patient population. showed PFS (Motzer et al. J Clin Oncol 2018; 36(6_suppl):578, Rini et al. Lancet 2019; 393:2404-15). A Phase Ib study of primary HCC, GO30140, revealed an ORR of 65% in 23 evaluable patients across etiology, geography, baseline alpha fetoprotein levels, and extrahepatic spread (Stein et al. J Clin Oncol 2018; 36 (Stein et al. J Clin Oncol 2018; 36) Suppl 15):4074, Lee et al. Lancet Oncol. 2020 Jun; 21(6):808-820). Based on these results, the treatment was recognized as a novel solution, and the results were confirmed in the YO40245 (IMbrave150) study, a randomized phase 3 clinical study. Study YO40245 (IMbrave150) was designed to evaluate the efficacy and safety of atezolizumab and bevacizumab versus sorafenib in patients with advanced or metastatic hepatocellular carcinoma who have not previously received systemic therapy. The study enrolled 501 patients randomized in a 2:1 ratio. The most recent study results showed statistically significant and clinically significant improvements in PFS and OS. The risk of death was reduced by 42% in the atezolizumab plus bevacizumab group compared to the sorafenib group (stratified HR 0.58 (95% CI: 0.42 to 0.79), median OS, NE vs. 13.24 months). PFS evaluated by an independent review facility according to the Response Evaluation Criteria for Solid Tumors (RECIST) v1.1 showed improvement in favor of combination therapy (stratified HR 0.59 (95% CI: 0.47 to 0.76); median PFS, 6.83 vs. 4.27 months) (Cheng et al. Ann Oncol 2019; 30:ix186-ix187, Finn et al. N Engl J Med 2020; 382:1894-1905).

This is an example of a potential synergistic effect between atezolizumab and bevacizumab in various tumor types and supports further exploration of combinations with tiragolumab.

Example 5. Pharmacokinetics, Pharmacodynamics, Safety and Efficacy in Phase Ia/Ib Dose Escalation Study of Anti-TIGIT Antibody Tiragolumab as Single Agent and in Combination with Atezolizumab in Patients with Advanced Solid Tumors

A. Patient characteristics

The baseline characteristics of patients in the Phase Ia and Phase Ib portions of the study are shown in Table 37. Patients in both Phase Ia and Ib include a highly prior-treated population, with 42% of Phase Ia patients and 37% of Phase Ib patients receiving 4 or more prior cancer therapies. Phase Ia and Ib patients share similar baseline characteristics.

Characteristics, n (%) Phase Ia: Tiragolumab (n=24) Phase Ib: Tiragolumab +
Atezolizumab (n=49) age, median (range) 59.5 (40-77) 54.0 (25-81) male 10 (42%) 24 (49%) ECOG PS 1 17 (71%) 36 (74%) race White 15 (63%) 30 (61%) Asian 7 (29%) 13 (27%) antecedent cancer therapy One 2 (8%) 7 (14%) 2 6 (25%) 14 (29%) 3 6 (25%) 10 (20%)

4

4 10 (42%) 18 (37%) Primary cancer history type colon 4 (17%) 8 (16%) rectal 4 (17%) 4 (8%) breast 2 (8%) 9 (18%) non-small cell lung cancer - 6 (12%) head and neck cancer - 4 (8%) ovary 1 (4%) 3 (6%) Etc* 13 (54%) 15 (31%) ECOG = Eastern Corporate Oncology Group; PS = whole body activity
*Others include:
Phase Ia: endometrial (n=2), melanoma (n=2); and appendix, bladder, cervix, cholangiocarcinoma, kidney, neuroendocrine, peritoneum, sarcoma and stomach (n=1 each)
Phase Ib: sarcoma (n=4), gastric (n=2), melanoma (n=2); and anus, cecum, bladder, esophagus, GE junction, Merkel cells and peritoneum (n=1 each)

Baseline Characteristics

Most patients in the Phase Ia and Phase Ib portions of the study discontinued treatment for disease progression (42% in Phase Ia and 76% in Phase Ib). None of the patients with phase Ib transition showed a response. Patient propensity is shown in Table 38.

state, n (%) Phase Ia: Tiragolumab (n=24) Phase Ib: Tiragolumab + Atezolizumab (n=49) in treatment 0 5 (10%) stop 24 (100%) 44 (90%) disease progression 10 (42%) 37 (76%) withdraw 2 (8%) 6 (12%) lost track 0 1 (2%) transition to phase Ib 12 (50%) --

patient disposition

B. Pharmacokinetics and Pharmacodynamics of Tiragolumab

The pharmacokinetics of tyragolumab as a single agent (Phase Ia) and in combination with atezolizumab (Phase Ib) were determined. The exposure of tiragolumab increased with dose administration as a single agent and in combination with atezolizumab ( FIG. 9 ). The pharmacokinetics of tiragolumab are not altered when co-administered with atezolizumab.

The pharmacodynamics of tiragolumab as a single agent (phase Ia) were measured ( FIG. 10 ). Occupancy of peripheral TIGIT receptors on CD8 ⁺ T cells and NK cells was measured at doses of 2 mg, 8 mg, 30 mg, 100 mg, 400 mg, 600 mg and 1200 mg every 3 weeks. Complete and persistent occupancy of peripheral TIGIT receptors was observed after 2 days (C1D2) at doses of tyragolumab above 30 mg.

C. safety

A summary of adverse events is presented in Table 39. The overall rate of Grade 3 to 5 adverse events was low in the phase Ia and Ib sections, and none of them had Grade 5 adverse events. No dose limiting toxicity of tiragolumab as a single agent or in combination with atezolizumab was observed. All adverse events present in more than 10% of phase Ia and Ib patients are shown in FIGS. 11 and 12 , respectively. All immune-mediated adverse events are shown in Table 40. Tiragolumab was well tolerated as a single agent and in combination with atezolizumab.

Phase Ia: Tiragolumab (n=24) Phase Ib: Tiragolumab + Atezolizumab (n=49) Adverse events of any cause (AE) 24 (100%) 46 (94%) Grade 3-5 adverse reactions 6 (25%) 28 (57%) Relevant Grade 3-5 Adverse Events ^* 1 (4%) 2 (4%) serious adverse reactions 6 (25%) 26 (53%) AEs leading to study drug(s) discontinuation 4 (17%) 12 (25%) AEs leading to study drug(s) withdrawal 0 1 (2%) ^* Relevant AE on phase Ia was a grade 3 increase in blood creatinine (n=1). Grade 5 AEs were not related to tiragolumab.
Relevant AEs in phase Ib were grade 3 hyperlipidemia (n=1) and grade 3 decreased lymphocyte count (n=1). Grade 5 AEs were not associated with tiragolumab and/or atezolizumab.
^** One patient withdrew from a Phase Ib study of gastrointestinal disorders related to clinical progression.

Summary of Safety of Adverse Events

Phase Ia: Tiragolumab (n=24) Phase Ib: Tiragolumab + Atezolizumab (n=49) All immune-mediated AEs 4 (17%) 29 (59%) Grade 3-5 immune-mediated AE ^* 0 2 (4%) Infusion-related reactions 2 (8%) 4 (8%) rash 2 (8%) 14 (29%) Hepatitis (diagnostic and laboratory) 1 (4%) 10 (20%) Pancreatitis (lab) 1 (4%) 1 (2%) hyperthyroidism 0 4 (8%) hypothyroidism 0 3 (6%) anemia 0 1 (2%) ^* Grade 5 immune-mediated AE was not associated with tiragolumab and/or atezolizumab.

Any immune-mediated adverse reaction

D. effectiveness

A preliminary efficacy analysis was performed in phase Ia and phase Ib dose escalation studies. In the phase la portion, a reduction in tumor size was observed in neuroendocrine cancer, ovarian cancer and rectal cancer ( FIG. 13 ). Although there was no objective response in the Phase Ia portion of the study, most patients had tumor types that did not normally respond to cancer immunotherapy (CIT), had tumors with low PD-L1 expression, or received excessive prior treatment. . Objective responses were observed in the Phase Ib portion of the study for NSCLC, TNBC, HNSCC and esophageal cancer types ( FIG. 14 ).

In patients treated with tiragolumab in combination with atezolizumab, the size of PD-L1-positive NSCLC tumors including CIT-naive tumors was significantly reduced ( FIG. 14 ). CIT-naive PD-L1-positive NSCLC treated with tiragolumab in combination with atezolizumab had an overall response rate of 46%, including two complete responses and multiple responses with persistence (Figs. 16).

Example 6: Atezolizumab in combination with tiragolumab and bevacizumab for advanced liver cancer

Liver cancer is the fifth most common cancer and the second most common cancer-related cause of death worldwide, with 854,000 new cases and 810,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and accounts for approximately 90% of all primary liver cancers. Less diffuse primary liver cancers include intrahepatic cholangiocarcinoma (iCCA), angiosarcoma, and hepatoblastoma.

Study YO40245 (IMbrave150) is an ongoing, randomized, phase 3 study evaluating atezolizumab plus bevacizumab versus sorafenib as first-line treatment in patients with advanced or metastatic HCC. This study is the first to demonstrate a statistically significant and clinically significant improvement in OS and progression-free survival (PFS) for a new treatment combination in a one-to-one comparison with sorafenib. At the time of primary analysis, the atezolizumab + bevacizumab group had a 42% reduction in the risk of death compared to the sorafenib group (stratified hazard ratio [HR] 0.58 [95% CI: 0.42 to 0.79]; p = 0.0006; OS median, unestimable [NE] vs. 13.24 months). PFS evaluated by an independent review facility according to RECIST v1.1 also showed statistically significant and clinically significant improvement in favor of combination therapy (stratified HR = 0.59 [95% CI: 0.47 to 0.76]; p = < 0.0001; median PFS, 6.83 vs. 4.27 months). Overall, in HCC, atezolizumab plus bevacizumab was generally well tolerated with manageable toxicity, and the safety profile was consistent with the individual study treatments and the known risk of underlying disease (Cheng et al. IMbrave150: unresectable hepatocellular carcinoma). Efficacy and Safety Results of a Ph 3 Study Evaluating Atezolizumab (Atezo) Bevacizumab (Bev) vs Sorafenib (Sor) as First Treatment (tx) in (HCC) patients (pts) at ESMO Asia 2019. Procedure: 22-24 November 2019 [citation: 27 November 2019]; Singapore.

This is a Phase Ib/II, open-label, multicenter, randomized, comprehensive study in patients with locally advanced or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy for the disease.

Patients are randomly assigned to a control group (atezolizumab + bevacizumab [atezo + bev]) or a treatment group consisting of atezolizumab and bevacizumab in combination with tiragolumab (atezo + bev + tyra).

Control (Atezo + Bev)

Patients in the atezolizumab + bevacizumab (atezo + bez) group receive treatment as summarized in the table below.

cycle length Dose, route, and regimen
(Drugs listed in order of administration) 21 days Atezolizumab 1200 mg IV infusion per day
Bevacizumab 1200 mg IV infusion per day Artezo + Bev = Atezolizumab + Bevacizumab.

Therapeutic regimen of the Artezo + Bev group

Artezo + Bev + Tyra

Patients in the Atezolizumab + Bevacizumab + Tiragolumab (Atezo + Bev + Tira) group receive treatment as summarized in the table below.

cycle length Dose, route, and regimen
(Drugs listed in order of administration) 21 days Atezolizumab 1200 mg IV infusion per day
15 mg IV infusion of bevacizumab on day 1
Tiragolumab 600 mg IV infusion per day ^a atezo + bev + tyra = atezolumab + bevacizumab + tyragolumab; IRR = infusion-related reaction
^a On Day 1 of Cycle 1, tiragolumab is administered 60 minutes after completion of the bevacizumab infusion. The interval between subsequent infusions is 30 minutes if the previous bevacizumab infusion was given without a predose and was well tolerated without an infusion-related reaction (IRR), or 60 minutes if the patient experienced an IRR with a previous bevacizumab infusion. will be.

Artezo + Bev + Tyra-kun’s treatment regimen

B. Selection Criteria

Patients must meet all of the following criteria:

연령 ≥ 18세.

Age ≥ 18 years.

치료 전 7일 이내에 0 또는 1의 ECOG 전신 활동도.

ECOG systemic activity of 0 or 1 within 7 days prior to treatment.

간경변 환자에게서 조직학/세포학 또는 임상적으로 AASLD 기준에 의해 진단이 확인된 국소 진행성 또는 전이성 및/또는 절제 불가능한 HCC

Locally advanced or metastatic and/or unresectable HCC diagnosed by AASLD criteria histologically/cytologically or clinically in patients with cirrhosis

For cirrhosis patients without histological confirmation of diagnosis, clinical confirmation is required according to AASLD criteria.

무작위 배정 전 7일 이내 차일드-퍼 부류 A

Child-Fur Class A within 7 days prior to randomization

근치적 외과적 및/또는 국소적 요법을 받을 수 없는 질병

Diseases that cannot be treated with curative surgical and/or local therapy

Patients with progressive disease following surgery and/or topical therapy are eligible.

HCC에 대한 선행 전신 치료(전신 임상시험용 제제 포함) 없음

No prior systemic treatment for HCC (including systemic investigational products)

Prior treatment with herbal remedies with labeled anticancer activity, including herbal remedies, are permitted if these medications are discontinued prior to randomization.

기대 수명 ≥3 개월

Life expectancy ≥3 months

Efficacy and safety objectives and endpoints are listed in the table below. Here, patients treated with the triple combination of atezo+bev+tyra had acceptable toxicity but compared efficacy endpoints (ORR, PFS, OS, DOR, and/or) compared to placebo atezo+bev (i.e. without tyra). or disease control).

ADA = 　 anti-drug antibody; DOR = 　 duration of response; HCC　=　Hepatocellular Carcinoma; HCC　mRECIST　=　HCC modified RECIST; iRECIST　=　modified RECIST v1.1 for immune-mediated therapeutics; NCI CTCAE v5.0 = 　 National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0; ORR　=　objective response rate; OS　=　overall survival; PFS　=　Progression-free survival; PK　=　pharmacokinetics; RECIST　=　Criteria for evaluating the response of solid tumors.

ADA = 　 anti-drug antibody; DOR = 　 duration of response; HCC　=　Hepatocellular Carcinoma; HCC　mRECIST　=　HCC modified RECIST; iRECIST　=　modified RECIST v1.1 for immune-mediated therapeutics; NCI CTCAE v5.0 = 　 National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0; ORR　=　objective response rate; OS　=　overall survival; PFS　=　Progression-free survival; PK　=　pharmacokinetics; RECIST　=　Criteria for evaluating the response of solid tumors.

Example 7. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Atezolizumab + Carboplatin and Etoposide with or Without Tiragolumab in Patients with Untreated Diastolic Small Cell Lung Cancer

This example shows that the antitumor effect of atezolizumab plus chemotherapy, as measured by OS, PFS, ORR and DOR, could be improved by adding the anti-TIGIT antibody tyragolumab to atezolizumab and chemotherapy in patients with ES-SCLC. Describe a randomized, phase 3, global, multicenter, double-blind, placebo-controlled study designed to evaluate whether To compare the safety and efficacy of tiragolumab in combination with atezolizumab and CE with placebo treatment in combination with atezolizumab in patients with ES-SCLC and naïve chemotherapy for expanded-stage disease.

A. Study Design

Safety and efficacy of atezolizumab and tiragolumab in combination with CE compared to treatment with atezolizumab and placebo in combination with CE in patients with ES-SCLC but no chemotherapy experience for their advanced stage disease Details of a randomized, phase 3, multicenter, double-blind, placebo-controlled study to evaluate efficacy are described below. 17 depicts the study design.

Eligible patients were stratified by ECOG systemic activity (0 vs. 1), LDH (≤ upper limit of normal (ULN) vs. >ULN), presence or history of brain metastases (yes vs. no), and treated with the following treatment as shown in Table 46. They were randomized in a 1:1 ratio to receive one of the regimens. Additional details on ECOG systemic activity can be found in Oken et al., Am. J. Clin Oncol. 1982, 5: 649-655.

A total of approximately 470 patients were randomly assigned to the study. The primary population (PP) includes approximately 400 patients assuming a 15% prevalence of the presence or history of brain metastases at baseline. The intent-to-treat (ITT) population includes all patients.

Induction treatment is given in 21-day cycles for 4 cycles. After the induction phase, patients continued maintenance therapy with atezolizumab plus tiragolumab (group A) or atezolizumab plus placebo (group B). During the maintenance phase, prophylactic cranial examination (PCI) is permitted according to local standards of care and is reported according to the preventive cranial examination electronic case report form (eCRF). Palliative radiation for symptom management is permitted. The doses and dosing schedules in Table 46 are provided in Table 47 below.

On Day 1 of each cycle, all eligible patients received study drug.

It is administered in the following order.

Group A: atezolizumab, tiragolumab, carboplatin and etoposide

Group B: atezolizumab, placebo, carboplatin and etoposide

Patients may receive antiemetics and IV hydration for carboplatin and etoposide according to local standards of care and manufacturer's guidelines. Premedication with corticosteroids should be minimized to the extent clinically feasible. All drugs should be recorded on the appropriate concomitant drug eCRF.

During the induction phase, the study treatment is

It should be administered in the following manner per day”

One. After intravenous administration of atezolizumab 1200 mg over 60 (±15) minutes (reduced to 30 [±10] minutes for the first infusion and subsequent infusions) (see Table 48),

2. After intravenous administration of tiragolumab/placebo 600 mg over 60 (±15) minutes (reduced to 30 [±10] minutes for the first infusion and for subsequent infusions) (see Table 48),

3. After carboplatin was administered intravenously (Calbert formula administration) over 30-60 min to achieve the initial target area under a concentration-time curve (AUC) of 5 mg/mL/min,

4. Etoposide (100 mg/m ² ) is administered intravenously over 60 minutes. During the induction phase, etoposide (100 mg/m ² ) is also administered intravenously over 60 minutes on days 2 and 3.

Cycles for which no chemotherapy was given are not included in the total number of induction chemotherapy cycles. After the induction phase, patients begin maintenance therapy with atezolizumab plus tiragolumab/placebo. The recommended infusion times for carboplatin and etoposide should be adjusted according to local standards of care. Administration of atezolizumab and tiragolumab/placebo is performed in a monitoring environment with trained staff and immediate access to appropriate equipment and medications to manage potentially severe reactions.

Treatment was tested in the absence of unacceptable toxicity or worsening of symptoms due to disease progression until radiological disease progression according to RECIST v1.1 or after an integrated evaluation of radiographic data, biopsy results (if available), and clinical status. Continue self-evaluation as long as patients experience clinical benefit. Patients who meet the disease progression criteria per RECIST v1.1 may continue on study treatment if all inclusion criteria are met (tiragolumab + atezolizumab or placebo + atezolizumab).

atezolizumab

Patients receive 1200 mg atezolizumab as an IV infusion on Day 1 of each 21-day cycle. Atezolizumab dose is fixed and does not vary with body weight. Atezolizumab infusion is administered according to the guidelines summarized in Table 48. Atezolizumab dose is not changed. Detailed information on dosage preparation, storage and administration instructions for atezolizumab can be found in the pharmacy manual and/or in the atezolizumab investigator's brochure.

Tiragolumab/placebo

Following atezolizumab administration and the observation period (see Table 48), patients receive 600 mg tyragolumab/placebo as an IV infusion on Day 1 of each 21-day cycle. The tiragolumab/placebo dose is fixed and does not vary with body weight. Tiragolumab/placebo infusion is administered according to the guidelines summarized in Table 48. The tiragolumab/placebo dose is not changed. Detailed information on dosage preparation, storage, and administration instructions for tiragoluumab/placebo can be found in the pharmacy manual and/or the tiragolumab investigator's brochure.

carboplatin

During the induction phase, carboplatin is administered as an IV infusion over 30-60 minutes to achieve an initial target AUC of 5 mg/mL/min (Calvert Official Dosing) using standard antiemetics according to local practice guidelines. /administered after completion of placebo. Premedication with corticosteroids can be minimized to the extent clinically feasible. Carboplatin infusion times are adjusted according to local standards of care.

The carboplatin dose of AUC 5 is calculated using the Calvert formula (Calvert et al. (1989) J Clin Oncol 7:174856) (Calvert et al., J. Clin. Oncol . 1989, 7:1748-56). ):

Calvert's formula:

Total dose (mg)　=(target AUC)　´(glomerular filtration rate [GFR]　+25)

Note: The GFR used in the Calvert formula above to calculate the AUC-based dose should not exceed 125 mL/min.

As used herein, GFR is considered equivalent to creatinine clearance (CRCL). The CRCL is calculated using the following formula according to institutional guidelines or the method of Cockcroft and Gault, Nephron 1976, 16:31-41:

CRCL = (140 - age) x (wt)

(x 0.85, for women)

72　x　Scr

where: CRCL = creatinine clearance, mL/min

Age 　 = patient's age

wt　= patient's weight, kg

Scr = serum creatinine, mg/dL

Note: For patients with abnormally low serum creatinine levels, the GFR is estimated using a minimum creatinine level of 0.8 mg/dL, or the upper limit of the estimated GFR is 125 mL/min.

When a patient's GFR is estimated based on serum creatinine measurements by isotopic dilution mass spectrometry, physicians consider limiting the dose of carboplatin for the desired exposure (AUC) to avoid potential toxicity due to overdose. Based on the Calvet formula described on the carboplatin label, the maximum dose can be calculated as follows:

Maximum carboplatin dose (mg) = target AUC (mg x min/min) x (GFR + 25 mL/min)

This maximum dose is based on an estimate of GFR with an upper limit of 125 mL/min in patients with normal renal function. GFR estimates higher than this are not used.

For a target AUC = 5, the maximum dose is 5 x (125 + 25) = 5 x 150 = 750 mg.

For a target AUC = 4, the maximum dose is 4 x (125 + 25) = 4 x 150 = 600 mg.

etoposide

During the induction phase, etoposide (100 mg/m ² ) is administered as an IV infusion over 60 minutes following administration of carboplatin on Day 1 of each cycle. On days 2 and 3 of each cycle, etoposide (100 mg/m ² ) is administered as an IV infusion over 60 minutes. Premedication should be done according to local standards of care. Premedication with corticosteroids can be minimized to the extent clinically feasible. Etoposide infusion times can be adjusted according to local standards of care.

Evidence for evaluation of patients without brain metastases at baseline (primary population for statistical analysis)

The brain is a common site of metastasis in patients with ES-SCLC, and in some studies, up to 18% of patients have brain metastases at diagnosis, and up to 80% are expected to have brain disease involvement during the first 2 years after diagnosis (Seute et al. ., Cancer , 100: 801-806, 2004; Pacheco and Bunn, Clin Lung Cancer , 20: 148-160, 2019). In general, the benefit of combining immunotherapy and chemotherapy has been shown in patients with ES-SCLC. However, this benefit may be attenuated in patients with brain metastases at baseline, as shown in the IMpower133 trial, where the HR of this patient subgroup was 1.07 compared to 0.68 in patients without brain metastases. (Horn et al., New Engl J Med , 379: 2220-2229, 2018).

KEYNOTE-604 is another phase 3 trial suggesting that patients with ES-SCLC with brain metastases at diagnosis may have less or no overall survival benefit for first-line immunotherapy plus chemotherapy compared to those without. to be. Indeed, the OS HR of patients with brain metastases is 1.32 and those without brain metastases are 0.75 (Rudin et al., J Clin Oncology , 38: 2369-2379, 2020). The CASPIAN study initially reported an OS HR of 0.69 in patients with brain metastases, but an updated analysis showed an HR of 0.79. In the initial and updated reports, the OS HR of patients without brain metastases was 0.74 and 0.76, respectively (Paz-Ares et al., N Engl J Med , 379: 2040-2051, 2018; Paz-Ares et al., Am Soc ). Clin Oncol 2020 , abstract 9002, 2020).

It is important to understand the benefits of the study regimen in both patient subgroups. Therefore, a test statistics hierarchy was implemented to test the PP first and then the ITT.

B. evaluation

Patients receive tumor assessments at baseline and every 6 weeks (± 7 days) for 48 weeks after Day 1 of Cycle 1. Samples of pretreated tumor tissue (archival or freshly obtained) are submitted before or within 4 weeks of randomization. The specimen is accompanied by an associated pathology report. All available tumor tissue samples may be submitted, but biomarker analysis (e.g., markers related to PD-L1 status, immune or SCLC biology, e.g., T cell markers identified via NGS in extracted DNA, RNA or other biological molecules or It is recommended to submit representative tumor specimens of paraffin blocks (preferred) or 10 (or more) consecutive fresh, unstained slides for non-genetic biomarkers. Exemplary sample types include ablation, core needle, ablation, incision, punch, forceps biopsy, fine needle aspiration, and formalin fixed paraffin embedded (FFPE) samples prepared from cell pellet specimens (e.g., pleural effusion and lavage samples). Tumor tissue should be of good quality based on total and viable tumor content. Tumor tissues of bone metastases that are subject to decalcification are not recommended.

After completing the 48-week tumor assessment, tumor assessments are performed every 9 weeks (77 days) thereafter. Patients treated for disease progression abnormality according to RECIST v1.1 receive tumor evaluation until treatment is discontinued. Patients who discontinued treatment for reasons other than radiological disease progression according to RECIST v1.1 (e.g., toxicity, worsening symptoms), regardless of whether the patient starts new chemotherapy or not, 6 weeks for 48 weeks after Day 1 of Cycle 1 Continue with scheduled tumor assessments every (±7 days) and every 9 weeks (±7 days) thereafter.

Serum samples are collected to monitor tiragolumab and atezolizumab pharmacokinetics. In selected patients, plasma samples are collected for chemotherapy pharmacokinetics. Safety assessments include the incidence, nature and severity of adverse events, protocol essential vital signs, and laboratory abnormalities.

Tumor biopsy is performed during radiographic progression. Exemplary sample types include FFPE samples prepared from ablation, core needle, ablation, incision, punch, forceps biopsy, fine needle aspiration, and cell pellet specimens (eg, pleural effusion and lavage samples). DNA and/or RNA extraction may be performed from the tissue.

C. Patient Reported Results

Patient Reported Outcome (PRO) data is collected to document treatment benefit and more fully characterize the clinical profile of tiragolumab plus atezolizumab. PRO data was collected using the following tools: EORTC QLQ-C30, single item EORTC IL46, selection of PRO-CTCAE, and EQ-5D-5L.

The EORTC QLQ-C30 measures five aspects of patient functioning (physical, emotional, role, cognitive, social), three symptom scales (fatigue, nausea and vomiting, pain), overall health/quality of life, six single items ( Dyspnea, insomnia, anorexia, constipation, diarrhea, economic hardship) is a validated and reliable self-report method consisting of 30 questions (Aaronson et al., J. Natl. Cancer Inst . 1993, 85:365). -76; Fitzsimmons et al., Eur. J. Cancer 1999, 35:939-41). Scale scores can be obtained for multi-item scales.

The EORTC QLQ-C30 module takes about 15 minutes to complete. Also collect the single entry EORTC IL46. The validated single-item question assesses the overall adverse effect.

PRO-CTCAE is a validated question bank used to characterize the presence, frequency, severity, and disturbance of daily functioning of 78 patient-reportable symptomatic treatment toxicities (Basch et al., J. Natl Cancer Inst. 2014, 106:1-11; Dueck et al., JAMA Oncol . 2015, 1:1051-52). PROCTCAE contains 124 questions rated on a 5-point Likert scale (frequency, severity, and interference) or dichotomous (presence/absence). The therapeutic toxicity terms included are predominantly observable with or without an observable component (eg, vomiting and nausea, respectively) or with a subjective or subjective component (eg, rash). The standard PRO-CTCAE recall period is “last 7 days”. A subset of the three symptoms currently considered most suitable for treatment was selected for this study.

EQ-5D-5L is a general preference-based health utility measure that includes questions about mobility, self-management, daily activities, pain/discomfort, and anxiety/depression used to comprehensively build a patient's health status. EQ-5D-5L takes about 2 minutes to complete. EQ-5D-5L will be utilized in this study for economic modeling.

The paper version of the PRO tool is self-administered during treatment visits and interviewed by field staff calling patients during follow-up visits, allowing patients to collect data without having to travel to clinical hunger. PRO data is entered into the research database by field staff.

To ensure the validity of the tool and to ensure that data standards meet the requirements of health authorities, questionnaires scheduled for administration during clinic visits are biased toward patient responses prior to receiving any information about disease status, unless otherwise specified. Patients complete complete prior to conducting non-PRO evaluations that may give

Questionnaires (EORTC QLQ-C30, EORTC IL46, PRO-CTCAE (optional) and EQ-5D-5L) were administered during the induction phase on Day 1 (baseline) of Cycle 1 prior to dosing of study drug; Complete on all study treatment cycles (ie, Day 1 of Cycle 2; Day 1 of Cycle 3; and Day 1 of Cycle 4) prior to administration of study drug. During the maintenance phase, the questionnaire is completed on every other study treatment cycle (ie, Day 1 of Cycle 5; Day 1 of Cycle 7; Day 1 of Cycle 9, etc.) prior to study drug administration and at the study treatment discontinuation visit. During survival follow-up, PRO is collected at the first survival follow-up at 3 months (±30 days) and at the second survival follow-up at 6 months (±30 days). Patients who discontinued study treatment (e.g., toxicity, worsening symptoms) for reasons other than radiological disease progression according to RECIST v1.1 should have radiological disease progression, death, loss of follow-up, withdrawal of consent, or trial according to RECIST v1.1. EORTC QLQ-C30, PRO-CTCAE (optional), and EQ-5D-5L, respectively, are completed at each tumor assessment visit, up to the sponsor's end of study, whichever occurs first. Patients whose mother tongue is not available on the questionnaire are exempt from completing all PRO assessments.

Adverse event reports are not derived from PRO data.

D. evaluation variable

Investigator-assessed PFS (as assessed by inventor according to RECIST v1.1) and OS of PP were the joint primary endpoints of this study. Objective response rates in PP and ITT populations, duration of response in PP and ITT populations, and PFS and OS in ITT populations are secondary endpoints.

progression-free survival

PFS is the time between the date of randomization and the first recorded date of disease progression or death (as assessed by the investigator according to RECIST v1.1), whichever occurs first. Patients who have not experienced disease progression or have not died by the data deadline will be censored at the final tumor evaluation. Patients without post-baseline tumor evaluation are censored on the date of randomization.

PFS as an endpoint can reflect tumor growth and can be evaluated before determining survival benefits. In addition, these decisions are generally not confounded by subsequent therapy. Whether an improvement in PFS represents a direct clinical benefit or a surrogate of clinical benefit depends on the effect and benefit-risk magnitude of the new treatment compared to available therapies (US Food and Drug Administration (2007) ) Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics ).

To ensure investigator-assessed efficacy of PFS as the primary endpoint, several measures were implemented: a practical target scale of benefit and study evaluations that would enable a robust benefit-risk assessment (the same fixed fixed size in both treatment groups). Existing RECIST v1.1 criteria for defining radiological disease progression as an evaluation interval, and robust definitions and prospectively defined methods of PFS for assessing, quantifying, and analyzing PFS, including sensitivity analysis).

A primary analysis of the co-primary endpoint of PFS is made when approximately 300 cases of PFS (75% of 400 patients) are observed in PPP. This gives 96% power to detect a target HR of 0.56 for PFS at a two-sided significance level of 0.001 based on: PFS curve following exponential distribution; median PFS of 5.2 months in the placebo + atezolizumab + EC group and 9.2 months in the tiragolumab + atezolizumab + EC group (corresponding to a target HR of 0.56); dropout rate of 5% over 12 months for PFS; and no interim analysis for PFS.

An observed HR of 0.68 or greater in PFS corresponds to a statistically significant difference between treatment groups. That is, an HR of 0.68 is the minimally detectable difference in this assay; This corresponds to a 2.4-month improvement in median PFS from 5.2 months in the placebo + atezolizumab + CE group to 7.6 months in the tiragolumab + atezolizumab + CE group.

The Kaplan-Meier method is used to estimate the median PFS for each treatment group, and a Kaplan-Meier curve is created to visually account for differences between treatment groups. The Brookmeyer-Crowley method was used to generate a 95% CI for the median PFS for each treatment group (Brookmeyer and Crowley, Biometrics 1982, 38: 29-41).

PFS rates at 6 months and 1 year after randomization were estimated using the Kaplan-Meier method for each treatment group with a 95% CI calculated using standard errors derived from Greenwood's formula. A 95% CI for the difference in PFS rates between the two treatment groups was estimated using a normal approximation.

overall survival

OS is the co-primary endpoint in this study. OS is the time between the date of randomization and death from any cause. Improvement in OS is generally accepted as the best measure of clinical benefit for patients with advanced/resectable or metastatic lung cancer.

A stratified log-rank analysis is used to compare PFS and OS between treatment groups. HR for PFS and OS are estimated using a stratified Cox proportional hazards model. 95% CI is given to HR. Stratification factors are factors used for randomization in IxRS (ie ECOG systemic activity and lactate dehydrogenase (LDH)). The stratification element(s) may be removed from the stratification analysis if there is an excessive risk of stratification. If significant discrepancies are observed between IxRS records and eCRFs, an analysis based on the stratification factors recorded on the Electronic Case Reporting Form (eCRF) will also be provided. Non-stratified analysis results are also provided.

The final analysis of the co-primary endpoint of OS occurs when approximately 288 deaths (72% of 400) are observed in the PP cohort. This provides 85% analytical power to detect a target HR 0.70 for OS at a two-sided significance level of 0.049 based on: OS curve following exponential distribution; median OS of 12.3 months in the placebo + atezolizumab + EC group and 17.6 months in the tiragolumab + atezolizumab + EC group (corresponding to a target HR of 0.70); 5% dropout rate over 24 months for OS; One planned interim analysis for OS in approximately 70% of the pieces of information with median bounds for statistical significance determined based on the Lan-DeMets approximation of the O'Brien-Fleming function.

An observed HR of 0.789 or greater for Os in PP corresponds to a statistically significant difference between treatment groups. That is, an HR of 0.789 is the minimally detectable difference in this assay; This corresponds to a 3.3-month improvement in the median OS from 12.3 months in the placebo + atezolizumab + CE group to 15.6 months in the tiragolumab + atezolizumab + CE group.

Interim and final analysis times for OS are summarized in Table 49, and subject incidence is further assumed.

FPI = first patient dose; IA = interim analysis; PP = treatment population; OS = overall survival

^a The analytical power is calculated using a two-sided α of 0.049

The OS interim analysis is performed at the time of the final PFS analysis. The Kaplan-Meier methodology is used to estimate the median OS for each treatment group, and a Kaplan-Meier curve is created to visually account for differences between treatment groups. The Brookmeyer-Crowley methodology was used to generate a 95% CI for the median OS for each treatment group (Brookmeyer and Crowley, Biometrics 1982, 38: 29-41).

OS rates at 1 and 2 years after randomization were estimated using the Kaplan-Meier method for each treatment group, with a 95% CI calculated using standard errors derived from the Greenwood formula. A 95% CI for the difference in OS ratio between the two treatment groups was estimated using a normal approximation.

secondary efficacy endpoint

Progression-Free Survival and Overall Survival in the Intent-to-Treat Population

If the OS difference in PP is statistically significant, PFS and OS are tested in the ITT population according to the same α-assignment ratio (1:49) and α-recycling strategy for co-primary endpoint analysis described above. The PFS and OS of the ITT population were

The same method as described above, except that all three stratification factors used for randomization from IxRS (i.e., ECOG systemic activity, LDH, and presence or history of brain metastases) were included in the stratified analysis for the ITT population. will be analyzed simultaneously with the PP. Stratification factor(s) may be removed from the stratification analysis if there is an excessive risk of stratification.

Confirmed objective response rate

An identified objective response may be a confirmed CR or PR in two consecutive events with an interval of at least 4 weeks as determined by the investigator according to RECIST v1.1. Patients who do not meet these criteria, including those without a post-baseline tumor assessment, are considered non-responders.

Confirmed ORR is defined as the proportion of patients with an identified objective response. Analysis populations for identified ORRs are PP and ITT populations with measurable disease at baseline.

An estimate of the identified ORR and its 95% CI are calculated using the Klopper-Pearson method for each treatment group. The CI for the identified ORR differences between the two treatment groups is determined using a normal approximation to the binomial distribution.

duration of response

The DOR of confirmed response is assessed in patients with confirmed objective responses as determined by the investigator using RECIST v1.1 in the PP and ITT populations. The DOR of a confirmed reaction is defined as the time from the date of the first occurrence of the identified objective reaction to the first date of progressive progression as determined by the investigator in accordance with RECIST v1.1 or until death is recorded, whichever occurs first. Patients with no disease progression and no death at the time of analysis are censored on the last tumor assessment date. Because the DOR is based on a non-randomized subset of patients (particularly those who achieved an identified objective response); No formal hypothesis testing is conducted for this endpoint. Treatment groups are compared for illustrative purposes. The methodology detailed for the PFS analysis is used for the DOR analysis.

layered elements

Stratification factors are factors used for randomization in IxRS (ie ECOG systemic activity, LDH, presence or history of brain metastases). At least one stratum (i.e., ECOG systemic activity [0 vs. 1], LDH [≤ULN vs. >ULN], and a combination of stratification factor levels across the presence or history of brain metastases according to IxRS [yes vs. no]) For those with fewer than 10 events (PFS or OS events), the stratification factor containing the lowest number of patients (one of the three stratification factors: ECOG performance status, presence or history of brain metastases according to LDH and IxRS) was removed from the stratified analysis. Removal of stratification elements continues until there are no tiers with less than 10 events (PFS or OS events). The final set of stratification elements used for stratification analysis is applied to all endpoints for which stratification analysis is planned. Where significant discrepancies are observed between IxRS records and eCRFs, an analysis based on the stratification factors recorded on the Electronic Case Reporting Form (eCRF) is also provided.

E. eligibility

Patients are eligible if they have never received chemotherapy for their ES-SCLC and meet the following eligibility criteria: 18 years of age or older; ability to comply with study protocols at the discretion of the investigator; ECOG systemic activity of 0 or 1; Histologically or cytologically confirmed ES-SCLC (according to the modified VALG (US Department of Veterans Affairs Research Group) staging system (Micke et al., Lung Cancer 2002, 37: 271-6)); No prior systemic treatment for ES-SCLC; Patients who received prior chemoradiation for limited-stage SCLC must have been treated for a curative purpose and a treatment-free interval of at least 6 months between the last dose/cycle of chemotherapy, chest radiotherapy, or chemoradiation and the diagnosis of ES-SCLC must have; Measurable disease as defined in RECIST v1.1 (a previously irradiated lesion is (1) an unambiguous documented disease progression at that site following radiation therapy, and (2) a previously irradiated lesion is not the only site of measurable disease. can only be considered a measurable disease); submission of tumor tissue samples prior to treatment; For patients receiving therapeutic anticoagulant therapy: stable anticoagulant therapy; negative HIV test at screening; negative hepatitis B surface antigen (HBsAg) test at screening; Adequate hematological and end organ function as defined by the following laboratory test results obtained within 14 days prior to study treatment initiation (Day 1 of Cycle 1): Absolute neutrophil count (ANC) ≥ 1.5 × 10 ⁹ without granulocyte colony stimulating factor support /L (1500/μL); Lymphocyte count ≥ 0.5 × 10 ⁹ /L (500/μL); platelet count ≥ 100 × 10 ⁹ /L (100,000/μL) without transfusion; hemoglobin ≥ 90 g/L (9 g/dL) (patient may receive transfusion or erythropoietic therapy according to local standards of care to meet the above criteria); INR or aPTT ≤ 1.5 x ULN (for patients not receiving therapeutic anticoagulant, INR or aPTT ≤ 1.5 x ULN); AST, ALT, and ALP ≤ 2.5 × ULN, with the following exceptions: (Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN; Patients with documented liver or bone metastases: ALP ≤ 5 × ULN); bilirubin ≤ 1.5 x ULN (with the following exceptions: patients with known Gilbert's disease: bilirubin ≤ 3 x ULN); creatinine ≤ 1.5 x ULN; Albumin ≥ 25 g/L (2.5 g/dL).

Exclusion criteria included: Asymptomatic patients with symptomatic or actively progressing CNS metastases (note: treated (i.e., local CNS directed therapy) or untreated CNS lesions are eligible if all of the following criteria are met) : Existing measurable disease according to RECIST v1.1; patient has no history of intracranial or spinal cord hemorrhage due to CNS disease; metastasis is limited to the cerebellar or supranial region (i.e., midbrain, midbrain, does not metastasize to the pons, medulla or spinal cord); patient has no symptoms due to CNS disease (i.e., no headache, nausea, vomiting, convulsions, paralysis, etc.); patient has ongoing requirements for anticonvulsant medications for CNS disease patient does not have an ongoing requirement for dexamethasone/corticosteroids for CNS disease (previously untreated patients must also have no history of needing or receiving dexamethasone/corticosteroids for CNS disease); In patients with previously treated CNS metastases, there is no evidence of intermediate CNS progression between completion of CNS-directed therapy and randomization; in previously untreated patients, evidence of cerebral edema associated with CNS disease In patients without prior treatment (e.g., angioedema); a brain magnetic resonance imaging (MRI) scan with a contrast medium is required at screening, which is the preferred method for all subsequent tumor evaluations scheduled thereafter (Note: Computed tomography (CT) scans with contrast media are acceptable for all patients if the following criteria are met: brain MRI and CT scans with contrast media at screening to evaluate untreated CNS disease. CT scan with contrast agent can be used to reliably evaluate lesions identified on screening MRI with contrast agent; CT scan with contrast agent confirmed on screening MRI with contrast agent If the lesion cannot be reliably evaluated, all subsequent planned follow-up MRI scans with contrast media should be used in both assessments; Compression that has not been definitively treated with surgery and/or radiation, or previously diagnosed and treated without evidence of clinical stability of disease for at least 1 week prior to randomization, if the same approach is used in all tumor evaluations ; leptomeningeal disease; uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (once a month or more often); Patients with indwelling catheters (eg, PLEURX®) are admitted regardless of the frequency of drainage; uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, total serum calcium > 12 mg/dL, or corrected calcium > ULN); known clinically significant liver disease, including active viral, alcoholic or other hepatitis, cirrhosis, hereditary liver disease or current alcohol abuse; Malignant tumors other than SCLC within 5 years prior to randomization, with the proviso that expected treatment outcomes (e.g., appropriately treated intraepithelial carcinoma of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated with an intent-to-treat surgical procedure) , with negligible risk of metastasis or death treated with surgically treated ductal in situ breast cancer with an intended treatment (eg, predicted 5-year OS > 90%); Activity or history of autoimmune disease or immunodeficiency, with the following exceptions: (patients with a history of autoimmune-associated hypothyroidism receiving thyroid replacement hormone therapy are eligible for study; controlled type 1 receiving insulin therapy Patients with diabetes mellitus are eligible for the study; patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only dermatological signs (e.g., excluding patients with psoriatic arthritis) are eligible for the study if all of the following conditions are met; The rash must cover <10% of the body surface area; disease must be well controlled at baseline and require only low titer topical corticosteroids; UV A radiation, methotrexate, retinoids, biologics, oral calci in addition to psoralen within the past 12 months No acute exacerbation of underlying conditions requiring neuroin inhibitor or high titer or oral corticosteroids; history of idiopathic pulmonary fibrosis, organized pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonia or idiopathic pneumonia, or screening chest CT There is evidence of active pneumonia on the scan; a history of radiation pneumonia in the radiation field (fibrosis) is accepted; active EBV infection or known or suspected chronic active EBV infection at screening; EBV IgG and/or EBV nuclear antigen (EBNA) ) are eligible only if they are negative for EBV IgM and/or EBV polymerase chain reaction (PCR); active tuberculosis; at randomization time points including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Severe infection of; New York Heart Association heart disease (Class II or greater) within 3 months prior to randomization, serious cardiovascular disease such as myocardial infarction or cerebrovascular accident, unstable arrhythmia or unstable angina; Known coronary artery disease, meeting the above criteria Patients with congestive heart failure, or left ventricular ejection fraction < 50%, should receive stable medical therapy optimized in the opinion of the treating physician in consultation with a cardiologist as appropriate; within 28 days prior to randomization a major surgical procedure for purposes other than diagnosis within the hospital or anticipation of the need for a major surgical procedure during the course of the study; previous allogeneic bone marrow transplant or solid organ transplant; Other diseases, metabolic dysfunctions, physical examination findings, or clinical laboratory findings that reasonably constitute a disease or condition that would contraindicate the use of the investigational drug, influence the interpretation of results, or place the patient at a high risk of complications of treatment in case of doubt; patients with diseases or conditions that interfere with their ability to understand, comply with, and/or follow research procedures; treatment with any other investigational drug within 28 days prior to initiation of study treatment; Current treatment with antiviral therapy for HBV or HCV; Administered live attenuated vaccine within 4 weeks prior to randomization or expected to require live attenuated vaccine during the study; Patients should not receive live attenuated influenza vaccine (eg, Flumist®) within 4 weeks prior to randomization, on treatment, and for 5 months after administration of the last dose of study treatment; prior treatment with CD137 agonists or immune checkpoint blockade therapy, anti-CTLA-4, anti-TIGIT, anti-PD-1 and anti-PD-L1 therapeutic antibodies; treatment with systemic immunostimulants (including but not limited to interferon and interleukin 2 (IL-2)) or drug elimination half-lives of 5 (whichever is longer) within 4 weeks prior to randomization; Treatment with systemic immunosuppressants (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents) within 1 week prior to randomization or systemic during the period Patients receiving an acute, low-dose systemic immunosuppressant or a single pulse dose of a systemic immunosuppressant (e.g., 48 hours of corticosteroids for contrast allergy) are eligible for study after confirmation by a medical monitor; Patients receiving mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose mineralocorticoids for orthostatic hypotension or low-dose mineralocorticoids and corticosteroids for adrenal insufficiency suitable for research; history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins; known hypersensitivity to any component of the Chinese Hamster Ovary Cell Products or tiragolumab or atezolizumab formulations; history of allergic reactions to carboplatin or etoposide; Pregnant or breastfeeding during study treatment or within 90 days of the last dose of tiragolumab or placebo, 5 months after the last dose of atezolizumab, or 6 months after the last dose of carboplatin or etoposide, or intention to become pregnant ; Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

F. cytokine release syndrome

No premedication is indicated for Cycle 1 administration of tiragolumab/placebo or atezolizumab. However, patients experiencing cytokine release syndrome (CRS) with tiragolumab/placebo or atezolizumab may be premedicated with an antihistamine, antipyretic and/or analgesic (e.g., acetaminophen) for subsequent infusions. . CRS is defined as a superphysiological response following administration of any immunotherapy that results in activation or binding of endogenous or infused T cells and/or other immune effector cells. Symptoms can be progressive and always include fever at onset, and can include hypotension, capillary leakage (hypoxia), and end-organ dysfunction (Lee et al., Biol Blood Marrow Transplant , 25(4): 625). -638, 2019). CRS is well documented as a chimeric antigen receptor T cell therapy and as a bispecific T cell engaging antibody therapy, but has also been reported in immunotherapy targeting PD-1 or PD-L1, including atezolizumab (Rotz et al., Pediatr Blood Cancer , 64: e26642, 2017; Adashek and Feldman, J Oncol Practice , 15: 502-504, 2019).

Example 8. Tiragolumab plus atezolizumab plus pemetrexed and carboplatin/cisplatin vs pembrolizumab plus pemetrexed and carboplatin in patients with previously untreated advanced non-squamous non-small cell lung cancer /Phase II, randomized, double-blind, placebo-controlled study of concomitant use of cisplatin

This example demonstrates Ate versus placebo in combination with pembrolizumab plus pemetrexed and carboplatin/cisplatin in previously untreated patients with locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC). Describe a randomized, phase II, global, multicenter, double-blind study designed to evaluate the efficacy and safety of tiragoluumab in combination with zolizumab plus pemetrexed and carboplatin/cisplatin.

A. study design

Eligible patients for this study included untreated male and female patients 18 years of age or older with locally advanced unresectable or metastatic nonsquamous NSCLC without EGFR or ALK genomic abnormalities, and ECOG systemic activity (0 to 1). .

Patients with tumors with known EGFR or ALK rearrangements

excluded from the study. Patients with tumors of unknown EGFR or ALK mutation status should be screened prior to enrollment. Eligible patients included PD-L1 expression (tumor percentage score (TPS)/tumor cells (TC) < 1% vs. 1%-49% vs. ³ 50% by regional or central analysis), geographic region (Asian vs. non-Asian). ), and ECOG systemic activity (0 versus 1), and randomized 1:1 to receive the following treatment regimens:

Group A: atezolizumab plus pemetrexed and tiragolumab in combination with cisplatin/carboplatin;

Group B: Pembrolizumab plus pemetrexed and placebo in combination with cisplatin/carboplatin.

The choice of carboplatin or cisplatin is at the discretion of the investigator. The selection of carboplatin or cisplatin is made prior to randomization and cannot be changed after Day 1 of Cycle 1.

The randomization scheme is designed to enroll an approximately equal number of patients adequately representing all PD-L1-expressing subgroups (TPS/TC < 1%, 1%-49%, and ³ 50%). To reflect the natural distribution of PD-L1 expression observed in patients with primary NSCLC, the proportion of patients enrolled in each PD-L1 subgroup was calculated as: Investigational VENTANA (VENTANA) PD-L1 (SP263) Companion Diagnostics (CDx) Limited to approximately 80 patients (approximately 40% of total planned enrollment) per central trial using the analysis. To account for differences in regional and median outcomes, selective enrollment based on regional PD-L1 status is enforced when the subgroup enrollment defined by the median outcome is on a trajectory that exceeds the upper limit.

Induction treatment for Groups A and B is administered in 21-day cycles for 4 cycles. After the induction phase, the patient will continue on the maintenance regimen outlined below.

A군: 아테졸리주맙 + 페메트렉시드와 병용한 티라골루맙

Group A: atezolizumab + tiragolumab in combination with pemetrexed

B군: 펨브롤리주맙 + 페메트렉시드와 병용한 위약

Group B: Pembrolizumab + placebo in combination with pemetrexed

Patients receive tumor assessments at baseline and every 6 weeks (± 7 days) for 48 weeks after Day 1 of Cycle 1, regardless of treatment dose delay. After completion of the oncology assessment at Week 48, tumor assessments are performed every 9 weeks thereafter (± 7 days) thereafter, regardless of dose delay, until radiological disease progression, withdrawal of consent, study termination, or death according to RECIST v1.1, whichever occurs first is required every Patients treated after disease progression according to RECIST v1.1 will receive tumor assessments at this frequency until study treatment is discontinued. Patients who discontinued treatment for reasons other than radiological disease progression (e.g., toxicity, worsening symptoms) according to RECIST v1.1 continued on study treatment, regardless of whether or not the patient started new chemotherapy. will continue with scheduled tumor evaluations at the same frequency as they would have subsequently progressed (i.e., every 6 weeks [± 7 days] for 48 weeks after day 1 of cycle 1, and thereafter radiological disease progression according to RECIST v1.1, consent every 9 weeks [± 7 days] until withdrawal, study termination, or death, whichever occurs first).

Patients are asked to complete a Patient Reported Outcome Questionnaire (EORTC QLQ-C30, EORTC QLQ-LC13 and EORTC IL46) on treatment, at study treatment discontinuation, and at study treatment discontinuation visits.

Safety assessments at study visits include the incidence, nature and severity of adverse events, protocol-essential vital signs, laboratory abnormalities, and other protocol-specific tests considered important for the safety assessment of the study.

Serum samples are collected during the study to monitor tiragolumab and atezolizumab pharmacokinetics and detect the presence of antibodies to tiragolumab and atezolizumab.

Patient samples, including archived and freshly obtained tumor tissue, serum, plasma and blood samples, are also collected for exploratory biomarker evaluation.

During the study, patients who met the disease progression criteria according to RECIST v1.1 and showed evidence of clinical benefit were tiragolumab/placebo and atezolizumab/pembrolizumab at the investigator's discretion if all of the following criteria were met: treatment can be continued with

시험자에 의해 평가된 임상적 이점의 증거

Evidence of clinical benefit assessed by the investigator

질병의 명백한 진행을 나타내는 증상 및 징후의 부재(실험실 값의 악화(예컨대, 신규 또는 악화되는 고칼슘혈증)를 포함)

Absence of symptoms and signs indicative of apparent progression of disease (including worsening laboratory values (eg, new or worsening hypercalcemia))

질병 진행에 기인할 수 있는 ECOG 전신 활동도의 감소 없음

No decrease in ECOG systemic activity that could be attributed to disease progression

프로토콜이 허용하는 의료 개입으로 관리할 수 없는 중요한 해부학적 부위(예컨대, 연수막 질환)에서 종양 진행의 부재

Absence of tumor progression in critical anatomical sites (e.g., leptomeningeal disease) that cannot be managed with medical interventions permitted by the protocol

환자는 RECIST v1.1에 따라 초기 방사선학적 진행 시점에 연구 치료를 계속하기 위해 다른 치료 선택사항을 연기하는 것을 인정하는 서면 동의서를 제공해야 한다.

Patients must provide written informed consent to defer other treatment options to continue study treatment at the time of initial radiological progression in accordance with RECIST v1.1.

Investigator assessments of overall tumor response at all time points are based solely on RECIST v1.1. Objective responses according to iRECIST are calculated on the program based on the investigator's assessment of individual lesions at each designated time point.

B. Dosage and administration

The treatment regimen is summarized in FIG. 18 .

Atezolizumab and Pembrolizumab

Patients receive a fixed dose of 20 mL (1200 mg) atezolizumab in group A or 8 mL (200 mg) pembrolizumab in group B on Day 1 of each 21-day cycle. Infusions of atezolizumab/pembrolizumab are administered according to the guidelines summarized in Table 50.

Tiragolumab and placebo

Patients receive a fixed dose of 10 mL (600 mg) tiragolumab in group A or 10 mL placebo in group B on Day 1 of each 21-day cycle. Tiragolumab/placebo infusion is administered according to the guidelines summarized in Table 50.

Pemetrexed, cisplatin and carboplatin

Table 51 lists the doses and recommended infusion times for therapeutic administration of pemetrexed, carboplatin or cisplatin.

Patients receive antiemetics and IV hydration for platinum-based therapies according to local standards of care and manufacturer's guidelines. However, the premedication of steroids is limited when clinically feasible due to the immunomodulatory effect. In addition, for skin rashes associated with pemetrexed, topical steroids are recommended as first-line treatment whenever clinically feasible.

Table 52 lists the proposed premedication for pemetrexed.

During the induction phase, chemotherapy cycles are included in the number of 4 cycles of induction chemotherapy if at least one platinum-based chemotherapy component is administered at least once for a 21-day cycle. Cycles for which no chemotherapy was given are not included in the total number of induction chemotherapy cycles.

capacity change

Dose changes of pemetrexed and cisplatin/carboplatin are permitted for toxicity according to prescribing information and local standards of care.

Dosage change instructions are provided below. Once reduced, the dose cannot be increased back to 100%.

Discontinue treatment with pemetrexed or cisplatin/carboplatin if the patient experiences any hematologic or non-hematologic Grade 3 or 4 toxicity after 2 dose reductions or if toxicity delays treatment for more than 63 days do.

blood toxicity

At the beginning of each cycle, the ANC is ³ 1500/νL and the platelet count is ³ 100,000/νL. Treatment may be delayed for up to 63 days to allow sufficient time for recovery. Growth factors are used according to the American Society of Clinical Oncology (ASCO) and NCCN guidelines (Smith et al. 2015; NCCN 2019). Upon recovery, dose adjustments are made at the start of subsequent cycles based on trough platelet and neutrophil values from the previous cycle (Table 53). If a dose adjustment is required for both ANC and platelets, the patient should receive the lower dose.

Investigators are vigilant for early and obvious signs of myelosuppression, infection, or febrile neutropenia so that these complications can be managed promptly and appropriately. Patients are encouraged to recognize these signs and seek medical attention as soon as possible.

If chemotherapy is withheld due to hematologic toxicity, a complete blood count (including differential WBC) is obtained weekly until the count reaches the summarized lower limit of treatment. Then, treatment is resumed.

Dose reduction is not recommended for anemia. Patients are supported according to the investigator's instructions.

non-hematologic toxicity

For non-hematologic toxicity (Table 54), treatment is delayed for up to 63 days until recovery below the patient's baseline value (or grade 1 or lower if the patient is nontoxic at baseline). Dose reduction at the start of a subsequent cycle is based on the non-hematologic toxicity of the dose administered in the previous cycle. Table 54 provides recommended dose modifications for non-hematologic toxicity.

Diarrhea is controlled with appropriate laxatives. Nausea and/or vomiting can be controlled with appropriate antiemetics. In case of grade 3 or 4 neurotoxicity, chemotherapy is resumed at 50% of the previous dose or stopped immediately upon improvement (according to the investigator's clinical judgment).

C. combination therapy

Combination therapy includes any drugs (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient in addition to protocol essential treatment from 7 days prior to study drug initiation until the study discontinuation visit. The total drug is reported and recorded to the investigator.

accepted therapy

Patients are allowed to use the following regimens during the study period:

연간 실패율이 1% 미만인 경구 피임약

Oral contraceptives with an annual failure rate of less than 1%

호르몬 대체 요법

hormone replacement therapy

하기에 개략된 바와 같은 완화 방사선 요법(예컨대, 공지된 골 전이의 치료 또는 통증의 증상 완화):

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

For patients with no documented radiologic disease progression, it is strongly recommended to maximize supportive treatment for symptom management and to avoid radiation therapy, which will interfere with the evaluation of tumor-targeted lesions. Treatment with tiragolumab/placebo and atezolizumab/pembrolizumab may be continued during palliative radiation therapy.

골중 미네랄 밀도를 증가시키는 핵인자-B 리간드 표적 요법의 수용체 활성제

Receptor activators of nuclear factor-B ligand-targeted therapy to increase mineral density in bone

뼈 손실의 진행을 늦추는 비스포스포네이트

Bisphosphonates slow the progression of bone loss

예방적 또는 치료적 항응고 요법(예컨대, 안정된 용량의 와파린 또는 저분자량 헤파린)

Prophylactic or therapeutic anticoagulant therapy (eg, stable doses of warfarin or low molecular weight heparin)

비활성화 인플루엔자 예방 접종

Inactivated influenza vaccination

식욕 자극제로 투여되는 메게스트롤 아세테이트

Megestrol acetate administered as an appetite stimulant

미네랄로코르티코이드(예컨대, 플루드로코르티손)

Mineralocorticoids (such as fludrocortisone)

만성 폐쇄성 폐질환 또는 천식에 투여되는 흡입용 또는 저용량 코르티코스테로이드

Inhaled or low-dose corticosteroids for chronic obstructive pulmonary disease or asthma

기립성 저혈압에 대해 투여된 저용량 미네랄 코르티코이드 또는 부신피질 기능 부전에 대한 저용량 미네랄 코르티코이드 및 코르티코스테로이드, 페메트렉시드 및 시스플라틴 또는 카보플라틴에 대한 예비투약이 허용된다. 항히스타민제, 해열제, 및/또는 진통제의 예비투약은 시험자의 재량에 따라 제2 및 후속의 아테졸리주맙/펨브롤리주맙 및 티라골루맙/위약 주입에 대해서만 투여할 수 있다.

Premedication for low dose mineralocorticoids administered for orthostatic hypotension or low dose mineralocorticoids and corticosteroids for adrenocortical insufficiency, pemetrexed and cisplatin or carboplatin is permitted. Premedication of antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent atezolizumab/pembrolizumab and tiragolumab/placebo infusions at the discretion of the investigator.

In general, the investigator is defined as a clinically directed caution or contraindicated therapy in accordance with local standard practice.

Manage patient care with other supportive care. Patients experiencing infusion-related symptoms may be treated with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice, depending on the symptoms. have. Severe infusion-related reactions, such as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation or dyspnea, are managed with supportive care as clinically indicated (e.g., oxygen supplementation and β2 adrenergic agonists).

care

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with tiragolumab and/or atezolizumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines are considered. If no alternative is possible, systemic corticosteroids and TNF-α inhibitors may be administered at the investigator's discretion.

For the treatment of certain adverse events associated with tiragolumab and/or atezolizumab therapy, systemic corticosteroids are recommended at the discretion of the investigator.

forbidden therapy

The use of the following combination therapies is contraindicated as follows:

연구 치료제 개시 전 28일 이내 및 연구 치료 기간 동안 (프로토콜 필수 연구 치료 이외의) 임상시험 요법은 금지된다.

Investigational therapies (other than protocol essential study treatments) are contraindicated within 28 days prior to initiation of study treatment and during study treatment.

연구 치료를 시작하기 전 다양한 기간 동안, 작용제에 따라서, 및 질병 진행이 문서화되고, 특정 상황 하에 환자가 완화 방사선 요법을 제외하고 연구 치료를 중단할 때까지, 암 치료를 위한 병용 요법(화학요법, 호르몬 요법, 면역요법, 방사선 요법 및 한약 요법을 포함하지만, 이에 제한되지는 않음)을 금지한다.

Combination therapy for cancer treatment (chemotherapy, chemotherapy, including, but not limited to, hormone therapy, immunotherapy, radiation therapy and herbal therapy) is prohibited.

연구 치료제 개시 전 4주 이내, 연구 치료제 중, 및 연구 치료제의 최종 용량 후 5개월 동안 독성 약화 생백신

Toxic attenuated live vaccine within 4 weeks prior to initiation of study treatment, during study treatment, and 5 months after the last dose of study treatment

연구 치료제 개시 전 및 연구 치료제 동안 4주 또는 5회의 약물 제거 반감기(둘 중 더 긴 것) 이내의 전신 면역자극제(인터페론 및 IL-2를 포함하지만, 이에 제한되지는 않음) - 상기 제제는 연구 치료제와 병용 투여 시 자가면역 질환의 위험을 증가시킬 가능성이 있기 때문임

Systemic immunostimulants (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment - the agent is the study treatment This is because it has the potential to increase the risk of autoimmune diseases when administered in combination with

연구 치료제 중 전신 면역억제제(시클로포스파미드, 아자티오프린, 메토트렉세이트 및 탈리도마이드를 포함) - 상기 제제는 연구 치료제의 유효성 및 안전성을 변경할 가능성이 있기 때문임.

Systemic immunosuppressants among study treatments (including cyclophosphamide, azathioprine, methotrexate and thalidomide) because these agents have the potential to alter the efficacy and safety of study treatments.

D. Selection Criteria

Patients must meet the following criteria for study entry:

서명한 사전 동의서

signed informed consent

사전 동의서에 서명할 당시의 연령 ³ 　18세

Age at time of signing informed consent ³ 18

연구 프로토콜을 준수할 능력

Ability to comply with research protocols

0 또는 1의 ECOG 전신 활동도

ECOG systemic activity of 0 or 1

조직학적 또는 세포학적으로 문서화된 국소 진행성 절제 불가능 또는

Histologically or cytologically documented locally advanced unresectable or

Metastatic nonsquamous NSCLC

Patients with tumors of mixed NSCLC histology should be classified as nonsquamous based on their major histological components. Patients with mixed NSCLC and small cell lung cancer are not eligible for this study.

전이성 비편평 NSCLC에 대한 선행 전신 치료 없음

No prior systemic treatment for metastatic nonsquamous NSCLC

Patients receiving neoadjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiation therapy for non-metastatic disease must have experienced a treatment-free interval of at least 12 months from randomization after administration of the last dose of chemotherapy and/or radiotherapy do.

지역 보건 당국이 승인한 분석법(SP263[바람직한] 또는 SP263이 입수 가능하지 않은 경우에만 22C3)의 사용을 통한, 또는 승인된 지역 검사가 입수 가능하지 않은 경우 중앙 실험실 분석(임상시험 벤타나[SP263] CDx 분석)을 통해 공지된 종양 PD-L1 상태

Central laboratory analysis (Clinical Trial Ventana [SP263]), either through the use of a local health authority-approved assay (SP263 [preferred] or 22C3 only if SP263 is not available), or if an approved local test is not available. known tumor PD-L1 status via CDx analysis)

Confirmed availability of representative tumor specimens in formalin-fixed, paraffin-embedded (FFPE) blocks (preferred) or 15-20 unstained serial slides with relevant pathology reports. If central screening for EGFR mutations and/or ALK translocation is required, an additional 5 unstained slides should be provided.

Tumor tissue is of good quality based on total and viable tumor content (ie, at least 100 viable tumor cells with preserved cellular environment and tissue structure). Acceptable samples include excisional samples, core-needle biopsies of deep tumor tissue (with a minimum of 3 cores for freshly collected biopsies), or excisional, incisional, punch or forceps biopsies of skin, subcutaneous or mucosal lesions, or Endobronchial ultrasound (EBUS) core needle biopsy is included.

Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA), sometimes also referred to as fine needle aspiration, is performed, as described above, if the tissue is of good quality (i.e., at least 00 viable tumor cells with a preserved cellular environment and tissue structure). ), which is acceptable. For needle aspiration, an 18 gauge needle or larger is recommended.

Fine needle aspiration, brushing, cell pellets in pleural effusion, and wash samples that do not preserve tissue structure and do not produce cell suspensions and/or smears are not acceptable.

Tumor tissue from bone metastases is not acceptable as it cannot be evaluated for tumor PD-L1 expression by IHC.

If storage tissue is insufficient or not available, patients may be biopsied at screening if the biopsy site is safely accessible. If biopsies cannot be provided, patients may still be eligible, in discussion with medical monitor personnel, if 10 or more consecutive unstained slides can be provided.

RECIST v1.1에서 정의한 측정 가능한 질병

Measurable disease as defined by RECIST v1.1

A previously irradiated lesion can be considered measurable disease only if, after radiation, disease progression at that site has been clearly documented and the previously irradiated lesion is not the only site of measurable disease.

기대 수명 ³ 12주

Life expectancy ³ 12 weeks

Adequate hematological and terminal organ function, as defined by the following laboratory test results, obtained within 14 days prior to study treatment initiation (Day 1 of Cycle 1):

- ANC ³ 1.5 ´ 109/L (³ 1500/νL), without granulocyte colony stimulating factor adjuvant

- Lymphocyte count ³ 0.5 ´ 109/L (³ 500/νL)

- platelet count ³ 100 ´ 109/L (³ 100,000/νL), no transfusion

- Hemoglobin ³ 90 g/L (³ 9 g/dL)

Patients may receive transfusions or receive erythropoiesis according to local standards of care to meet these criteria.

- AST, ALT, and ALT ￡ 2.5 ´ Upper limit of normal (ULN), with the following exceptions:

Patients with documented liver metastases: AST and ALT ￡　5 ´　ULN

Patients with documented liver or bone metastases: ALP ￡ 5 ´ ULN

- Total Bilirubin ￡ 1.5 ´ ULN, with the following exceptions:

Known Gilbert's Disease Patients: Bilirubin Levels ￡ 3 ´ ULN

- Creatinine clearance (CrCl) ³ 40 mL/min (³ 60 mL/min, required for cisplatin), calculated using the Cockcroft-Gault equation (1976) or by 24-hour urine collection for CrCl determination

- albumin ³ 25 g/L (³ 2.5 g/dL)

For patients not receiving therapeutic anticoagulants: INR and aPTT ￡ 1.5 ´ ULN

치료적 항응고 요법을 투여 받은 환자의 경우: 안정적인 항응고 요법

For patients receiving therapeutic anticoagulant therapy: stable anticoagulant therapy

선별 검사 시 HIV 검사 음성

HIV test negative at screening

선별 검사 시 B형 간염 표면 항원(HBsAg) 검사 음성

Hepatitis B surface antigen (HBsAg) test negative at screening

선별 검사 시 B형 간염 표면 항체(HBsAb) 검사 양성 또는 하기 중 하나를 동반한 선별 검사 시 HBsAb 음성:

Hepatitis B surface antibody (HBsAb) positive at screening or HBsAb negative at screening with one of the following:

- Total hepatitis B core antibody (HBcAb) negative

- Total HBcAb test positive, then hepatitis B virus (HBV) DNA test negative (according to local laboratory definition)

선별 검사시 C형 간염 바이러스(HCV) 항체 검사 음성, 또는 선별 검사시 HCV 항체 검사 양성 후 HCV RNA 검사 음성. HCV RNA 검사는 HCV 항체 검사 양성인 환자에게만 시행된다.

Hepatitis C virus (HCV) antibody test negative at screening test, or HCV RNA test negative after HCV antibody test positive at screening test. The HCV RNA test is only performed on patients with a positive HCV antibody test.

가임 여성의 경우: 금욕 유지(이성간 성교 금지) 또는 하기에 정의된 바와 같이 피임법 사용에 대한 동의 및 난자 기증 자제에 대한 동의

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods as defined below and to refrain from egg donation

Women during the treatment period and 90 days after the last dose of tiragolumab or placebo, 5 months after the last dose of atezolizumab or pembrolizumab, and 6 after the last dose of pemetrexed and carboplatin or cisplatin Either abstinence for months or use of contraception with an annual failure rate of <1% should be used. Women should refrain from donating eggs during the same period as above.

The woman is post-menopausal, has not reached post-menopausal status (3 continued amenorrhea for 12 consecutive months without an identified cause other than menopause), and has not undergone surgery (i.e., removal of the ovaries, fallopian tubes and/or uterus) or as determined by the investigator. If it is not permanent infertility due to other causes (eg, absence of Muller's canal), it is considered to be of childbearing age. The definition of childbearing age may be adapted to local guidelines or regulations.

Examples of contraceptive methods with an annual failure rate of < 1% include bilateral tubal ligation, male sterilization, hormonal contraceptives that suppress ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

The reliability of sexual abstinence is assessed with respect to the duration of the clinical trial and the patient's preferred daily lifestyle.

Periodic abstinence (eg calendar, ovulation, symptom temperature, post-ovulation method) and extracorporeal ejaculation are not suitable methods of contraception.

Women wishing to become pregnant after discontinuation of study treatment should seek advice on oocyte preservation prior to initiating study treatment due to the potential for irreversible infertility with carboplatin treatment.

남성의 경우: 하기에 규정된 바와 같이, 금욕을 유지하거나(이성간 성교를 자제하거나) 또는 피임법을 이용하는 데 동의, 및 정자 기증의 자제하는 데 동의:

For Men: Consent to maintain abstinence (abstain from heterosexual intercourse) or use contraceptive methods, and to refrain from donating sperm, as provided below:

With a non-pregnant female partner of childbearing potential, men who are not surgically infertile during treatment and for 90 days after the last dose of tiragolumab or placebo, 4 months after the last dose of atezolizumab or pembrolizumab; Prevent embryonic and/or genotoxic exposure by maintaining abstinence for 6 months after administration of the last dose of pemetrexed and carboplatin or cisplatin, or by using condoms plus an additional method of contraception with a failure rate of less than 1% per year. Men should refrain from donating sperm during the same period.

With a female partner of childbearing potential, males should receive carboplatin and carboplatin during treatment and for 90 days after administration of the last dose of tiragolumab or placebo, 4 months after administration of the last dose of atezolizumab or pembrolizumab, to avoid embryo exposure. Abstinence or use of a condom should be maintained for 6 months after administration of the last dose of paclitaxel or nap-paclitaxel.

The reliability of sexual abstinence is assessed with respect to the duration of the clinical trial and the patient's preferred daily lifestyle.

Periodic abstinence (eg calendar, ovulation, symptom temperature, post-ovulation method) and extracorporeal ejaculation are not suitable methods of contraception.

Men wishing to have children after initiation of study treatment should seek advice on sperm conservation before beginning study treatment due to the potential for irreversible infertility due to treatment with chemotherapy pemetrexed, cisplatin, or carboplatin.

E. Exclusion Criteria

Patients with NSCLC known to have a mutation in the EGFR gene or ALK fusion oncogene are excluded from study participation. Patients with nonsquamous NSCLC of unknown EGFR or ALK status are screened at prescreening or screening. EGFR and/or ALK status is assessed locally or in a central laboratory. Locally assessed EGFR status is performed in tissue or cytology using validated health authority approved tests that detect mutations in exon 1821. Additional slides are provided when samples are submitted for central EGFR and/or ALK testing.

F. evaluation

Patients are closely monitored for safety and tolerability throughout the study. Evaluate patients for toxicity prior to each dose administration; Dosing should be performed only when clinical evaluation and local laboratory test values are acceptable.

Medical history, baseline conditions, concomitant medications, and demographic data

Clinically significant disease, surgery, history of cancer (including prior cancer therapies and procedures) and lung cancer mutation status (e.g., EGFR and ALK ), reproductive status, history of smoking, history of alcohol and drugs of abuse are recorded at baseline. . In addition, all medications (eg, prescription medications, over-the-counter medications, vaccines, herbal or homeopathic remedies, nutritional supplements) taken by patients within 7 days prior to initiation of study treatment are recorded. At each subsequent physical examination, an interval medical record is obtained and any changes in medications and allergies are recorded.

Demographic data include age, gender, and self-reported race/ethnicity.

Physical examination

A full physical examination is performed at screening and includes evaluation of the head, eyes, ears, nose, and throat, and cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, urogenital, and nervous system. Any abnormalities identified at baseline are recorded.

A limited, symptom-oriented physical examination is performed at designated post-baseline visits and as clinically indicated. Changes from baseline abnormalities are recorded in the patient's patient note. Record new or worsening clinically significant abnormalities.

vital signs

Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure, and body temperature when the patient is seated.

General History and Baseline Status Document abnormalities observed at baseline in the eCRF. New or worsening clinically significant abnormalities are recorded at follow-up visits.

ECOG whole body activity

Performance status is measured using ECOG systemic activity at baseline and is assessed regularly throughout the study.

Tumor and Response Assessment

Screening and subsequent tumor evaluation include CT scans of the abdomen and chest (with IV contrast media and oral contrast media where appropriate according to institutional standards unless contraindicated). Contrast CT scans of the pelvis are required at screening and as clinically indicated or according to local standards of care in subsequent response assessments. Contrast-based MRI scans of the chest, abdomen, and pelvis in combination with non-contrast CT scans of the chest may be used in patients for whom CT scans with contrast agents are contraindicated (ie, patients with iodine-based contrast agent allergy or impaired renal clearance).

To evaluate CNS metastases in all patients, a CT scan of the head (contrast medium) or an MRI scan (if CT contrast medium is contraindicated) should be performed at screening. If a CT scan with a contrast agent is performed and the presence of brain metastases is considered uncertain, an MRI scan of the head is needed to confirm or refute the diagnosis of CNS metastases at baseline.

If CT scans for tumor evaluation are performed on a positron emission tomography (PET)/CT scanner, the CT acquisition should be consistent with the standard for full contrast diagnostic CT scans.

If clinically indicated, additional investigations such as neck bone scans and CT scans should also be performed. At the discretion of the investigator, other methods of assessment of measurable disease according to RECIST v1.1 may be used.

Instead of repeating the test, a tumor assessment conducted as a standard of care prior to obtaining informed consent and within 28 days of Day 1 of Cycle 1 may be used. All known disease sites, including measurable and/or non-measurable disease, are recorded at screening and re-evaluated at each subsequent tumor assessment.

Patients receive tumor assessments at baseline and every 6 weeks (± 7 days) for 48 weeks after Day 1 of Cycle 1, regardless of treatment delay. After completion of the oncology evaluation at Week 48, the tumor evaluation, regardless of treatment delay, will result in radiological disease progression according to RECIST v1.1 (or clinical benefit for patients continuing study treatment following disease progression according to RECIST v1.1). loss), withdrawal of consent, death, or study termination, whichever occurs first, every 9 weeks (± 7 days). Scans may be performed at any time at the discretion of the investigator if progressive disease or loss of clinical benefit is anticipated.

Response is assessed by the investigator using the imaging modality detailed above using RECIST v1.1. Investigator's assessment of overall tumor response at all time points is based on RECIST v1.1 only. Assessments are conducted by the same evaluator whenever possible to ensure internal consistency throughout the visit. Results should be reviewed by the investigator prior to dosing in the next cycle.

Study treatments with tiragolumab/placebo and atezolizumab/pembrolizumab showed unacceptable toxicity or worsening of symptoms due to disease progression after an integrated evaluation of radiographic data, biopsy results (if available), and clinical status. Continued as long as patients experience clinical benefit, as assessed by the investigator in the absence. Patients who meet disease progression criteria per RECIST v1.1 may continue on study treatment provided they meet all specified criteria and provide written consent.

Patients who discontinued treatment for reasons other than radiological disease progression according to RECIST v1.1 (e.g., toxicity, worsening of symptoms) were treated according to RECIST v1.1 radiological disease progression, withdrawal of consent, death, or study termination, whichever occurs first. Tumor assessments scheduled at the frequency described above will continue until the time point. Patients starting new chemotherapy without radiologic disease progression according to RECIST v1.1 may continue tumors at the frequencies described above until radiological disease progression, withdrawal of consent, death, or study termination, whichever occurs first, according to RECIST v1.1. will be.

Investigator's assessment of overall tumor response at all time points is based on RECIST v1.1 only. Overall tumor assessment is according to iRECIST, which is based on items for all target lesions, non-target lesions, and new lesions. To facilitate response evaluation according to iRECIST, tumor evaluation should continue after progression according to RECIST v1.1 for patients receiving study treatment after disease progression. These assessments include continuous measurement of target lesions, assessment of non-target lesions (including monitoring for further deterioration of non-target lesions with clear progression), and evaluation of newly identified lesions at all subsequent assessments (including measurements if lesions are measurable). ) is included.

electrocardiogram

ECG is required at screening and when clinically indicated. ECGs for each patient are obtained on the same device as far as possible. Lead placement is as consistent as possible. ECG recordings should be performed after the patient has been in the supine position for at least 10 minutes.

For safety monitoring purposes, the investigator reviews all ECG traces. Copies of ECG traces are kept at the institution as part of the patient's permanent study file. Morphological waveform changes or other ECG abnormalities should be documented.

Clinical Outcome Evaluation

The PRO device is complete to document the therapeutic benefit and more fully characterize the clinical profile of tiragolumab and atezolizumab plus carboplatin in combination with paclitaxel/nap-paclitaxel. PRO data was collected using the following tools: single entry of EORTC QLQ-C30, EORTC QLQ-LC13 and EORTC IL46.

The questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13 and EORTC IL46) were administered on Day 1 of Cycle 1 (baseline) prior to study drug administration; then complete all treatment cycles of Day 1 prior to administration of study drug through Cycle 4 (i.e., Day 1 of Cycle 2, Day 1 of Cycle 3, and Day 1 of Cycle 4);

In Cycle 5, the questionnaire was completed on every other study treatment cycle of 1 day prior to study drug administration (i.e., Day 1 of Cycle 5; Day 1 of Cycle 7; Day 1 of Cycle 9, etc.) and study until the Study Treatment Discontinuation visit. Complete at the treatment discontinuation visit.

Blood samples for whole genome sequencing or whole exome sequencing

At participating institutions, monitoring or investigation of adverse events that are predictive of response to study drug, associated with progression to a more serious disease state, associated with acquired resistance to study drug, associated with susceptibility to adverse events, or improved Collect blood samples for DNA extraction so that WGS or WES can identify variants that can induce cancer or improve knowledge and understanding of disease biology and drug safety. By comparing DNA extracted from blood with DNA extracted from tissues, germline variants and somatic variants can be distinguished to identify somatic variants. The sample may be sent to one or more laboratories for analysis.

The collection and submission of blood samples for WGS or WES is subject to exploratory study review and approval by each institution's IRB/EC and, where applicable, the appropriate regulatory body.

Genomics further enhances researchers' understanding of disease pathology. WGS and WES provide comprehensive characterization of the genome and exome, respectively, and, together with the clinical data collected in this study, can be used to monitor efficacy and safety or predict which patients are more likely to respond to drugs or develop adverse events. It can increase the chances of developing new therapeutic approaches or new methods. The data are analyzed in the context of this study, but can also be explored in conjunction with data from other studies. The availability of larger data sets will aid in the identification and characterization of important biomarkers and pathways to support future drug development.

Blood samples collected for WGS or WES should be stored until they are no longer needed or are depleted.

Samples for Research Biosample Repository

The Research Biosample Repository is a group of centrally managed facilities used for long-term storage of human biological samples, including body fluids, solid tissues and their derivatives (eg DNA, RNA, proteins, peptides). The collection, storage, and analysis of RBR samples could facilitate the rational design of new drugs and the development of diagnostic tests, enabling individualized drug therapy for future patients.

Samples for RBR are collected from patients who specifically consented to participate in this elective study. RBR samples are analyzed to achieve one or more of the following goals:

Study of the association of biomarkers to efficacy or disease progression

Identification of safety biomarkers that may lead to susceptibility to developing adverse events or to monitor or investigate the occurrence of ameliorated adverse events.

Improve knowledge and understanding of disease biology and drug safety

Study drug response, including drug effects and drug absorption and processing processes

Developing biomarkers or diagnostic assays and establishing performance characteristics of these assays

sample collection

The following samples are stored in RBR and used for research purposes, including, but not limited to, studies for tyragolumab, atezolizumab, nonsquamous NSCLC, or biomarkers related to drug safety:

연구 과정 동안 시험자의 재량에 따라 수행된 절차(예: 기관지경검사, 식도위십이지장경검사, 대장내시경검사)로부터 수득된 의학적으로 지시된 잔류 조직 샘플을 포함한, 잔류 혈액, 혈청, 혈장 및 종양 조직 샘플(현장으로 반환되는 남은 보관 조직 블록 제외) 그리고 그 파생물(예: DNA, RNA, 단백질, 펩티드)

Residual blood, serum, plasma and tumor tissue, including medically indicated residual tissue samples obtained from procedures (e.g., bronchoscopy, esophageal gastroduodenoscopy, colonoscopy) performed at the discretion of the investigator during the course of the study. Samples (excluding the remaining archived tissue blocks returned to the field) and their derivatives (e.g., DNA, RNA, proteins, peptides)

주기 1의 1일차 투여 전, 그리고 주기 2의 15일차 및 주기 3의 1일차 투여 전 사이에 수집된 임의의 대변 샘플. 이 샘플들은 집에서 수집할 수 있다.

Any stool samples collected prior to dosing on Day 1 of Cycle 1 and prior to dosing on Day 15 of Cycle 2 and Day 1 of Cycle 3. These samples can be collected at home.

The samples may be sent to one or more laboratories for analysis of germline or somatic variants via WGS, WES or other genomic analysis methods. Genomics further enhances researchers' understanding of disease pathology. WGS and WES provide comprehensive characterization of the genome and exome, respectively, and, together with the clinical data collected in this study, new novel approaches for monitoring efficacy and safety or predicting which patients are more likely to respond to drugs or develop adverse events. It can increase the chances of developing therapeutic approaches or new methods.

Data generated from the RBR sample are analyzed in the context of this study, but may be explored in conjunction with data from other studies. The availability of larger data sets will aid in the identification and characterization of important biomarkers and pathways to support future drug development.

G. Treatment and patient discontinuation

cessation of treatment

Patients should permanently discontinue study treatment if they experience any of the following:

Unacceptable toxicities associated with the study treatment, including the occurrence of immune-related adverse events determined by the investigator to be unacceptable, given the individual patient's potential response to treatment and the severity of the condition.

Any medical condition determined by the investigator that the patient's safety may be at risk if the subject continues to receive study treatment

Investigator's decision that discontinuation of treatment is in the patient's best interest

· Pregnant

- Use of non-protocol-specific anticancer therapies

Radiologic disease progression according to RECIST v1.1 (if study treatment does not continue beyond radiological progression)

For patients treated beyond radiological disease progression, loss of investigator-determined clinical benefit after integrated evaluation of radiological and biochemical data (tiragolumab/placebo and atezolizumab/pembrolizumab treatment is radiological disease) If it persists beyond progression), local biopsy results (if available), and clinical status (e.g. worsening of symptoms)

The main reasons for discontinuation of study treatment are documented in the appropriate eCRF. Patients who prematurely discontinue study treatment will not be replaced.

Patients return to the clinic for a treatment discontinuation visit before 30 days have elapsed after the last dose of study drug. Visits where response assessments indicate progressive disease may be used as discontinuation visits. Patients who discontinue study treatment for reasons other than progressive disease or loss of clinical benefit (for patients continuing treatment beyond radiation disease progression) will continue to receive tumor response assessments and PRO assessments.

Following study treatment discontinuation and disease progression according to RECIST v1.1, information on survival follow-up and new chemotherapy via phone calls, patient medical records and/or clinic visits is collected approximately every 3 months until death (if the patient If consent is not withdrawn)

H. analysis

Validity analysis

Efficacy analyzes are performed in the ITT population with patients grouped according to randomization treatment. An estimate of ORR difference between the two treatment arms and PFS HRs is calculated with 95% CIs.

Hypothesis testing for joint primary efficacy endpoints will also be performed in the ITT population.

All joint primary analyzes of disease progression and objective response are based on investigator reviews of tumor assessments using RECIST v1.1.

Primary efficacy endpoint

The joint primary endpoints are confirmed ORR and PFS.

Confirmed ORR is defined as the proportion of patients who achieved an objective response characterized by two consecutive CRs or PRs spaced no more than 4 weeks apart.

Objective response is assessed by treatment arm, and patients without an overall response assessment after baseline are counted as non-responders.

An estimate of the ORR difference between the two sectors is calculated with a 95% CI. The Mantel-Haenszel test is used to compare the ORR between two treatment arms at a two-sided significance level of 5% stratified with protocol-defined stratification factors.

PFS is defined as the time between the date of randomization and the first recorded date of disease progression or death, whichever occurs first. Patients who have not experienced disease progression or who have not died at the time of analysis are censored at the final tumor evaluation. Patients without post-baseline tumor evaluation are censored on the date of randomization.

A stratified log-rank analysis is used to compare PFS between treatment arms.

HR and 95% CI for PFS are estimated using a stratified Cox proportional-hazard model.

The Kaplan-Meier methodology is used to estimate the median PFS for each treatment group, and a Kaplan-Meier curve is created to visually explain the difference between the treatment groups.

secondary efficacy endpoint

overall survival

OS is defined as the time from randomization to death from any cause. Data for patients surviving at the time of data blockade will be deleted on the last date survival was confirmed. Data for patients with no post-baseline information will be deleted on the randomization date. OS HR and 95% CI were estimated using a stratified Cox proportional-hazard model. The Kaplan-Meier methodology was used to estimate OS curves and median OS for each treatment arm.

Confirmed response period

DOR is defined as the time between the first occurrence of a documented objective response and death from disease progression or other cause, whichever occurs first. The DOR analysis included only patients who achieved an objective response to study treatment. The DOR is estimated using the Kaplan-Meier methodology. Since the DOR is determined based on a non-random subset of patients, no formal hypothesis testing is performed.

Patient Reported Results

EORTC QLQ-LC13, TTCD for symptoms of cough, dyspnea and chest pain using GHS/QoL, and TTCD for physical function using EORTC QLQ-C30 were the time from randomization to first clinically significant deterioration. is defined as Identified clinically significant worsening of symptoms is defined as a score increase of 10 points or less from baseline or an initial increase of 10 points or less from baseline in symptom scores that must be maintained for at least two consecutive assessments, leading to death. A clinically significant worsening of symptoms identified for GHS/QoL and body function is defined as a decrease of 10 points or less or a decrease of 10 points or less from baseline in GHS/QoL or a body function scale score that must be maintained for at least two consecutive assessments. defined, leading to death.

In the case of TCD, data on patients are deleted at the last point of completion of the evaluation if they did not experience a clinically significant deterioration identified by the clinical deadline. If no baseline or post-baseline evaluation is performed, patients are withdrawn on the randomization date.

TTCD using the EORTC scale is analyzed using the same method as PFS.

The mean change from baseline in summary statistics and linear-transformation scores was calculated on all items and subscales of the EORTC QLQ-C30, EORTC QLQ-LC13, and EORTC IL46 (item for pain due to adverse reactions) questionnaires according to the EORTC score manual guidelines. is reported about

Safety analysis

The safety analysis includes all treated patients who received any amount of study treatment.

Safety analyzes are performed in the treatment sector and are based on actual treatment received. Specifically, if a patient receives any amount of tiragolumab or atezolizumab, the patient is included in Arm A in the safety analysis, regardless of randomized initial treatment assignment.

Drug exposure is summarized, including duration, dose, and dose intensity. Verbose descriptions of adverse events follow MedDRA Thesaurus Terminology.

The severity of all adverse events is rated by the investigator according to the NCI CTCAE v5.0, and the severity for CRS is graded by the investigator according to the ASTCT consensus rating scale. All adverse events are summarized by treatment arm and NCI CTCAE grade. CRS will also be summarized by treatment arm and ASTCT consensus grade. In addition, serious adverse events and adverse events leading to discontinuation or discontinuation of study treatment are summarized accordingly. Multiple occurrences of the same event are counted only once at maximum severity. Laboratory data with values outside the normal range are identified. In addition, selected laboratory data, including ADA results, are summarized by treatment arm. Deaths and causes of death are summarized.

Pharmacokinetic analysis

Pharmacokinetic samples are collected for pharmacokinetic analysis and to compare the performance of this study with those obtained in previous studies. Serum concentrations of tiragolumab and atezolizumab are reported as individual values and, where appropriate, summarized by treatment arm and cycle as data permits (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean coefficient of variation) do.

Individual and median serum tiragolumab and atezolizumab concentrations are plotted by treatment group and day. Tiragolumab and atezolizumab concentration data can be integrated with data from other studies using established population PK models to derive PK parameters such as clearance, volume of distribution and AUC as warranted by the data. . Potential correlations between relevant PK parameters and safety, efficacy, or biomarker outcomes can be investigated.

Immunogenicity assay

Immunogenicity assays include patients who have undergone an ADA assessment, and patients are classified according to treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients for both tiragolumab and atezolizumab are summarized by treatment arm. The relationship between ADA status and safety, efficacy, and PK endpoints can be analyzed and reported through descriptive statistics.

Biomarker analysis

Biomarker analysis can be performed to understand the association of an appropriate marker (eg, TIGIT) with the efficacy of the study treatment. These efficacy outcomes can be explored in patient populations with high biomarker expression in tumors as determined by IHC and/or RNA analysis. Exploratory analysis of WGS data can be performed in connection with this study, which can be explored in conjunction with data from other studies to improve researchers' understanding of disease pathobiology and guide the development of new therapeutic approaches. WGS does not apply to organizations that do not have regulatory approval for WGS sampling.

exploratory analysis

To assess the consistency of study outcomes in subgroups defined by demographic (e.g., age, sex, race/ethnicity) and baseline prognostic characteristics (e.g., central laboratory testing, geographic region, and PD-L1 expression by ECOG) For this purpose, we review the joint primary efficacy endpoints of ORR and PFS identified in these subgroups. A summary of the identified ORRs and PFSs is generated separately for each level of the categorical variable for comparison between the two treatment arms.

Interim analysis

Periodic analyzes of cumulative safety data are planned for this study. Interim analysis of effectiveness of PFS was performed when approximately 86 PFS events were observed in the ITT population. This is expected to occur approximately 19 months after the first patient is randomized. An initial analysis of ORR is performed even when approximately 120 patients have undergone at least two tumor evaluations. This is expected to occur approximately 14 months after the first patient is randomized.

Example 9. Neoadjuvant and adjuvant tyragolumab + ate with or without platinum-based chemotherapy in patients with previously untreated locally advanced resectable stage II, IIIA, or some stage IIIB non-small cell lung cancer A Phase II, Open Label, Multicenter Study Evaluating the Safety and Efficacy of Zolizumab

A. Overview of Study Design

GO42501 includes platinum-based chemotherapy (chemo) or This is a global Phase II, open-label, multicenter study evaluating the safety and efficacy of non-neoadjuvant and adjuvant atezolizumab (Atezo) + tiragolumab (Tira). This study is a proof-of-concept clinical trial that neoadjuvant treatment with atezo + tyra or atezo + tyra + chemistry is safe, tolerable, and has no clinically significant adverse effects on surgical outcomes in patients with early-stage resectable NSCLC. It is designed to establish data. This study was also designed to evaluate the potential antitumor effect of neoadjuvant atezo + tyra or atezo + tyra + chemistry as measured by major pathological response (MPR). The study is designed to have the flexibility to open new cohorts as new treatment combinations become available.

Study treatments administered are provided in Table 55. In this protocol, "study treatment" refers to the combination of treatment assigned to a patient as part of this study (ie, atezo + tyra, atezo + tyra + chemo, or chemotherapy).

atezo = atezolizumab; Chemistry = platinum-based chemotherapy; PD-L1 = programmed death-ligand 1; Tira = tiragolumap.

^a Investigator's choice to administer chemotherapy as an adjuvant treatment.

19 shows an outline of the study design. Patients are assigned to cohorts according to PD-L1 status and are treated as follows:

Cohort A (PD-L1 high) : neoadjuvant atezo + tyra for 4 cycles followed by surgical resection and either adjuvant atezo + tyra for 16 cycles or adjuvant chemotherapy for 4 cycles.

Cohort B (PD-L1 all entrants): neoadjuvant atezo + tyra + chemistry for 4 cycles followed by surgical excision and adjuvant atezo + tyra for 16 cycles

The choice of platinum-based chemotherapy is based on histological subtype and is at the discretion of the investigator documented at the time of initiation. The following platinum-based chemotherapy options are permitted in this study:

비편평 NSCLC의 경우:

For nonsquamous NSCLC:

- Cisplatin + Pemetrexed

- Carboplatin + Pemetrexed

- Carboplatin + Paclitaxel

· For squamous NSCLC:

- Cisplatin + Gemcitabine

- Carboplatin + Gemcitabine

- Carboplatin + Paclitaxel

Surgical specimens are evaluated for pathologic response (MPR and complete pathological response (pCR)) at the independent central pathology laboratory and the investigator's on-site pathology laboratory. In addition, exploratory biomarker analysis can be performed on remaining surgical specimens (primary tumor tissue and dissected lymph nodes).

Postoperative radiotherapy (PORT) is permitted in patients with confirmed pathological N2 + disease or benign tumor margin at the time of surgical resection (ypN2 and/or R1/R2), prior to adjuvant atezo plus tyra therapy or adjuvant platinum-based It should be administered after chemotherapy.

All patients complete scheduled tumor evaluation of the chest and abdomen by both computed tomography (CT) and positron emission tomography (PET) at screening and by CT only after cycles 2 and 4 of neoadjuvant treatment. Tumor evaluation continues after surgery until recurrence. If disease follow-up evaluation shows evidence of disease recurrence, this should be confirmed pathologically and/or by clear radiological evidence from the scan. If the scan reveals equivocal findings (eg, mediastinal nodule measurements < 1.5 cm for short axis, lung parenchymal lesions or visceral lesion measurements < 1 cm for longest diameter), a biopsy should be performed. A biopsy should be performed prior to initiating the next chemotherapy. If biopsies are performed to confirm disease recurrence, it is strongly recommended that the remaining biopsy tissue be submitted for exploratory biomarker studies. If a biopsy is not possible or unsafe, a confirmatory scan should be performed again within 4 to 8 weeks.

If the biopsy does not show evidence of disease recurrence (eg, non-malignant infiltrates), the patient may continue with the scheduled study treatment, evaluation, and/or follow-up. In the absence of disease recurrence, disease follow-up evaluation should continue until disease recurrence, withdrawal of consent, death, loss of follow-up, or end of study by the sponsor, whichever occurs first.

All patients undergo safety, tolerability, and exploratory evaluations on Day 1 of each cycle in the neoadjuvant treatment phase (cohort) and the adjuvant treatment phase. After discontinuation of treatment, follow-up periodically for patient survival and additional anticancer treatment. Safety assessments include the incidence, nature and severity of adverse events, protocol-essential vital signs, laboratory abnormalities, and other protocol-specific tests considered important for the safety assessment of the study. Investigators rate adverse events according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v 5.0).

As well as stored and fresh tumor and/or lymph node tissue

Patient samples, including serum, plasma and blood, are collected for future exploratory biomarker evaluation. In addition, patients are given the opportunity to consent to selective stool collection for exploratory microbiome studies.

The specific study objectives and corresponding endpoints are summarized in Table 56.

ADA = anti-drug antibody; ASTCT = American Society for Transplantation and Cell Therapy; atezo + tyra = atezolizumab + tyragolumab; atezo + tyra + chemo = atezolizumab + tyragolumab + platinum-based chemotherapy; CRS = cytokine release syndrome; ctDNA = circulating tumor DNA; EFS = event-free survival; EORTCE = European Agency for Research and Treatment of Cancer; GHS/QoL = global health status and quality of life; IL = list of items; MPR = major pathological response; NCI CTCAE v5.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0; NSCLC = non-small cell lung cancer; PBMC = peripheral blood mononuclear cells; pCR = pathological complete response; PK = pharmacokinetics; PRO = patient-centric outcome; QLQ-C30 = Quality of Life Questionnaire for Cancer; QLQLC13 = Quality of Life Questionnaire Lung Cancer Module; RECIST v1.1 = Criteria for Response Evaluation of Solid Tumors, Version 1.1.

B. Treatment assignment and safety introduction

Patients must be eligible for an intended R0 resection on screening treatment and meet all eligibility criteria set forth herein. Patients who do not meet these study entry criteria (screening failure) may be eligible for two rescreening opportunities (3 total screenings per participant) at the investigator's discretion.

Treatment assignment and safety introduction according to tumor PD-L1 status

After giving informed consent, the patient undergoes a screening procedure including a central assessment of PD-L1 status by SP263 immunohistochemistry (IHC) (tumor cell (TC) based assay).

Enrollment is completed in phases as follows (see Figure 20), with approximately 41 patients enrolled in each cohort.

1. Initially there is a safety introduction:

- Six patients with tumors with a PD-L1 Tumor Rate Score (TPS) ≥50% at screening treatment are enrolled in Cohort A (PD-L1 High Cohort).

- Cohort B (PD-L1 all entrant cohort) begins with enrollment of 6 tumor patients with PD-L1 TPS <50%.

2. Assess the safety of each cohort, and if deemed safe:

- Patients are enrolled in cohort B (PD-L1 all entrants) until 8 patients with tumors with PD-L1 TPS ≥50%, including those with tumors with PD-L1 TPS ≥50%, are enrolled in that cohort. ) is registered only.

- The remaining cohort B patients consist of tumor patients with PD-L1 TPS <50%.

3. After a total of 8 patients with tumors with PD-L1 TPS ≥50% were enrolled in Cohort B (PD-L1 all entrants), enrollment into Cohort A (PD-L1 high) resumed, and PD-L1 All subsequent patients with tumors with L1 TPS ≥50% are enrolled in this cohort.

Safety introduction

To account for potential surgical delays, cancellations, or complications associated with study treatment, enrollment within each cohort is discontinued for safety assessment after approximately 6 patients have completed neoadjuvant treatment and completed surgery or surgical plan change. Cohorts cannot be enrolled at the same rate, and each cohort is evaluated individually and independently.

The safety assessment is based on safety and surgical data. Based on data review, it is recommended to either continue enrollment in the cohort or terminate the cohort. During the safety introduction period, patients who do not proceed with surgery for reasons other than adverse events of particular interest or disease progression may be replaced.

Surgery and adjuvant treatment

The patient undergoes surgical resection of the tumor upon completion of 4 cycles of neoadjuvant therapy. Prior to surgery, the patient is reevaluated by the attending surgeon and oncologist.

Preoperative visits should be made within 30 days of the last dose of neoadjuvant therapy: Repeat Pulmonary Function Test (PFT) (if clinically indicated) and related evaluations should be performed in accordance with local institutional practice. Within 30 days of the preoperative visit, if both the attending physician and the medical oncologist determine that it is clinically feasible

A surgical procedure must be performed.

Patients who are confirmed to have disease progression at any time during scheduled tumor evaluation (cycle 2 and after cycle 4) or neoadjuvant therapy, and still considered resectable and non-metastatic, remain compliant and eligible for all study treatments and evaluations. If so, proceed with surgery.

If the investigator plans to allow the patient to proceed with surgery without disease progression prior to completing all four neoadjuvant treatments, the medical monitor should be consulted.

Patients who prematurely discontinue neoadjuvant treatment due to disease progression and do not proceed with surgery will be discontinued from further clinical study procedures and continue receiving other treatments as determined by the investigator. These patients are the subject of study for survival follow-up. responsive to neoadjuvant therapy

For patients unable to proceed with surgery due to unforeseen medical problems (e.g., pulmonary embolism or myocardial infarction), patients receive chemotherapy (cohort A [PD-L1 high]) or atezotira (cohort A or B) and radiation therapy. You can continue with protocol-directed treatment, such as

After surgical resection, patients continue to receive adjuvant atezo + tyra or adjuvant chemotherapy (cohort A [PD-L1 high] only) until one of the following occurs: 16 cycles of adjuvant atezo + tyra, acceptable unavoidable toxicity, disease recurrence, death, or decision of the patient and/or physician to discontinue study treatment.

Study End and Study Duration

End of this study is defined as the date on which the last patient's last visit occurred, approximately 3 years after the last patient received the last dose of study drug after surgery.

The total duration of the study from screening the first patient to the end of the study may be approximately 56 years.

C. Rationale for Study Design

This study evaluates the surgical safety and feasibility of atezo + tyra or atezo + chemo as neoadjuvant treatment for previously untreated locally advanced NSCLC patients. This study also evaluates the efficacy, pharmacokinetics, immunogenicity and safety of adjuvant atezo or atezo followed by adjuvant atezo or adjuvant chemotherapy.

Rationale for Atezolizumab + Tiragolumab Dosage and Schedule

Atezolizumab is administered as a fixed dose of 1200 mg Q3W (1200 mg on Day 1 of each 21-day cycle), the approved dose for atezolizumab as outlined in the prescribing information. Antitumor activity was observed at doses ranging from 1 mg/kg to 20 mg/kg Q3W. In Study I GO27381 (PCD4989g), the maximally tolerated dose of atezolizumab was not reached and no dose limiting toxicity (DLT) was observed at any dose. A fixed dose of 1200 mg Q3W (corresponding to a mean body weight dose of 15 mg/kg Q3W) was obtained from two nonclinical studies (Deng et al., MAbs, 8: 593-603, 2016), available clinical pharmacokinetics (PK), and efficacy. and safety data.

Tiragolumab was administered by intravenous injection of Q3W on Day 1 of each 21-day cycle at a fixed dose of 600 mg to all patients in the experimental group. The fixed-dose tiragolumab 600 mg IV Q3W was selected based on available clinical pharmacokinetic, efficacy, and safety data from study GO30103, in which patients were either single agent tiragolumab or tiragolumab plus atezolizumab. In study GO30103, the maximum tolerated dose was not reached and no DLTs were observed with tiragolumab monotherapy or in combination with atezolizumab 1200 mg Q3W (tiragolumab dose range 2-1200 mg Q3W). Complete occupancy of peripheral TIGIT receptors on CD4+, CD8+ and NK cells was observed starting at the tyragolumab dose level of 30 mg Q3W and maintained at all higher doses. Anti-tumor activity (as assessed by radiographic partial response (PR)) was observed for tiragolumab in the dose range of 30600 mg Q3W when given in combination with atezolizumab 1200 mg Q3W.

In phase II study GO40290, all patients enrolled in the atezolizumab plus tiragolumab group received 600 mg of tiragolumab. At this dose, tiragolumab was well tolerated, and the combination of atezolizumab plus tiragolumab resulted in clinically significant improvement in PFS and higher ORR compared to the combination of placebo and atezolizumab. Given the beneficial benefits observed at 600 mg, this same dose of tiragolumab is used in this study.

Evidence of Patient Population

This study enrolls patients with resectable stage II, IIIA, and some stage IIIB (T3N2 only) NSCLC determined at screening practice. Patients with tumors with high PD-L1 expression (TPS ≥50%, determined by immunohistochemistry [IHC] by SP263 in the central laboratory) are enrolled in cohort A (PD-L1 high), and all entrants (PD-L1 high) regardless of L1 expression) are enrolled in Cohort B (PD-L1 all entrants).

Neoadjuvant and adjuvant chemotherapy have shown significant but modest benefits in patients with early-stage resectable NSCLC, and there is still a significant unmet need to improve outcomes in this treatment setting.

Tumor cell death by cytotoxic chemotherapy can expose the immune system to high levels of tumor antigens. Enhancing tumor-specific T-cell immunity in this setting by blocking the PD-L1 and TIGIT pathways may result in deeper and more sustained responses than observed with standard chemotherapy alone (Merritt et al., J Thorac Cardiovasc Surg). , 126: 1609-1617, 2003; Apetoh et al., Nat Med, 13: 1050-1059, 2007), which can reasonably occur in tumors regardless of PD-L1 expression.

Given the magnitude of benefit in the PD-L1 TPS ≥50% population and the robust data from CITSCAPE demonstrating the need to improve survival and reduce recurrence rates in patients with resectable early-stage NSCLC, this study demonstrates the efficacy of a atezo + Tyra combination as a chemo-free option. review A chemotherapy-free option for patients with resectable non-small cell lung cancer would be a significant improvement in patients and could prevent the early and late toxicity associated with platinum-based chemotherapy in patients.

Evidence for Major Pathological Responses as Primary Endpoints

The main efficacy goal of this study was to achieve atezo + tyra or atezo + tyra + chemotherapy in patients with resectable stage II, IIIA, or some stage IIIB (T3N2 only) NSCLC, as measured by the Central Pathology Laboratory-Assessed Major Pathological Response (MPR). To evaluate the efficacy of neoadjuvant treatment using

Although overall survival (OS) is the standard for evaluating clinical benefit in adjuvant and neoadjuvant NSCLC trials, OS readouts often take years, especially in early-stage disease. Therefore, the adoption of meaningful surrogate endpoints may facilitate the evaluation of new therapies and provide new therapies to NSCLC patients more quickly. Pathological response after surgical resection of NSCLC has been proposed as a surrogate endpoint for OS (Hellmann et al., Lancet Oncol, 15: e42-50, 2014). Hellmann et al. (2014) cited the U.S. Food and Drug Administration's (FDA) definition of a surrogate endpoint, where the endpoint must be "possible to reasonably predict clinical benefit". They argue that the use of pathologic responses in neoadjuvant settings meets this definition based on three findings: 1) pathological responses are strongly correlated with OS; 2) pathological response reflects neoadjuvant chemotherapy; and 3) the degree of pathological response correlates with the degree of OS benefit.

The use of pathological response as a surrogate endpoint is not without precedent. The trial for breast cancer used pathological complete response (pCR) to evaluate the efficacy of neoadjuvant treatment. However, pCR ratios varied in neoadjuvant NSCLC studies. In addition, the relatively low pCR rates reported in NSCLC may not be interpreted as clinically significant overall survival (OS) benefits, thus limiting the utility of pCR as a surrogate survival endpoint in NSCLC trials. In fact, few trials have reported compelling survival data for pCR in NSCLC because of the low pCR rate (median rate 4%) (Hellmann et al., Lancet Oncol, 15: e42-50, 2014).

Instead of pCR, Hellman et al. proposed the use of MPR, defined as 10% residual viable tumor tissue, as a surrogate for survival in patients with resectable NSCLC receiving neoadjuvant chemotherapy (Hellmann et al., Lancet Oncol, 15: e42-50, 2014). . It is based on a study where, while acknowledging the rarity of pCR in NSCLC, investigators considered other definitions of pathologic responses, including residual survival tumors as surrogate survival endpoints. Junker et al. ( J Cancer Res Clin Oncol, 123: 469-477,1997) performed a pathological analysis of 40 tumors from stage IIIA and IIIB patients who underwent sequential neoadjuvant chemotherapy, chemoradiation, and surgical resection. did. In this group, patients with ≤10% residual tumors had a median survival of 36 months, while those with viable tumor tissue >10% had a median survival of 14 months.

In two prospective trials, the MPR rate of neoadjuvant chemotherapy in NSCLC was reported to be approximately 22%. In the first study, among 90 patients with stage IIIA disease who received neoadjuvant chemotherapy (cisplatin + docetaxel), the median pathological response (amount of tumor necrosis and fibrosis) was 60% and the pathological response was ≤60%. The median overall survival (OS) was 61 months when compared to 22 months in Betticher et al., Br J Cancer, 94(8): 1099-1106, 2006). In another study, among 50 patients who received neoadjuvant chemotherapy (cisplatin + docetaxel) in combination with bevacizumab, those who received MPR had a 3-year survival rate compared to those who did not achieve MPR (61 months versus 22 months, respectively). significantly longer (Chaft et al., J Thorac Oncol , 8: 1084-1090, 2013). A retrospective study of William and colleagues at the MD Anderson Cancer Center (William et al., J Thorac Oncol, 8: 222-228, 2013) found that MPR was the clinical response of solid tumors in 160 patients receiving neoadjuvant platinum-based chemotherapy. It has been shown to be a stronger predictor of OS than RECIST response.

The sponsor believes that there is considerable evidence to use MPR as a surrogate endpoint based on its correlation with the degree of improvement in OS. A global phase III neoadjuvant enrollment trial of chemotherapy plus PD-L1/PD-1 inhibitors versus chemotherapy alone evaluating MPR as a primary or secondary goal is currently underway. The use of MPR as a surrogate endpoint could increase the effectiveness of clinical studies and accelerate new therapies for patients with NSCLC.

Example 10. Materials and Methods for Studying GO42501

Approximately 82 patients with stage II, IIIA, or some stage IIIB (T3N2 only) were enrolled in study GO42501.

A. Selection Criteria

Patients must meet the selection criteria listed below to be eligible for study participation.

사전 동의서에 서명할 당시의 연령 ≥18세

Age ≥18 years at the time of signing informed consent

연구 프로토콜을 준수하는 능력.

Ability to comply with study protocols.

조직학적 또는 세포학적으로 확인된 편평 또는 비-편평 조직의 II기, IIIA기 또는 일부 IIIB(T3N2만) 비소세포폐암(NSCLC). 병기는 American Joint Committee on Cancer/Union Internationale Contre le Cancer NSCLC 병기 결정 시스템의 제8판에 기반해야 한다.

Histologically or cytologically confirmed stage II, IIIA, or part IIIB (T3N2 only) non-small cell lung cancer (NSCLC) of squamous or non-squamous tissue. Staging should be based on the 8th edition of the American Joint Committee on Cancer/Union Internationale Contre le Cancer NSCLC Staging System.

- Patients with T4 primary non-small cell lung cancer are eligible only on the basis of size (tumor >7 cm). Patients with involvement of the diaphragm, mediastinum, heart, great blood vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, ridge, and other individual tumor nodules of the ipsilateral lobe are not eligible.

- NSCLC patients with mixed histology (squamous and nonsquamous) are eligible and must be classified based on their major histologic component (nonsquamous or squamous).

Patients can be screened according to clinical stage, but for PET-positive N2 nodules, mandatory preoperative documentation of N2 nodule involvement by invasive mediastinal stage (e.g. CT-guided biopsy, bronchial ultrasound, mediastinoscopy) is required. Preoperative staging of level 5 and level 6 nodes is optional.

No abrasive glass opacity (GGO) is shown, solid or subsolid of NSCLC on CT scan. For subsolid lesions, tumor size (i.e., clinical stage T) should be determined based on the solid component only, excluding the GGO component.

연구 등록 전에 수술 담당 외과의 및 관련 종양 전문의에 의해 확인된 바와 같이 선별 치료 시점에 치료 의도가 있는 R0 절제에 적격.

Eligible for intentional R0 resection at the time of screening treatment as confirmed by the surgical surgeon and relevant oncologist prior to study enrollment.

폐 용적, 폐활량 측정 및 확산 능력을 포함하여 임상적으로 지시된 경우, 계획된 절제 후 6개월 이내에 수행되고 선별 치료 시 반복되는 폐 기능 검사(PFT)에 의해 평가된 치료 목적의 외과적 절제에 적합한 적절한 폐 기능; 및 다음 기준 중 하나 이상을 충족:

When clinically indicated, including lung volume, spirometry, and diffusion capacity, appropriate appropriate for therapeutic surgical resection performed within 6 months of planned resection and assessed by repeated lung function tests (PFT) in screening therapy. lung function; and meet one or more of the following criteria:

≥40% of the lung's ppo diffusion capacity relative to the expected postoperative (ppo) forced expiratory volume (FEV1) and carbon _monoxide (DLCO) for 1 second.

- Maximum oxygen consumption (VO ₂ max) ≥15 mL/kg/min.

o If either ppoFEV ₁ or ppoDL _CO is <40% or if pneumonectomy is planned, perform cardiopulmonary exercise test, VO ₂ max ≥15 mL/kg/min.

o PFTs performed during the screening treatment period if PFTs were or have not been performed before 6 months of planned resection.

Eligibility for platinum-based chemotherapy. The Warnings and Cautions section in the prescribing information for each individual chemotherapy treatment (ie, carboplatin, cisplatin, pemetrexed, paclitaxel, or gemcitabine) in the regimen intended for the patient is used to determine eligibility.

o Measurable disease assessed by the investigator per RECIST v1.1.

o Availability of representative tumor specimens suitable for determination of PD-L1 status and other exploratory biomarkers via central testing.

o Eastern Oncology Collaborating Group (ECOG) Performance Status 0 or 1

o Normal life expectancy, excluding the risk of lung cancer death.

o Adequate blood and terminal organ function, as defined by the following laboratory results, obtained within 14 days prior to initiation of study treatment:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10 ⁹ /L (1500/μL), no granulocyte colony stimulating factor 0 support.

- Lymphocyte count ≥0.5 x 10 ⁹ /L (500/μL).

- Platelet count ≥100 x 10 ⁹ /L (100,000/μL) without transfusion.

- Hemoglobin ≥90 g/L (9 g/dL). Patients were accepted for transfusions to meet the above criteria.

-aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) ≤2.5 x upper limit of normal (ULN).

Total bilirubin ≤ 1.5 x ULN, with the following exceptions: Patients with known Gilbert's disease: Total bilirubin ≤3 x ULN.

- Creatinine clearance 45 mL/min (calculated using the Cockcroft-Gault formula). Patients receiving cisplatin: creatinine clearance ≥60 mL/min.

혈청 알부민 25 g/dL(2.5 g/dL)

Serum albumin 25 g/dL (2.5 g/dL)

- For patients not receiving therapeutic anticoagulants: INR or aPTT ≤1.5 x ULN

치료적 항응고 요법을 받는 환자의 경우: 안정적인 항응고 요법

For patients receiving therapeutic anticoagulant therapy: stable anticoagulant therapy

선별 치료시 HIV 검사 음성

HIV test negative during screening treatment

선별 치료시 B형 간염 표면 항원 (HBsAg) 검사 음성

Hepatitis B surface antigen (HBsAg) test negative during screening treatment

선별 치료시 B형 간염 표면 항체(HBsAb) 검사 양성 또는 다음 중 하나를 동반한 선별 치료시 HBsAb 음성:

Hepatitis B surface antibody (HBsAb) test positive for screening treatment or HBsAb negative for screening treatment with one of the following:

- Total hepatitis B core antibody (HBcAb) negative

- Quantitative hepatitis B virus (HBV) DNA <500 IU/mL after positive total HBcAb test. The HBV DNA test is only performed on patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test.

선별 치료 시 C형 간염 바이러스(HCV) 항체 검사 음성 또는 선별 치료 시 HCV 항체 검사 양성 후 HCV RNA 검사 음성. HCV RNA 검사는 HCV 항체 검사 양성인 환자에게만 시행된다.

Hepatitis C virus (HCV) antibody test negative during screening treatment or HCV RNA test negative after positive HCV antibody test during screening treatment. The HCV RNA test is only performed on patients with a positive HCV antibody test.

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods and to refrain from egg donation.

남성의 경우: 금욕을 유지하거나 (이성간 성교 금지) 또는 콘돔을 이용하는 데 동의, 그리고 정자 기증 자제에 대한 동의.

For men: Consent to maintain abstinence (no intercourse) or to use condoms, and consent to refrain from donating sperm.

B. Exclusion Criteria

Patients meeting any of the following criteria are excluded from study entry.

대세포 신경내분비 암종, 육종양 암종 또는 달리 명시되지 않은 NSCLC의 조직학이 있는 NSCLC.

NSCLC with histology of large cell neuroendocrine carcinoma, sarcoma carcinoma, or NSCLC not otherwise specified.

소세포폐암(SCLC) 조직학 또는 SCLC의 구성요소가 있는 NSCLC.

Small cell lung cancer (SCLC) histology or NSCLC with components of SCLC.

연구 절차를 이해하고, 따르고, 및/또는 준수하는 환자의 능력을 방해할 수 있는 질병 또는 상태.

A disease or condition that may interfere with the patient's ability to understand, follow, and/or comply with research procedures.

면역 요법, 화학요법 또는 방사선 요법을 포함한 모든 이전 폐암 요법.

Any previous lung cancer therapy, including immunotherapy, chemotherapy, or radiation therapy.

중증 근무력증, 근염, 자가면역 간염, 전신성 홍반성 루푸스, 류마티스 관절염, 염증성 장질환, 항인지질항체 증후군, 베게너 육아종증, 쇼그렌 증후군, 및 길랭-바레 증후군을 포함하나 이에 국한되지 않는 자가면역 질환 또는 면역 결핍의 활성 또는 병력, 또는 다발성 경화증으로서 다음을 예외로함: 갑상선 대체 호르몬을 투여받고 있는 자가면역 관련 갑상선 기능 저하증의 병력이 있는 환자는 연구에 적합하다. 인슐린 요법을 받고 있는 조절된 제1형 진성 당뇨병 환자는 연구에 적합하다.

Autoimmune disease or immunity including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjogren's syndrome, and Guillain-Barré syndrome Active or history of deficiency, or multiple sclerosis, with the following exceptions: Patients with a history of autoimmune-associated hypothyroidism who are receiving thyroid replacement hormone are eligible for study. Patients with controlled type 1 diabetes mellitus on insulin therapy are eligible for study.

Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with dermatological signs only (e.g., excluding patients with psoriatic arthritis) are eligible for study if all of the following conditions are met:

- The rash should occupy <10% of the body surface area.

Disease is well controlled at baseline and only low titer topical corticosteroids are required.

- No acute exacerbation of an underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the past 12 months.

특발성 폐섬유증, 폐색성 기관지염(예: 폐쇄성 세기관지염), 약물 유발성 폐렴 또는 특발성 폐렴의 병력, 또는 선별 흉부 CT 스캔에서 활동성 폐렴의 증거.

A history of idiopathic pulmonary fibrosis, obstructive bronchitis (eg, bronchiolitis obliterans), drug-induced pneumonia or idiopathic pneumonia, or evidence of active pneumonia on a screening chest CT scan.

활성 결핵;

active tuberculosis;

연구 치료 시작 전 3개월 이내에 심각한 심혈관 질환(예: New York Heart Association Class II 이상의 심장 질환, 심근경색증 또는 뇌혈관 사고), 불안정성 부정맥 또는 불안정형 협심증.

Serious cardiovascular disease (eg, New York Heart Association Class II or higher heart disease, myocardial infarction or cerebrovascular accident), unstable arrhythmia, or unstable angina within 3 months prior to study treatment initiation.

A major surgical procedure within 4 weeks prior to initiation of study treatment, or if a major surgical procedure is expected during the course of the study.

활성화 EGFR 돌연변이 또는 ALK 융합 종양 유전자가 있는 NSCLC. 비편평 NSCLC 조직학이 있는 환자의 경우: EGFR 및/또는 ALK 상태가 알려지지 않은 경우 선별 치료시 검사 필요. ALK 및/또는 EGFR 상태는 국부적으로 평가되거나 중앙 실험실 테스트를 위해 제출될 수 있다.

NSCLC with an activating EGFR mutation or ALK fusion oncogene. For patients with nonsquamous NSCLC histology: Screening treatment required if EGFR and/or ALK status is unknown. ALK and/or EGFR status may be assessed locally or submitted for central laboratory testing.

알려진 c-ros 종양유전자 1(ROS1) 재배열. 선별 치료 시 ROS1 테스트는 연구에 포함될 필요 없다: 그러나 알려진 ROS1 재배열이 있는 환자는 제외된다.

Known c-ros oncogene 1 (ROS1) rearrangement. In screening treatment, ROS1 testing does not need to be included in the study; however, patients with known ROS1 rearrangements are excluded.

선별 치료 전 5년 이내에 NSCLC 이외의 악성 종양의 병력으로서, 적절하게 치료된 자궁경부의 상피내 암종, 비흑색종 피부 암종, 국소 전립선암, 관내 상피내 암종, 또는 I기 자궁암과 같은 전이 또는 사망 위험이 무시될 수 있는 악성 종양(예: 5년 OS 비율 90%)은 제외.

History of malignancy other than NSCLC within 5 years prior to screening treatment, with a risk of death or metastasis, such as an appropriately treated intraepithelial carcinoma of the cervix, non-melanoma skin carcinoma, focal prostate cancer, ductal carcinoma in situ, or stage I uterine cancer Excludes malignancies that can be ignored (eg, 90% 5-year OS rate).

감염, 균혈증 또는 중증 폐렴의 합병증으로 인한 입원을 포함하나 이에 국한되지 않는 연구 치료 시작 전 4주 이내의 중증 감염, 또는 시험자의 의견으로 환자 안전에 영향을 미칠 수 있는 활성 감염.

Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or active infection that, in the opinion of the investigator, could affect patient safety.

연구 치료 시작 전 2주 이내에 치료적 경구 또는 IV 항생제에 의한 치료. (예를 들어, 요로 감염 또는 만성 폐쇄성 폐질환 악화를 예방하기 위해) 예방적 항생제를 투여받는 환자는 연구에 적격임.

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (eg, to prevent exacerbation of urinary tract infection or chronic obstructive pulmonary disease) are eligible for study.

선행 동종 줄기 세포 이식 또는 고형 장기 이식

Prior allogeneic stem cell transplantation or solid organ transplantation

임상시험용 약물의 사용을 금하거나, 결과 해석에 영향을 미치거나, 환자를 치료 합병증으로 인한 높은 위험에 처하게 할 수 있는 기타 질환, 대사 기능 장애, 신체 검사 소견 또는 임상 검사 소견.

Other diseases, metabolic dysfunctions, physical examination findings or clinical laboratory findings that may contraindicate the use of investigational drugs, affect the interpretation of results, or place the patient at high risk for complications of treatment.

연구 치료 시작 전 4주 이내에 약독화 생백신으로 치료하거나, 연구 치료 중 티라골루맙의 최종 투여 후 90일 이내에 또는 아테졸리주맙의 최종 투여 후 5개월 이내에 이러한 백신이 필요할 것으로 예상되는 경우. 화학요법(즉, 카보플라틴, 시스플라틴, 페메트렉시드, 파클리탁셀 또는 젬시타빈)으로 치료를 받고 있는 환자는 생백신을 접종해서는 안된다.

Treatment with live attenuated vaccine within 4 weeks prior to initiation of study treatment, or expected to require such vaccine within 90 days of the last dose of tiragolumab during study treatment, or within 5 months of the last dose of atezolizumab. Patients who are being treated with chemotherapy (ie, carboplatin, cisplatin, pemetrexed, paclitaxel, or gemcitabine) should not receive live vaccines.

HBV에 대한 항바이러스 요법에 의한 현재 치료.

Current treatment with antiviral therapy for HBV.

Positive Epstein-Barr Virus (EBV) Viral Capsid Antigen Immunoglobulin M (IgM) Test in Selective Treatment. EBV PCR testing should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded.

연구 치료 시작 전 42일 이내에 임상시험 요법에 의한 치료.

Treatment by investigational regimen within 42 days prior to initiation of study treatment.

항-CTLA-4, 항-PD-1, 항-TIGIT 및 항-PD-L1 치료 항체를 포함한 CD137 작용제 또는 면역 관문 차단 요법을 사용한 선행 치료.

Prior treatment with CD137 agonists or immune checkpoint blockade therapy, including anti-CTLA-4, anti-PD-1, anti-TIGIT and anti-PD-L1 therapeutic antibodies.

연구 치료 시작 전 4주 또는 5개의 약물 제거 반감기(둘 중 더 긴 것) 이내에 전신 면역자극제(인터페론 및 IL-2를 포함하지만 이에 국한되지 않음)를 사용한 치료.

Treatment with systemic immunostimulants (including but not limited to interferon and IL-2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to study treatment initiation.

연구 치료 시작 전 2주 이내에 전신 면역억제제(코르티코스테로이드, 사이클로포스파미드, 아자티오프린, 메토트렉세이트, 탈리도마이드, 및 항-종양 괴사 인자α-[TNF-α] 제제를 포함하나 이에 국한되지 않음)로 치료하거나, 연구 치료 동안 전신 면역억제제가 필요할 것으로 예상되는 경우로서, 하기 예외 사항은 제외:

Systemic immunosuppressants (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor α-[TNF-α] agents) within 2 weeks prior to study treatment start Treatment or expected to require systemic immunosuppressive agents during study treatment, with the following exceptions:

- Patients receiving acute, low-dose systemic immunosuppressants or single pulse doses of systemic immunosuppressants (eg, corticosteroids for contrast allergy 48 hours) are eligible for study.

- Patients receiving mineralocorticoids (eg fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticoids for orthostatic hypotension or adrenal insufficiency are eligible for study.

키메라성 또는 인간화 항체 또는 융합 단백질에 대한 중증 알러지성 및 과민성, 또는 다른 과민증 반응.

Severe allergic and hypersensitivity, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.

햄스터 난소 세포 제품 또는 아테졸리주맙 또는 티라골루맙 제제의 성분에 대해 알려진 과민증.

Known hypersensitivity to a hamster ovary cell product or a component of an atezolizumab or tiragolumab formulation.

연구 동안 받을 수 있는 화학요법 요법의 구성 요소에 대해 알려진 알러지 또는 과민증.

Known allergy or hypersensitivity to any component of the chemotherapy regimen you may receive during the study.

최종 투여 후 90일 이내, 아테졸리주맙의 최종 투여 후 5개월 이내, 또는 페메트렉시드, 젬시타빈, 파클리탁셀, 카보플라틴 또는 시스플라틴의 최종 투여 후 6개월 이내, 연구 치료 중 임신 또는 수유 중이거나 임신 의도가 있는 경우. 가임 여성은 연구 치료 시작 전 14일 이내에 혈청 임신 검사 결과가 음성이어야 한다.

Within 90 days of the last dose, within 5 months of the last dose of atezolizumab, or within 6 months of the last dose of pemetrexed, gemcitabine, paclitaxel, carboplatin, or cisplatin, pregnant, lactating, or pregnant during study treatment If there is an intention. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

C. treatment assignment

This study is a public study.

Patients with high PD-L1 expression (TPS 50%, determined by SP263 IHC in the central laboratory) were enrolled in Cohort A (PD-L1 high), while all new entrants (regardless of PD-L1 expression level) were enrolled in Cohort B (PD-L1 all entrants) is registered. Enrollment is completed in phases as follows (see Figure 20), with approximately 41 patients enrolled in each cohort. Enrollment is completed in phases as follows (see Figure 20), with approximately 41 patients enrolled in each cohort.

One. First there is a safety introduction:

- Six patients with tumors with a PD-L1 TPS ≥50% on screening are enrolled in cohort A (PD-L1 high cohort).

- Cohort B (PD-L1 all entrant cohort) begins with enrollment of 6 tumor patients with PD-L1 TPS <50%.

2. Assess the safety of each cohort, and if deemed safe:

2. Assess the safety of each cohort, and if deemed safe:

- Patients are enrolled in cohort B (PD-L1 all entrants) until 8 patients with tumors with PD-L1 TPS <50%, including those with tumors with PD-L1 TPS ≥50%, are enrolled in that cohort. ) is registered only.

- The remaining cohort B patients consist of tumor patients with PD-L1 TPS <50%.

3. 3. After a total of 8 patients with tumors with PD-L1 TPS ≥50% were enrolled in Cohort B (PD-L1 all entrants), then enrollment into Cohort A (PD-L1 High) resumed; All subsequent patients with tumors with PD-L1 TPS ≥50% are enrolled in this cohort.

D. Study Treatment Dosage, Administration and Compliance

Each study treatment component is administered at the dose and frequency specified in Table 57.

AUC = area under the concentration-time curve; IV = intravenous.

^a. Carboplatin should be administered at an initial target AUC of 5 mg/mL/min after administration of pemetrexed or gemcitabine, and should be administered at an initial target AUC of 6 mg/mL/min after administration of paclitaxel.

^b. Gemcitabine should be administered at 1000 mg/m ² before carboplatin and 1250 mg/m ² before cisplatin.

^c. Paclitaxel should be administered at 175 mg/m ² in patients of Asian race/ethnicity and 200 mg/m ² in patients of non-Asian race/ethnicity.

The neoadjuvant treatment phase consists of 4 cycles of atezo + tyra or atezo + tyra + chemistry. The duration of each cycle is 21 days. On Day 1 of each cycle, all eligible patients were infused with study drug in the following order.

Cohort A (PD-L1 high): (1) atezolizumab, (2) tiragolumab.

Cohort B (PD-L1 all entrants): Investigators will receive one of the listed regimens based on histological subtype and local SOC.

- (1) atezolizumab, (2) tiragolumab, (3) paclitaxel, (4) carboplatin

- (1) atezolizumab, (2) tiragolumab, (3) pemetrexed, (4) (carboplatin or cisplatin)

- (1) atezolizumab, (2) tiragolumab, (3) gemcitabine, (4) (carboplatin or cisplatin)

Atezolizumab (1200 mg) and tiragolumab (600 mg) are administered as fixed doses. Patients received their first dose of study treatment on the day of enrollment, if available. If treatment is not possible on the day of registration, the first dose is administered within 5 days of registration.

For Cycle 1, premedication for primary prophylaxis (antihistamines, antipyretics and/or analgesics) of atezolizumab and tiragolumab is not permitted. Patients should receive antiemetics and IV hydration for the chemotherapeutic backbone regimen selected according to local SOC and manufacturer's guidelines. However, due to the immunomodulatory effect of corticosteroids, pre-administration of corticosteroids should be minimized to the extent clinically feasible.

Adjuvant treatment with Artezo + Tyra is started within 14 to 60 days after surgery or 7 to 42 days after the last PORT treatment. If adjuvant chemotherapy is required, start treatment within 28-72 days of surgery and then PORT (if selected) within 21-60 days of adjuvant chemotherapy. During postoperative adjuvant treatment, infusions are administered in the following order (one regimen per patient). The choice of cohort A (PD-L1 high) regimen is at the discretion of the investigator for each patient.

Cohort A (PD-L1 high): Investigators will receive one of the regimens listed below.

- (1) atezolizumab, (2) tiragolumab

- (1) paclitaxel, (2) carboplatin

- (1) pemetrexed, (2) (carboplatin or cisplatin)

- (1) gemcitabine, (2) (carboplatin or cisplatin)

Cohort B (PD-L1 all entrants): (1) atezolizumab, (2) tiragolumab

Atezolizumab and Tiragolumab

Atezolizumab is administered as an IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. Atezolizumab dose is fixed and does not vary with body weight. No dose reduction is permitted.

Following the atezolizumab administration and observation period, patients receive 600 mg of tyragolumab administered as an IV infusion on Day 1 of each 21-day cycle. The tiragolumab dose is fixed and does not vary with body weight. No dose reduction is permitted.

Administration of study therapeutics is performed in a monitoring environment with immediate access to trained staff and appropriate equipment and medications to manage potentially severe reactions. Atezolizumab and tiragolumab injections

Administer according to the guidelines summarized in Table 58.

IRR = infusion-related reactions

Delayed dosing of atezolizumab and tiragolumab

The following rules apply unless atezolizumab or tiragolumab is permanently discontinued:

치료 사이클은 각 21일 주기의 제 1일차에 아테졸리주맙 및 티라골루맙 투약으로 시작한다. 관련 독성으로 인해 연구 약물 중 하나가 지연되는 경우, 아테졸리주맙과 티라골루맙의 안전성 프로파일이 유사하므로, 다른 연구 약물도 지연되는 것이 좋다.

Treatment cycles begin with atezolizumab and tiragolumab dosing on Day 1 of each 21-day cycle. If one of the study drugs is delayed due to associated toxicity, it is recommended that the other study drug be delayed because the safety profiles of atezolizumab and tiragolumab are similar.

약물 관련 독성으로 인해 한 연구 약물의 투여가 지연되는 반면 다른 연구 약물은 계획대로 투여되는 경우, 지연되는 연구 약물은 다음 예정된 주입시 (즉, 다음 예정된 21일 주기)에 투여하는 것이 권장된다.

If administration of one study drug is delayed due to drug-related toxicity while the other study drug is administered as scheduled, it is recommended that the delayed study drug be administered at the next scheduled infusion (i.e., the next scheduled 21-day cycle).

chemotherapy

Agencies must adhere to the information below and local prescribing information. In general, institutions should also follow institutional and regional SOCs to determine dose adjustments in case of changes in patient weight. If a treatment cycle is delayed or interrupted due to toxicity arising from one of the components of the chemotherapy, both components of the chemotherapy should be maintained and, if resumed, both should be resumed to maintain synchronization.

paclitaxel

Patients of Asian ethnicity/ethnicity receive a lower starting dose of paclitaxel at 175 mg/m ² IV over 3 hours. An independent data monitoring committee's safety review of the IMpower150 and IMpower131 studies observed that lower starting doses of paclitaxel in patients of Asian ethnicity/ethnicity reduced the overall incidence of hematological toxicity in patients from Asian countries compared to patients from non-Asian countries. based on higher The term "Asian race/ethnicity" refers to a pan-ethnic/ethnic group comprising a diverse population of ancestral origin or residing in East Asia, Southeast Asia or South Asia. The application of this term to a particular patient is at the discretion of the treating investigator and should be based on the patient's clinical characteristics and country of origin.

Paclitaxel injections should be diluted prior to infusion. Paclitaxel, 0.9% sodium chloride USP; 5% Glucose Injection, USP; 5% Glucose and 0.9% Sodium Chloride Injection, USP; Alternatively, it should be diluted in 5% glucose in Ringer's injection to a final concentration of 0.3 to 1.2 mg/mL. The injection site should be closely monitored for possible infiltration during drug administration.

Contact of undiluted concentrates with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for injection is not recommended. Paclitaxel should be administered through an in-line filter with a microporous membrane of 0.22 m or less. The use of filter devices such as IVEX-2® filters incorporating short inlet and outlet PVC tubing did not result in significant leaching of bis(2-ethylhexyl)phthalate.

Institutions should follow their SOC guidelines to determine paclitaxel dose adjustments for changes in patient body weight. For paclitaxel infusions, an exception to the 3 hour infusion time is permitted for institutions with institutional policies to inject paclitaxel either faster (>90 minutes) or slower (up to 4 hours for the first infusion).

Pemetrexed

Institutions should follow standard dosing procedures for pemetrexed. Pemetrexed should be administered as an IV infusion over at least 10 minutes. Pre-dosage doses administered should be in accordance with the prescribing information. All patients eligible for pemetrexed therapy should avoid taking nonsteroidal anti-inflammatory drugs with long drug elimination half-lives for at least 5 days before, on the same day, and for at least 2 days after administration of pemetrexed.

Gemcitabine

Gemcitabine should be administered as an IV infusion 30 minutes prior to administration of carboplatin or cisplatin. It should be noted that the dose of gemcitabine was different when administered before carboplatin and before cisplatin (Table 57). Gemcitabine should be diluted prior to infusion. of gemcitabine

The recommended diluent for reconstitution is Preservative-Free 0.9% Sodium Chloride Injection, USP. Administration of gemcitabine should be done in accordance with local practice and prescribing information.

carboplatin

Carboplatin should be administered as an IV infusion over 15-30 minutes immediately after completion of dosing with paclitaxel or pemetrexed to achieve an initial target area of 6 mg/mL/min (Calbert's official dose) on the concentration-time curve (AUC). and use standard antiemetics according to local practice guidelines.

The carboplatin dose of AUC 6 mg/mL/min is calculated using the Calvert formula

(Calvert et al., J Clin Oncol , 7: 1748-1756, 1989):

Total dose (mg) = (target AUC) (glomerular filtration rate [GFR]+25)

The GFR used in the Calvert formula to calculate the AUC-based dose is

It should not exceed 125 mL/min. For the purposes of this study, the GFR was considered equivalent to creatinine clearance (CrCl). CrCl according to institutional guidelines or

It is calculated using the method of Cockcroft and Gault ( Nephron , 16: Nephron, 16: 31-41, (1976)) using the following formula.

CrCl = ((140 - age) (wt) / (72 x Scr)) 0.85 for women

where: CrCl = creatinine clearance (mL/min); age = patient's age in years; wt = patient's weight (kg);

Scr = serum creatinine (mg/dL)

For patients with abnormally low serum creatinine levels, the GFR was estimated using a minimum creatinine level of 0.8 mg/dL, or the upper limit of the estimated GFR was limited to 125 mL/min. If a patient's GFR is estimated based on serum creatinine measurements by isotopic dilution mass spectrometry, FDA recommends that physicians consider limiting the dose of carboplatin for the desired exposure (AUC) to avoid potential toxicity from overdose. Recommended. Based on the Calvert formula listed on the carboplatin label, the maximum dose can be calculated as follows:

min/mL) (GFR x 25 mL/min)Maximum carboplatin dose (mg) = target AUC (mg)

min/mL) (GFR x 25 mL/min)

This maximum dose is based on an estimate of GFR with an upper limit of 125 mL/min in patients with normal renal function. GFR estimates higher than this are not used. For a target AUC = 6, the maximum dose is 6 x (125 + 25) = 900 mg. For a target AUC = 5, the maximum dose is 5x (125 + 25) = 750 mg. For a target AUC = 4, the maximum dose is 4 x (125 + 25) = 600 mg.

cisplatin

Cisplatin is administered as an IV infusion at a dose of 75 mg/m² over 1-2 hours approximately 30 minutes after completion of the pemetrexed or gemcitabine infusion or depending on the SOC of the institution. Patients should receive adequate antiemetic treatment and adequate hydration before and after cisplatin administration.

E. surgical treatment plan

A attending thoracic surgeon with experience with early-stage resectable NSCLC will evaluate the patient during screening to determine surgical suitability and eligibility for surgical resection. Patients must be eligible for an intended R0 resection at the time of screening treatment. The intent to downstage a patient to be able to operate is not permitted.

In screening treatment, patients should confirm their suitability for surgery based on pulmonary function tests (PFT) as described in the selection criteria. ppoFEV ₁ and ppoDL _CO are calculated using the following methodology (Brunelli et al., Chest , 143(5 Suppl): e166S-e190S, 2013):

Perfusion method (if lung ventilation/perfusion scan (VQ scan) is performed:

ppoFEV ₁ or ppoDL _CO = preoperative FEV ₁ or DL _CO x (1 -x)

where: x fraction of total perfusion for lungs

Anatomical method:

ppoFEV ₁ or ppoDL _CO = preoperative FEV ₁ or DLCO _CO x (1 -(y/z))

where: y = functional or undisturbed lung segment to be removed; z = 19, total number of functional lung segments.

The total number of functional lung segments 19 is

It appears as 10 segments in the right lung (3 in the upper lobe, 2 in the middle, 5 in the lower lobe) and 9 segments in the left lung (5 in the upper lobe, 4 in the lower lobe).

Patients are reevaluated by the attending surgeon and oncologist after completion of neoadjuvant treatment and prior to surgery. Preoperative assessments, including but not limited to blood tests, coagulation, cardiac tests or PFTs (if necessary), anesthesia assessments, and other assessment procedures should be performed in accordance with the local SOC.

Surgical procedures should be performed as far as possible within 30 days of the preoperative visit. If surgery cannot be performed within this period (eg due to long-term adverse events), medical personnel should be consulted. If surgery is planned more than 30 days after the preoperative visit, a CT scan must be retaken before the planned surgery.

Resection should be performed through an open or minimally invasive procedure (eg, thoracotomy, sternotomy, clamshell or semi-clamshell incision, video-assisted thoracic surgery [VATS], or robot-assisted VATS).

Pathological complete resection (R0) of the primary tumor and associated lymph nodes should be performed. Anatomical resection through segmental resection, lobectomy, double lobectomy, or pneumonectomy is required. All resections should include segmentation of all anatomical structures (eg arteries, bronchi, veins). Wedge resection is not permitted. Deep wedge resections involving segments that do not provide the aforementioned anatomical details (eg, apical or superior segmental wedge resections) are not considered segmental resections.

Hilar and mediastinal lymph node dissection or sampling is mandatory. For right resection, at least 4R, 7, 10R and 11R level lymph nodes are included.

It is recommended to include level 2R nodes. For left resection, at least 5/6, 7, 10L and 11L level lymph nodes are included. Lower lobectomy with level 8 or 9 is recommended.

F. Radiation therapy after surgery

Postoperative radiation therapy (PORT) is permitted in patients with confirmed pathological N2+ disease (ypN2) or benign tumor margin (R1 or R2) at the time of surgical resection, prior to adjuvant atezo plus tyra therapy or adjuvant platinum-based chemotherapy. It should be administered after therapy.

At a fraction of 1.8 to 2 Gy, conformal three-dimensional or intensity-modulated radiation therapy for a recommended dose of 50 to 66 gray (Gy) should be administered in accordance with institutional and/or international guidelines. Strongly recommended constraints include an average lung dose ≤20 Gy and V20 (percentage of lung volume receiving radiation dose greater than 20 Gy) not to exceed 31% after lobectomy, with an average lung dose after lobectomy of 8 Gy and V20 ≤5% is included

G. Combination therapy:

Combination therapy consists of all drugs used by the patient (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) in addition to protocol-essential treatment from 7 days prior to study drug initiation until the treatment discontinuation visit.

accepted therapy

Patients are allowed to use the following regimens during the study period:

Oral contraceptives with an annual failure rate of <1%.

hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (eg, stable doses of warfarin or low molecular weight heparin).

Inactivated influenza vaccination.

Megestrol acetate administered as an appetite stimulant.

Mineralocorticoids, such as fludrocortisone.

Corticosteroids administered for COPD or asthma.

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency.

Premedication with antihistamines, antipyretics and/or analgesics may be administered only for secondary and subsequent infusions of atezolizumab at the discretion of the investigator.

In general, investigators should manage the patient's treatment (including pre-existing conditions) with adjuvant therapies other than those defined as clinically indicated cautions or contraindications according to local standard practice.

Patients experiencing infusion-related symptoms may be treated with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice, depending on the symptoms. have. Severe infusion-related events indicated by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation, or dyspnea are supported by supportive care (e.g., supplemental oxygen and β2-adrenergic agonists) as clinically indicated. should be managed as

Caution for patients treated with atezolizumab and tiragolumab

Corticosteroids and TNF-α inhibitors

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of atezolizumab treatment. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines should be considered. If no alternative is possible, systemic corticosteroids and TNF-α inhibitors may be administered at the investigator's discretion.

Systemic corticosteroids are recommended at the discretion of the investigator for the treatment of certain adverse events associated with atezolizumab and/or tiragolumab therapy.

forbidden therapy

The use of the following combination therapies is contraindicated as follows:

-Combination therapy (including, but not limited to, chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy) for the treatment of cancer, whether approved by health authorities or experimental, is And during study treatment, it is prohibited until disease progression is documented and the patient discontinues study treatment.

Investigation therapy within 42 days prior to initiation of study treatment and during study treatment.

- Live attenuated vaccines (eg, FLUMIST) are contraindicated within 4 weeks prior to the start of study treatment, during study treatment, for 90 days after the last dose of tiragolumab and for 5 months after the last dose of atezolizumab. Chemotherapy (i.e., carboplatin, cisplatin,

Vaccines. Patients being treated with pemetrexed, paclitaxel or gemcitabine) should not receive live vaccines.

-Systemic immunostimulants (including but not limited to interferon and IL-2) are contraindicated within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment, whichever is longer This is because co-administration with zolizumab and tiragolumab may potentially increase the risk of autoimmune diseases.

-Systemic immunosuppressants (including, but not limited to, cyclophosphamide, azathioprine, methotrexate and thalidomide) during study treatment are contraindicated because these agents may potentially alter the efficacy and safety of study treatment.

H. study evaluation

Patients are closely monitored for safety and tolerability throughout the study. Patients should be evaluated for toxicity prior to each dose; Administration is permitted only when clinical evaluation and local laboratory test values are acceptable.

All treatment visits must occur ±3 days after the scheduled date, unless otherwise specified. Unless a time period is specified, all assessments must be performed on the day of the designated visit. Patients should be evaluated for toxicity prior to each dose; Administration is permitted only when clinical evaluation and local laboratory test values are acceptable. Unless otherwise specified, assessments scheduled on the day of study treatment administration should be performed prior to dosing.

The following assessments may be performed 4 days before Day 1 of each cycle:

limited physical examination

- Local laboratory testing

With the exception of tumor assessments, screening treatment evaluations performed ≤4 days prior to Day 1 of Cycle 1 do not need to be repeated on Day 1 of Cycle 1.

If a scheduled dosing is not possible due to a holiday, weekend or other event, dosing may be postponed to the next earliest date, and subsequent dosing will continue according to the 21-day schedule. If treatment is delayed by less than 3 days, the patient may resume the original schedule.

I. Tumor response and disease status follow-up evaluation

After surgery and during the adjuvant treatment phase, all patients (both cohorts) were followed up for disease status by chest CT with IV contrast medium (including liver and adrenal glands) every 4 months from the date of surgery for 1 year and every 6 months for the 2nd year. get evaluated If CT scans with contrast media are contraindicated (eg patients with impaired renal clearance), a non-contrast CT scan of the chest may be performed. Patients who have not experienced a recurrence of the disease

Follow-up of disease status every 6 months by chest CT scan with IV contrast medium (including liver and adrenal) for 3-5 years after surgery.

Disease status follow-up assessments must be made within the permitted period of scheduled follow-up assessments. Disease status follow-up assessments must be made within the permitted period of scheduled follow-up assessments. The allowable period for disease status follow-up evaluation is ±7 days in Year 1, ±14 days in Years 2-3, and ±4 weeks thereafter.

Postoperative disease recurrence should be confirmed by pathological and/or clear radiological evidence. If the scan reveals equivocal findings (eg, mediastinal nodule measurements < 1.5 cm for short axis, lung parenchymal lesions or visceral lesion measurements < 1 cm for longest diameter), a biopsy should be performed. If a biopsy is not possible or unsafe, a confirmatory scan should be performed again within 4 to 8 weeks. If a confirmatory scan confirms disease recurrence, the event should be documented on the date of the previous confirmatory scan that marked an ambiguous event.

A biopsy should be performed prior to initiating the next chemotherapy. If the biopsy does not show evidence of disease recurrence (eg, non-malignant infiltrates), the patient may continue with the scheduled study treatment, evaluation, and/or follow-up.

Tumor or disease status follow-up evaluation should be continued for patients with early discontinuation of treatment for reasons other than disease progression or recurrence (eg, due to toxicity). In the absence of disease progression or recurrence, tumor or disease status follow-up assessment for all patients, whether starting new chemotherapy or not, disease progression or recurrence, withdrawal of consent, death, loss of follow-up, termination of study by sponsor This should continue until either one of them occurs.

J. study treatment discontinuation

Patients should permanently discontinue study treatment if they experience any of the following:

Unacceptable toxicity associated with atezolizumab and tiragolumab, including the occurrence of immune-related adverse events determined by the investigator to be unacceptable given the severity of the condition and the potential response to treatment of the individual patient. Chemotherapy may be continued if atezolizumab and tiragolumab are discontinued during the neoadjuvant treatment phase.

-Unacceptable toxicity associated with other components of the study treatment. During the neoadjuvant treatment phase, atezo should be continued even if some or all chemotherapeutic agents have been discontinued due to chemotherapy-related toxicity.

- Any medical condition that could endanger the patient's safety if the patient continued study treatment.

- Determination of the Investigator or Sponsor that discontinuation of treatment is in the patient's best interest.

- Use of another non-protocol directed anticancer therapy.

-Pregnant.

-Clear radiological disease progression according to RECIST v1.1 during the neoadjuvant treatment phase.

Pathologically confirmed or unequivocal radiological evidence of disease recurrence during the adjuvant treatment phase.

Patients who have received at least 2 cycles of neoadjuvant therapy and who have prematurely discontinued study treatment will not be replaced. Patients who received less than 2 cycles of neoadjuvant therapy may be replaced if the reason for early discontinuation of treatment is not of special interest or an adverse reaction to disease progression.

Patients who discontinue non-adjuvant study treatment prior to receiving 4 cycles (e.g., due to treatment intolerance or lack of response) are treated for surgical resection or non-surgical standard of care treatment (if surgery is not compliant). It is evaluated by a specialist and the attending surgeon. Patients undergoing planned protocol-directed surgery remain eligible for all postoperative study treatments and procedures.

Patients return to the clinic for a treatment discontinuation visit no later than 30 days after the last dose of study treatment. A visit where the disease assessment indicates progressive disease or confirms disease recurrence may be used as a treatment discontinuation visit. Patients who discontinue study treatment for reasons other than progressive disease or recurrence continue to undergo tumor or disease status assessment.

Example 11. Safety Assessment for the GO42501 Study

A. safety plan

The safety plan for patients in this study included the expected mechanism of action, results from nonclinical studies, published data for similar molecules, clinical experience with tiragolumab alone and atezolizumab in phase 1 and 2 studies, and ate It is based on the clinical safety profile of Zolizumab.

Measures are taken to ensure the safety of patients participating in this study, including using strict selection and exclusion criteria and closely monitoring patients during the study period. Administration of atezolizumab and durvalumab is performed in a monitoring environment with immediate access to trained personnel and appropriate equipment and medications to manage potentially severe reactions.

B. Adverse Event Management

capacity modification

There were no dose changes, including dose reductions, for atezolizumab or tiragolumab in this study.

cessation of treatment

Study treatment may be temporarily discontinued if appropriate for toxicity management. Based on the available characterization of the mechanism of action, tiragolumab may induce adverse events similar to but independent of atezolizumab and may exacerbate the frequency or severity of atezolizumab-related adverse events, or overlap with atezolizumab. may have non-toxic properties. Because these scenarios may not be distinct from each other in the clinical setting, immune-mediated adverse events should generally be attributable to both study drugs, and dosing or discontinuation of treatment for immune-mediated adverse events should be attributed to atezolizumab and tyragol It should be applied to lumab.

In the adjuvant setting, atezolizumab and tiragolumab may be maintained for up to 12 weeks. If tiragolumab is discontinued for any reason >12 weeks, the patient must permanently discontinue tiragolumab treatment, but if there are no contraindications and if toxicity is considered to be related to tiragolumab and/or combination Zumab can be continued. Exceptions may be made if the investigator determines that the patient is likely to obtain clinical benefit by resuming tiragolumab after a hold of >12 weeks. If atezolizumab is discontinued for >12 weeks, the patient must permanently discontinue atezolizumab. However, atezolizumab may be resumed if, in the investigator's judgment, the patient is likely to obtain clinical benefit from atezolizumab after a hold of >12 weeks.

However, atezolizumab may be resumed if, in the investigator's judgment, the patient is likely to obtain clinical benefit from atezolizumab after a hold of >12 weeks. To continue administering single agent atezolizumab to a patient, all other study eligibility criteria must continue to be met.

Permanent discontinuation of atezolizumab and continued administration of single agent tiragolumab

Not permitted.

If the patient needs to reduce the steroid used to treat the adverse event, atezolizumab and/or tiragolumab until the steroid is discontinued or the steroid is reduced to a prednisone dose ≥10 mg/day (or equivalent dose) may be withheld for ≥12 weeks or more additional time from the last dose, and tiragolumab may be withheld for >12 weeks or more additional time from the last dose. Discontinuation of dosing may be tolerated for reasons other than toxicity(s). After both study treatments are discontinued, patients are monitored for safety and efficacy. After both study treatments are discontinued, patients are monitored for safety and efficacy.

C. Safety parameters and definitions

Safety assessments monitor and document adverse events, including serious adverse events and adverse events of particular interest, perform protocol-specific safety laboratory assessments, measure protocol-specific vital signs, and evaluate the safety of the study. Other protocol-specific tests were included.

adverse reaction

According to the ICH guidelines for clinical trial practices for pharmaceuticals, an adverse event is any adverse medical occurrence in a clinically investigated subject administered a pharmaceutical product, regardless of causal attribution. Adverse events, for this reason, may be any of the following:

-Any adverse and unintended sign (including abnormal laboratory results), symptom or disease temporarily associated with the use of a drug, whether or not considered to be drug-related;

-Any new disease or exacerbation of an existing disease (exacerbates in the nature, frequency, or severity of a known disorder)

-recurrence of an intermittent medical condition (e.g., headache) that was not present at baseline

-Any exacerbation in laboratory values or other clinical trials (e.g. ECG, X-ray) that is associated with symptoms or that results in a change in study treatment or concomitant treatment or discontinuation from study treatment

- adverse events related to protocol-forced interventions (eg, screening invasive procedures such as biopsies), including those that occurred prior to assignment of study treatment

serious adverse reactions

A serious adverse event is any adverse event that meets one of the following criteria:

- (i.e., the adverse event actually causes or causes death).

- life-threatening (ie, from the investigator's point of view, an adverse event puts the patient at risk of immediate death); This does not include adverse events that have occurred in a more serious form or could result in death if allowed to continue.

-The patient's hospitalization is necessary or prolonged.

-results in persistent or severe disability/incapacity (ie, the adverse effect substantially interrupts the patient's ability to perform normal life functions).

-Congenital malformations/birth defects in newborns/infants born to mothers exposed to study treatment.

- a serious medical event at the discretion of the investigator (e.g. may put the patient at risk or may require medical/surgical intervention to prevent one of the outcomes listed above);

The terms “severe” and “severe” are not synonymous. Severity indicates the strength of an adverse event (e.g., rated as mild, moderate or severe, or assessed according to the NCI CTCAE): the response itself may be of relatively mild medical significance (e.g., severe headache with no further findings).

Adverse reactions of particular interest

Adverse events of specific interest in this study were:

-Potential drug-induced liver injury events, including elevated ALT or AST with elevated bilirubin or clinical jaundice, as defined by Hy's Law.

- Suspected transmission of an infectious agent by the study treatment as defined below:

Any organism, virus, or infectious particle, whether pathogenic or non-pathogenic (eg, a prion protein that transmits infectious spongiform encephalopathy), is considered an infectious agent. Transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings indicative of infection in a patient exposed to the drug. This term applies only when contamination of the study product is suspected.

-Pneumonia.

-colitis.

-Endocrinopathy: diabetes, pancreatitis, adrenal insufficiency, hyperthyroidism and pituitary insufficiency.

-Hepatitis including AST or ALT 10 ULN.

-Systemic lupus erythematosus.

- Neurological disorders. Guillain-Barré syndrome, myasthenia gravis or myasthenia gravis, meningoencephalitis.

-Reactions suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, hemophagocytic lymphohistiocytosis and macrophage activation syndrome.

-nephritis.

-ocular toxicity (eg uveitis, retinitis, optic neuritis).

- Myositis.

-myopathy, including rhabdomyolysis.

-2 grade heart disorders (eg, atrial fibrillation, myocarditis, pericarditis).

- Vasculitis.

- Autoimmune hemolytic anemia.

-Severe skin reactions (eg Stevens-Johnson syndrome, bullous dermatitis, toxic epidermal necrosis).

Assess the severity of adverse events

The Adverse Event Severity Rating Scale for NCI CTCAE (v5.0) is used to assess adverse event severity. When reporting the severity of CRS, the American Society for Transplantation and Cellular Therapy (ASTCT) CRS consensus rating scale with NCI CTCAE v5.0 should be used.

Example 12. Statistical Considerations and Analysis Plan for the GO42501 Study

Efficacy and safety analyzes are performed for all patients enrolled in the GO42501 study who received at least one dose of study drug for each cohort.

Determining sample size

The primary efficacy objective of this study was to evaluate the rate of major pathologic response (MPR). Approximately 41 patients are enrolled in each cohort of the study. Approximately 41 patients are enrolled in each cohort of the study.

Assuming 61%, this sample size provides adequate precision in estimating the point for the MPR rate for each cohort where the lower bound of the two-sided 95% CI is greater than 46%, which in this setting is a factor for further investigation into combination therapy. to guarantee .

Summary of Study Conduct

The number of patients who enrolled, discontinued, or completed the study is summarized. Reasons for early study withdrawal are listed and summarized. Enrollment and major protocol deviations are listed for each treatment cohort.

A. Summary of Demographic and Baseline Characteristics

Demographic information such as age and race is tabulated. Descriptive statistics are provided, including mean, standard deviation, range for continuous parameters, percentages and frequencies for categorical parameters. A summary of the total population and each treatment cohort is presented. Baseline measures, unless otherwise specified, are the last available data obtained before the patient received the first dose of the study drug component.

B. Safety analysis

For each cohort, the safety analysis included all enrolled patients who received at least one dose of study treatment.

Study treatment exposures are summarized including treatment duration, dosage, and dosing intensity.

The incidence and duration of surgical delay, the incidence of surgery and postoperative complications, and/or the number of surgical cancellations associated with study treatment are assessed for each cohort.

Verbose descriptions of adverse events follow MedDRA Thesaurus Terminology. The severity of all adverse events is rated by the investigator according to the NCI CTCAE v5.0, and the severity for CRS is graded by the investigator according to the ASTCT consensus rating scale. This summary is provided in the Therapeutic section. All adverse events are summarized by treatment arm and NCI CTCAE grade. CRS is also summarized by treatment arm and ASTCT consensus grade. In addition, with respect to the study treatment, treatment-occurring adverse events, severe (i.e., Grade 3 adverse events), fatal (i.e., Grade 5), and serious adverse events resulting in cancellation of study treatment leading to dose reduction or discontinuation, Adverse events of particular interest are also summarized. Multiple occurrences of the same reaction are counted once at maximum severity. Laboratory data with values outside the normal range are identified. In addition, selected laboratory data, including changes in ADA outcomes and vital signs, are summarized by treatment arm. Deaths and causes of death are summarized.

C. Validity analysis

The efficacy analysis population included all enrolled patients who received at least one dose of study treatment.

Primary efficacy endpoint

The MPR rate is defined as the proportion of patients who achieved MPR and is estimated for each treatment cohort in the efficacy analysis population. MPR is defined as ≤10% viable tumors at the time of surgical resection of primary tumors evaluated by the Central Pathology Laboratory. Patients not undergoing surgery are considered non-responders to MPR. A two-sided 95% CI for the MPR ratio calculated using the Clopper-Pearson method is reported.

secondary efficacy endpoint

The pathological complete response (pCR) rate is defined as the proportion of patients who achieved pCR. pCR is defined as the absence of viable primary tumors at the time of surgical resection, as assessed by the Central Pathology Laboratory. The pCR ratios are analyzed using the same statistical methods as the MPR ratios for each treatment cohort for the efficacy analysis population.

Event-free survival (EFS) is defined as the time from the first administration of study drug to the first of the following events: inoperable disease progression, as assessed by the investigator according to RECIST v1.1; local or distant disease recurrence (including the occurrence of new primary NSCLC); or death from any cause. Patients who have not experienced inoperable disease progression, local or distant disease recurrence, or who died at the time of analysis

Censored and deleted at the time of the last tumor or disease follow-up assessment. Patients with no post-baseline tumor assessment will be screened and deleted on the first dose of study drug. EFS is assessed using the Kaplan-Meier method for each treatment cohort for the efficacy analysis population.

D. Pharmacokinetic analysis

Samples are collected for pharmacokinetic analysis and to compare the performance of this study with those obtained in previous studies. Serum concentrations of atezolizumab and tiragolumab are reported as individual values and, where appropriate, summarized by cohort and period as data permits (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean coefficient of variation) do.

Individual and median serum concentrations of atezolizumab and tiragolumab are summarized by cohort and by day. Atezolizumab and tiragolumab concentration data can be combined with data from other studies using established population PK models to derive PK parameters - such as clearance, volume of distribution and AUC, as warranted by the data. have. Potential correlations between relevant PK parameters and safety, efficacy, or biomarker outcomes can be investigated.

E. Immunogenicity assay

Immunogenicity assays include patients who have undergone an antidrug antibody (ADA) assessment, and patients are classified according to the treatment they receive. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients for both atezolizumab and tiragolumab are summarized by cohort. The relationship between ADA status and safety, efficacy, and PK endpoints can be analyzed and reported through descriptive statistics.

F. Biomarker analysis

Exploratory biomarker analysis is performed to explore the relationship between several pathological, immunological and genomic characteristics of cancer and the clinical outcome of these patients. Such assays include, but are not limited to, characterization of immune cells and ctDNA in and/or in the tumor microenvironment. Clinical efficacy outcomes, including MPR, pCR, and EFS, are analyzed in biomarker subgroups (eg, based on PD-L1 and TIGIT status) to evaluate treatment benefit, if possible.

Example 13. Efficacy of anti-TIGIT antagonist antibody in combination with PD-1 axis binding antagonist for cervical cancer patients

For patients with metastatic and/or recurrent PD-L1-positive (tumor cells and tumor-associated immune cells [TICs] ≥5%) cervical cancer following progression or relapse on at least one but no more than two platinum-based systemic therapies An anti TIGIT antagonist (e.g., an anti-TIGIT antibody disclosed herein, e.g., Tyra in combination with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) Efficacy and safety of treatment with gorumab) and with atezolizumab monotherapy are evaluated. You must have PD-L1-positive cervical cancer.

The clinical trial consisted of a single phase, as detailed below and shown in FIG. 21 .

randomization

In this study, approximately 160 patients were enrolled and assigned to one of two treatment arms: tiragolumab in combination with atezolizumab or atezolizumab monotherapy. Randomization occurs in a 3:1 ratio using a permutation block randomization method to ensure a balanced assignment to each treatment arm. Randomization is stratified according to ECOG performance status (0 versus 1), previous use of chemoradiation or radiotherapy (yes versus no), and treatment history (persistent versus recurrent disease).

eligibility

This study enrolled female patients with a minimum age of 18 years according to the following inclusion criteria:

- Histologically confirmed recurrent or persistent squamous cell carcinoma, adenosquamous cell carcinoma, or uterine after 1 or 2 lines of previous systemic chemotherapy incapable of curative treatment with systemic chemotherapy, surgery, and/or radiation therapy Adenocarcinoma of the neck (neuroendocrine system, clear cell, sarcoma histology not allowed).

At least one previous line of platinum-based systemic chemotherapy. Radiation-sensitive cisplatin given with radiation therapy is not considered a class of systemic chemotherapy.

- Radiologically measurable disease

- Eastern Oncology Collaborative Group (ECOG) performance status of 0 or 1

- Cervical cancer tissue (archived or fresh biopsy specimens) for research analysis

- Life expectancy of ≥ 12 weeks

- Proper blood and organ function

- Women of childbearing age should be willing to adhere to appropriate contraceptive practices.

Patients are excluded from enrollment based on the following criteria:

- Treatment with an intended clinical trial regimen within 28 days prior to randomization and during study treatment

- Any central nervous system (CNS) or brain metastases

- active or history of autoimmune disease or immunodeficiency

- active tuberculosis;

- Known clinically significant liver disease

- Severe infection according to the investigator's judgment at randomization

- Prior treatment with CD137 agonists or immune checkpoint blockade therapy, anti-CTLA-4, anti-TIGIT, anti-PD-1 and anti-PD-L1 therapeutic antibodies

- Treatment with systemic immunostimulants within 4 weeks prior to randomization or within 5 drug elimination half-lives (whichever is longer)

- Treatment with systemic immunosuppressants within 1 week prior to randomization or if the need for systemic immunosuppressants is expected during the study

- Pregnant or breastfeeding women.

- Known hypersensitivity to any component of the formulation of tiragolumab or atezolizumab

A. Study Treatment Dosage and Administration

During the treatment period, patients receive a fixed dose of atezolizumab 1200 mg or a fixed dose of atezolizumab 1200 mg and a fixed dose of tiragoluumab 600 mg. Atezolizumab is administered as a fixed dose of 1200 mg Q3W (1200 mg on Day 1 of each 21-day cycle). Tiragolumab in combination with atezolizumab is administered IV Q3W on Day 1 of each 21-day cycle at a fixed dose of 600 mg to all patients in the experimental group.

In an alternative trial, on the day of dosing, atezolizumab is administered as monotherapy according to the guidelines summarized in Table 59. Prior to the first infusion, the patient's vital signs (e.g., pulse rate, respiration rate, blood pressure, body temperature) are recorded within 60 minutes prior to initiation of the infusion. The first infusion of atezolizumab is administered over 60 (± 15) minutes, and the patient's vital signs are recorded every 15 (± 5) minutes during the infusion and 30 (10) minutes after the infusion. Subsequent infusions may be administered over 30 minutes (±10) minutes if no infusion-related adverse events occurred during the first infusion. Pre-infusion recordings of vital signs continued to be recorded within 60 minutes prior to initiation of atezolizumab infusion.

Prior to the first infusion, the patient's vital signs (e.g., pulse rate, respiration rate, blood pressure, body temperature) are recorded within 60 minutes prior to initiation of the infusion. Prior to the first infusion, the patient's vital signs (e.g., pulse rate, respiration rate, blood pressure, body temperature) are recorded within 60 minutes prior to initiation of the infusion. The first infusion of atezolizumab is administered over 60 (±15) minutes, and the patient's vital signs are recorded every 15 (±5) minutes during the infusion and 30 (±10) minutes after the infusion. The first infusion of an anti-TIGIT antibody (eg, an anti-TIGIT antibody disclosed herein, eg, tiragolumab) is administered over 60 (±10) minutes while the patient's vital signs are 15 (±5) during the infusion. ) minutes and 30 (±10) minutes after injection. Subsequent infusions may be administered over 30 minutes (±10) minutes if no infusion-related adverse events occurred during the first infusion. Pre-infusion recordings of vital signs continued to be recorded within 60 minutes prior to initiation of atezolizumab infusion.

After an integrated evaluation of radiographic data, biopsy results, and clinical status, treatment can be continued as long as patients experience clinical benefit without unacceptable toxicity or worsening of symptoms due to disease progression. Patients who meet the criteria for ambiguous disease progression according to RECIST v1.1 as determined by the Independent Review Committee (IRC) may continue treatment (tiragolumab plus atezolizumab or atezolizumab alone) if all specified criteria are met. .

B. combination therapy

Certain combination therapies were permitted. Combination therapy includes any medications used by the patient other than protocol-essential study treatment (e.g., oral contraceptives, hormone replacement therapy, prescription drugs, over the counter, vaccines, herbal or homeopathic remedies; nutritional supplements). Patients are permitted to use the following combination therapies for the duration of the study.

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of atezolizumab treatment. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines should be considered. If no alternative is possible, systemic corticosteroids and TNF-α inhibitors may be administered at the discretion of the investigator.

Premedication with antihistamines, antipyretics and/or analgesics may be administered only for secondary and subsequent study infusions at the discretion of the investigator.

C. Efficacy endpoint

To evaluate the effectiveness of tiragolumab plus atezolizumab compared to atezolizumab monotherapy, two consecutive complete responses (CR) or The objective response rate (ORR), defined as the percentage of patients experiencing a partial response (PR), was measured as the primary endpoint. A primary efficacy analysis is performed when all patients are enrolled and a minimum of approximately 6 months of follow-up is achieved among patients remaining on follow-up for ORR evaluation. In the primary analysis, patients who miss an ORR assessment are considered to have failed to achieve a response. A 1-sample z-analysis of ratios is used to compare the ORR of the atezolizumab arm with tiragolumab combination to historical baselines. Estimates of ORR and 95% CI (Clopper-Pearson; Clopper and Pearson 1934) are calculated for each treatment arm. The lower limit of 95% CI of ORR in the combination arm (Table 61) and ORR observed in the monotherapy arm (Table 62) are expected to exclude baseline.

MDO = minimum detectable observation; ORR = overall response rate.

a Resource: Chung et al. 2019.

b MDO is defined as the smallest observed ORR showing statistical significance in the final analysis.

ORR = overall response rate.

The secondary efficacy goals of this study were based on duration of response (DOR), disease control rate (DCR), best clinical response (BCR), progression-free survival (PFS), and overall survival (OS). To evaluate the efficacy of tiragolumab and atezolizumab monotherapy in combination with zolizumab. DOR is the date of disease progression or death from any cause (whichever occurs first) from the first occurrence of a documented objective response (CR or PR) for a patient with an objective response, as determined by the IRC per RECIST v1.1. is defined as the time until the date). DCR is defined as the proportion of patients with CR, PR, or SD as determined by the IRC per RECIST v1.1. BCR is defined as the proportion of patients with CR, PR, or SD, as determined by the investigator. Progression-free survival (PFS) is defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the IRC per RECIST v1.1. OS is defined as the time from randomization to death from any cause.

Additional exploratory efficacy endpoints may additionally include disease control (defined as SD or CR or PR for ≥6 weeks), as determined by the investigator per RECIST v1.1.

To evaluate the safety and tolerability of tiragolumab in combination with atezolizumab compared to atezolizumab alone, the incidence, nature, and severity of adverse events (AEs) (e.g., National Cancer Institute adverse events) (AE CTCAE v5.0) graded according to Common Terminology Criteria Version 5.0 (NCI) for CTCAE (adverse events not specifically listed in NCI CTCAE are measured according to Table 63). The severity of cytokine release syndrome (CRS) is determined according to the American Society for Transplantation Cell Therapy CRS Consensus Rating Scale. In addition, clinically significant changes from baseline in vital signs, physical findings and clinical laboratory results during and after tiragolumab plus atezolizumab compared to atezolizumab alone are also measured from baseline.

^a Instrumental activities of daily life include preparing meals, shopping for groceries or clothes, using the phone, and managing money.

^b Examples of self-management activities of daily living include bathing, dressing and undressing, eating on their own, using the bathroom, and taking medications by a patient not lying in bed.

Result measurement period

The primary outcome measure, the objective response rate (ORR), will be the first occurrence of a documented objective response up to the date of disease progression or the date of all-cause death, whichever occurs first (up to 36 months). The secondary result measurement period can be found in Table 64.

biomarker

For exploratory biomarker evaluation for all patients in this randomized study, patient samples including archival tumor tissue, as well as serum, plasma, whole blood, and feces are collected. In addition to assessing PD-L1 status, biomarkers associated with resistance, disease progression and clinical benefit of tiragolumab and/or atezolizumab are analyzed. For example, potential predictive and prognostic biomarkers related to the clinical benefit and safety of tiragolumab and/or atezolizumab are analyzed.

Whole exome sequencing (WES) and/or next-generation sequencing (NGS) of tumor tissue and blood samples collected at baseline (and tumor tissue collected at the time of disease progression if deemed clinically feasible by the investigator) for study therapeutics that may be predictive of a response, associated with progression to a more severe disease state, associated with acquired resistance to a study treatment, associated with susceptibility to the development of an adverse event, or that may increase knowledge and understanding of disease biology Somatic mutations can be identified.

Biomarkers include, but are not limited to, PD-L1 and/or TIGIT expression on tumor tissue, germline and somatic mutations from circulating tumor DNA in tumor tissue and/or blood, including, but not limited to, mutation load, MSI, and MMR defects. , identification via WGS and/or NGS, genetic analysis (e.g. CD274) or genetic signatures relevant to tumor immunobiology, e.g. T _effector genes, PD-L1, TIGIT, HPV alterations, lymphocyte subpopulations, T cell-receptor repertoire , cytokines involved in T-cell and NK-cell activation, and plasma-derived cytokines.

To evaluate the effect of the PD-L1/PD-1 pathway on ORR, PFS, DOR and/or OS in the primary patient population, tumor tissue for efficacy, safety, PK, immunogenicity and patient-centred outcome (PRO). and/or assess relationships between proteins, RNA, DNA, tumor mutation burden, and other exploratory biomarkers in blood. Further, to evaluate the effect of the TIGIT pathway on ORR, PFS, DOR and/or OS in the primary population, ORR, DOR, PFS in a patient population with TIGIT expression in the tumor, defined as protein and/or RNA expression and OS.

Exploratory biomarker analysis can be performed to understand the association of these markers (eg, TIGIT IHC status) with study treatment efficacy. These efficacy outcomes can be explored in patient populations with high TIGIT expression in their tumors as determined by IHC and/or RNA analysis. Exploratory analysis of WGS data can be performed in connection with this study, which can be explored in conjunction with data from other studies to improve researchers' understanding of disease pathobiology and guide the development of new therapeutic approaches.

Immunogenicity assay

To evaluate the immune response to tiragolumab and atezolizumab, the incidence and potential impact on safety, efficacy, and pharmacokinetics (PK) of treatment-emergent anti-drug antibodies (ADA) are evaluated.

In December 2019, no therapeutic rescue antidrug antibodies (ADA) were detected against tyragolumab in the Phase Ia portion of study GO30103. In the Phase Ib portion of study GO30103, 3 of 154 evaluable patients (1.9%) were positive for treatment-emergent ADA to tiragolumab. In October 2019, 1 in 66 patients (1.5%) evaluated in study GO40290 was positive for treatment-emergent ADA to tiragolumab. In October 2019, 1 out of 66 patients (1.5%) evaluated in study GO40290 were positive for therapeutic emergency ADA to tiragolumab and the patient was positive at only one time point.

F. Pharmacokinetic Analysis

To characterize the pharmacokinetics of tiragolumab when administered in combination with atezolizumab, serum concentrations of tiragolumab are determined from subjects at different time points. In addition, plasma concentrations of atezolizumab are obtained from subjects at different time points during the study to characterize the pharmacokinetics of atezolizumab when administered in combination with tiragolumab or as monotherapy.

Example 14. A Phase Ib, Open Label, Multiple Cohort Study of the Safety, Efficacy and Pharmacokinetics of Tiragolumab in Combination with Atezolizumab and Chemotherapy in Patients with Triple Negative Breast Cancer

This example describes a Phase Ib, open label, multi-cohort study designed to evaluate the safety, efficacy and pharmacokinetics of tiragolumab in combination with atezolizumab and chemotherapy in patients with early triple negative breast cancer (eTNBC). This study consists of the following cohorts:

코호트 B는 수술에 적격한 임상적으로 평가된 T2-4d TNBC를 가진 환자(PD-L1 모든 진입자 집단)를 등록한다. 환자는 다음 두 치료군 중 하나에 1:1 비율로 무작위 배정된다:

Cohort B enrolls patients with clinically assessed T2-4d TNBC eligible for surgery (PD-L1 all entrant population). Patients are randomized in a 1:1 ratio to one of two treatment groups:

- Group A: tiragolumab in combination with atezolizumab, doxorubicin, and cyclophosphamide followed by atezolizumab in combination with tiragolumab, nap-paclitaxel, and carboplatin (tiragolumab and atezolizumab + referred to as nab-pac-carbo-AC)

- Group B: tiragolumab in combination with atezolizumab, followed by doxorubicin and cyclophosphamide, atezolizumab in combination with tiragolumab, nap-paclitaxel (with tiragolumab and atezolizumab + nab-pac-AC) referred to)

Additionally, AC and G-CSF (eg, filgrastim or pegfilgrastim) or GM-CSF are administered to patients in Cohort B as background treatment following nap-paclitaxel.

This study was conducted in patients eligible for surgery with initially clinically evaluated T2-4d TNBC, leading to AC, neoadjuvant tyragolumab in combination with atezolizumab, nap-paclitaxel, and carboplatin or leading to AC , designed to evaluate the safety and tolerability, preliminary efficacy and pharmacokinetics of neoadjuvant tiragolumab and nap-paclitaxel in combination with atezolizumab.

A. study design

This Phase Ib, multi-cohort, open-label, multi-center, global study initially demonstrated that doxorubicin and cyclophosphamide ( The safety and tolerability, preliminary efficacy and pharmacokinetics of neoadjuvant tiragolumab in combination with atezolizumab leading to AC) and carboplatin or neoadjuvant tiragolumab in combination with atezolizumab leading to AC), nap-paclitaxel designed to be investigated. 22 illustrates the study design for Cotote B.

Consent and eligible patients will be randomized in a 1:1 ratio to one of two treatment groups:

A군(최대 약 20명의 환자): 티라골루맙(420 mg) 및 아테졸리주맙(840 mg)이, 4 주기 동안 IV 주입 QW로 투여되는 냅-파클리탁셀(125 mg/m²) 및 IV 주입 Q3W로 투여되는카보플라틴(농도-시간 곡선 아래 영역[AUC]: 5 mg/mL/min])과 병용하여 IV 주입 Q2W로 투여되고, 이어서, 과립구 집락 자극 인자(G-CSF; 예를 들어, 필그라스팀 또는 그필그라스팀) 또는 과립구 대식세포 집락 자극 인자(GM-CSF) 지원과 함께 4회 용량으로 IV 주입 Q2W로 투여되는 독소루비신(60 mg/m²) 및 사이클로포스파미드(600 mg/m²)와 병용되는 티라골루맙(420 mg) 및 아테졸리주맙(840 mg)가 투여된다.

Group A (up to about 20 patients): Nap-paclitaxel (125 mg/m ² ) and IV infusion Q3W administered as tiragolumab (420 mg) and atezolizumab (840 mg) as IV infusion QW for 4 cycles administered as IV infusion Q2W in combination with carboplatin (area under the concentration-time curve [AUC]: 5 mg/mL/min]), followed by granulocyte colony stimulating factor (G-CSF; e.g., Doxorubicin (60 mg/m ² ) and cyclophosphamide (600 mg/m 2 ) administered as IV infusion Q2W in 4 doses with filgrastim or filgrastim) or granulocyte macrophage colony stimulating factor (GM-CSF) support m ² ) in combination with tiragolumab (420 mg) and atezolizumab (840 mg) are administered.

B군(최대 약 20명의 환자): 티라골루맙(420 mg) 및 아테졸리주맙(840 mg)은 12주 동안 IV 주입 QW에 의해 투여되는 냅-파클리탁셀(125 mg/m²)과 병용하여 IV 주입 Q2W에 의해 투여되고, 이어서, 티라골루맙(420 mg) 및 아테졸리주맙(840 mg)이, G-CSF(예: 필그라스팀 또는 페그필그라스팀) 또는 GM-CSF 지원과 함께 4회 용량으로 IV 주입 Q2W로 투여되는독소루비신(60 mg/m²) 및 사이클로포스파미드(600 mg/m²)와 병용하여 투여된다.

Group B (up to about 20 patients): Tiragolumab (420 mg) and atezolizumab (840 mg) were administered IV in combination with nap-paclitaxel (125 mg/m ² ) administered by IV infusion QW for 12 weeks. Administered by infusion Q2W followed by tiragolumab (420 mg) and atezolizumab (840 mg) 4 times with G-CSF (eg filgrastim or pegfilgrastim) or GM-CSF support It is administered in combination with doxorubicin (60 mg/m ² ) and cyclophosphamide (600 mg/m ² ) administered as IV infusion Q2W as a dose.

Exploratory endpoints (pathological complete response (pCR): eradication of invasive tumors of the breast and lymph nodes (ypT0/is ypN0)) are established by local review after completion of neoadjuvant therapy and surgery. Surgery should be performed within 14 days after the last administration of neoadjuvant therapy, and at the latest 6 weeks later. The platelet count should be checked prior to surgery and should be ≥ 75,000 cells/μL.

Postoperative patient management may include radiation therapy as clinically indicated, and management of patients who do not achieve pCR should follow current standard of care guidelines.

It is recommended that patients with clinically benign axillary nodules assessed by physical examination or radiographic imaging at baseline undergo micro-needle aspiration or core-needle biopsy prior to randomization, axillary lymph node dissection (ALND) or minimal surveillance It is recommended that a lymph node biopsy (SLNB) be performed at the final surgery. Results from baseline fine-needle aspiration or core-needle biopsy were used for nodular staging (according to the International Coalition for Control/American Cancer Joint Committee [UICC/AJCC], anatomical staging group according to 8th ed.), so that the biopsy results were Patients who are positive should be staged as lymph node positive (N1-N3c), whereas patients with negative or ambiguous biopsy results should be staged as lymph node negative (N0) regardless of other clinical measurements.

For patients with negative axillary nodules at baseline, clinically or evidenced by micro-needle biopsy or core-needle biopsy, management of axillary surgery after completion of neoadjuvant therapy may include SLNB or ALND. If SLNB is performed, all patients with one or more lymph nodes (at least 2-3) removed and with benign large metastases to the sentinel lymph nodes should receive an ALND, regardless of the number of benign lymph nodes.

Patients receive both clinical and radiation oncology assessments at scheduled intervals during the study.

To evaluate the mechanism of action and possible resistance mechanisms of drug combinations in the tumor microenvironment, tumor tissues can be collected prior to dosing on Day 1 of Cycle 2.

Tumor tissue is collected by biopsy, as assessed and documented by the investigator, and when there is first evidence of disease progression (before starting new chemotherapy), unless clinically feasible. The samples are used to enable analysis of tumor tissue biomarkers related to resistance or disease progression and clinical benefit of tiragolumab in combination with atezolizumab.

B. Dosage and administration

The treatment regimen is summarized in FIG. 22 .

On the scheduled infusion days of atezolizumab, tiragolumab, and chemotherapy, the atezolizumab and tiragolumab infusion are followed by chemotherapy.

After infusion of atezolizumab (840 mg), the patient receives tiragolumab 420 mg.

Administration of atezolizumab, tiragolumab, and chemotherapy is performed in a monitored environment with immediate access to trained personnel and appropriate equipment and medications to manage potentially severe reactions.

Refer to the pharmacy manual for detailed instructions on drug preparation, storage and administration.

Tiragolumab and Atezolizumab

In Cohort B, patients receive a fixed dose of 840 mg of atezolizumab as IV infusion Q2W on days 1 and 15 of each 28-day cycle, after which 420 mg of fixed dose tyragolumab is administered to patients each Administered as IV infusion Q2W on Days 1 and 15 of a 28-day cycle (see Figure 22). Tiragolumab and atezolizumab doses are fixed and do not vary with body weight. Tiragolumab and atezolizumab infusions (including observation period) are administered according to the guidelines summarized in Table 65.

Nap-paclitaxel

Nap-paclitaxel is administered to the patient as an IV infusion over 30 minutes.

Nap-paclitaxel should be administered after atezolizumab and tiragolumab. The dose of nap-paclitaxel is 125 mg/m ² administered to patients by IV infusion QW for 12 weeks. Doses of nap-paclitaxel should not be administered more frequently than every 7 days.

Institutions should follow institutional standards of care to determine dose adjustments of nap-paclitaxel in case of changes in patient weight. The injection site should be closely monitored due to possible infiltration during study drug administration.

For more information on the preparation and administration of nap-paclitaxel, see local prescribing information.

carboplatin

Carboplatin is administered after completion of nab-paclitaxel dosing by short IV infusion over 15-60 minutes with an AUC of 5 mg/mL/min every 3 weeks for 4 doses.

There is no known antidote for carboplatin overdose. If necessary, patients may require bone marrow suppression and supportive care related to renal, hepatic and auditory dysfunction. Doses of up to 1600 mg/m2 have been associated with patients experiencing extreme pain with onset of diarrhea and alopecia. The use of carboplatin in excess of the recommended dose was also associated with vision loss. See your local prescribing information for carboplatin for more information.

cyclophosphamide

Cyclophosphamide should be given as an IV bolus over 3-5 minutes or as an IV infusion according to local state standards. AC should be administered after atezolizumab and tiragolumab. The dose of cyclophosphamide is administered intravenously at 600 mg/m ² . Dose delays and dose reductions for toxicity are acceptable. Cyclophosphamide is administered as Q2W for 4 doses (dose density AC) with G-CSF or GM-CSF support. Note: Oral cyclophosphamide is not allowed.

Prevention and treatment of chemotherapy-induced nausea and vomiting should be administered as clinically indicated. Because systemic corticosteroids may attenuate the potentially beneficial immunological effects of atezolizumab and tiragolumab treatment, alternative agents should be considered when clinically feasible.

Refer to local prescribing information for details regarding the preparation and administration of cyclophosphamide.

doxorubicin

Doxorubicin should be administered as an IV bolus over 3-5 minutes or as an IV infusion over 15-30 minutes, depending on local state standards. AC should be administered after atezolizumab and tiragolumab. The dose of doxorubicin administered to a patient by IV infusion is 60 mg/m ² . Dose delays and reductions for toxicity are acceptable. Doxorubicin is administered as Q2W for 4 doses (dose density AC) with G-CSF or GM-CSF support.

For details on the preparation and administration of doxorubicin, see local prescribing information.

Pre-medication and supportive care

In general, chemotherapy supportive therapy is administered according to the American Society of Clinical Oncology (ASCO), European Organization for Research and Treatment of Cancer (EORTC), or ESMO guidelines or local state standards. should be

Prevention and treatment of chemotherapy-induced nausea and vomiting should be administered as clinically indicated. Because systemic corticosteroids may attenuate the potentially beneficial immunological effects of atezolizumab and tyragolumab treatment, alternative agents should be considered, if clinically feasible, outside the guidelines provided in the protocol.

Prophylactic G-CSF or GM-CSF may be used to mitigate the risk of hematologic toxicity according to local policy and is required during the AC portion of chemotherapy. Treatment of neutropenia with G-CSF or GM-CSF is permitted in accordance with local policy.

capacity change

There were no dose changes for atezolizumab or tiragolumab in this study. See Table 25 for administration of nap-paclitaxel (ie, dose adjustment and treatment discontinuation rules). For guidance on the management of carboplatin, doxorubicin, or cyclophosphamide-related toxicity (i.e., dosing adjustment and treatment discontinuation rules), refer to your local prescribing information for each agent.

C. combination therapy

Combination therapy includes any drugs (eg, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient in addition to protocol essential treatment from 7 days prior to study drug initiation until the treatment discontinuation visit.

accepted therapy

Patients are allowed to use the following regimens during the study period:

연간 실패율이 1% 미만인 경구 피임약

Oral contraceptives with an annual failure rate of less than 1%

호르몬 대체 요법

hormone replacement therapy

예방적 또는 치료적 항응고 요법(예컨대, 안정적인 용량의 와파린 또는 저분자량 헤파린)

Prophylactic or therapeutic anticoagulant therapy (eg, stable doses of warfarin or low molecular weight heparin)

비활성화 인플루엔자 예방 접종

Inactivated influenza vaccination

식욕 자극제로 투여되는 메게스트롤 아세테이트

Megestrol acetate administered as an appetite stimulant

미네랄로코르티코이드(예컨대, 플루드로코르티손)

Mineralocorticoids (such as fludrocortisone)

만성 폐쇄성 폐질환 또는 천식에 투여되는 코르티코스테로이드

Corticosteroids given for chronic obstructive pulmonary disease or asthma

기립성 저혈압 또는 부신피질 기능부전에 투여된 저용량 코르티코스테로이드

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency

골격성 사건의 예방을 위한 비스포스포네이트

Bisphosphonates for the prevention of skeletal events

하기에 개략된 바와 같은 완화 방사선 요법(예컨대, 공지된 골 전이의 치료 또는 통증의 증상 완화):

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

Palliative radiation therapy is acceptable as long as it does not interfere with the evaluation of tumor target lesions (eg, the lesion to be investigated should not be the only site of measurable disease). Treatment with tiragolumab and atezolizumab may be continued during palliative radiation therapy. Treatment with nap-paclitaxel should be discontinued according to institutional standards.

화학요법(nab-파클리탁셀)을 받는 환자에게 허용되고 화학요법의 AC 부분 중에 요구되는 G-CSF(예: 필그라스팀 또는 페그필그라스팀) 또는 GM-CSF 치료

G-CSF (eg filgrastim or pegfilgrastim) or GM-CSF treatment permitted for patients receiving chemotherapy (nab-paclitaxel) and required during the AC portion of chemotherapy

Primary prophylaxis should be administered to patients ≥ 60 years of age and/or with comorbidities according to ASCO, EORTC or ESMO guidelines or according to local standard practice (Smith et al. 2006; Crawford et al. 2010) ; Aapro et al. 2011).

Evidence supporting the use of a long-acting (pegylated) form of G-CSF in patients receiving weekly nab-paclitaxel is limited, and investigators should give preference to conventional G-CSF formulations.

Premedication of antihistamines, antipyretics, and/or analgesics may be administered only for the second and subsequent infusions of atezolizumab and tiragolumab at the discretion of the investigator.

attention therapy

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of treatment with atezolizumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines should be considered. If no alternative is possible, systemic corticosteroids and TNF-α inhibitors may be administered at the investigator's discretion.

For the treatment of certain adverse events associated with atezolizumab therapy, systemic corticosteroids are recommended at the discretion of the investigator.

forbidden therapy

The use of the following combination therapies is contraindicated as follows:

보건 기관의 승인을 받았거나 임상시험 단계에 있는지 여부와 상관없이, 연구 치료를 시작하기 전 다양한 기간 동안, 작용제에 따라서, 및 질병 진행이 문서화되고 환자가 완화 방사선 요법을 제외하고 연구 치료를 중단할 때까지, 암 치료를 위한 병용 요법(화학요법, 호르몬 요법, 면역요법, 방사선 요법 및 한약 요법을 포함하지만, 이에 제한되지는 않음)

Whether approved by the health agency or in the clinical trial phase, for various periods of time prior to initiation of study treatment, depending on the agent, and when disease progression is documented and patients discontinue study treatment with the exception of palliative radiation therapy. combination therapy for cancer treatment (including but not limited to chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy)

연구 치료 시작 전 및 연구 치료 동안 28일 이내의 임상시험 요법

Investigational therapy within 28 days prior to initiation of study treatment and during study treatment

연구 치료 시작 전 4주 이내, 아테졸리주맙 치료 중, 및 연구 치료의 최종 용량 후 5개월 동안 독성 약화 생백신(예컨대, 플루미스트(FLUMIST)^®)

Toxic attenuated live vaccine (eg, FLUMIST ^® ) within 4 weeks prior to initiation of study treatment, during atezolizumab treatment, and 5 months after the last dose of study treatment

연구 치료제 개시 전 및 연구 치료제 동안 4주 또는 5회의 약물 제거 반감기(둘 중 더 긴 것) 이내의 전신 면역자극제(인터페론 및 IL-2를 포함하지만, 이에 제한되지는 않음) - 상기 제제는 아테졸리주맙 및 티라골루맙과 병용 투여 시 자가면역 질환의 위험을 증가시킬 가능성이 있기 때문임.

Systemic immunostimulants (including but not limited to interferon and IL-2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment - the agent is This is because co-administration with zumab and tiragolumab may increase the risk of autoimmune disease.

연구 치료 중 전신 면역억제제(아자티오프린, 메토트렉세이트 및 탈리도마이드를 포함) - 상기 제제는 아테졸리주맙 및 티라골루맙의 유효성 및 안전성을 변경할 가능성이 있기 때문임.

Systemic immunosuppressive agents (including azathioprine, methotrexate, and thalidomide) during study treatment, as these agents have the potential to alter the efficacy and safety of atezolizumab and tiragoluumab.

Additional limitations related to carboplatin chemotherapy

황열병 백신의 병용은 금지되며, 다른 약독화 생백신과의 접종은 피해야 한다.

Concomitant use of yellow fever vaccine is prohibited, and vaccination with other live attenuated vaccines should be avoided.

사균되거나 비활성화된 백신을 투여할 수 있다; 다만, 상기 백신에 대한 반응은 감소될 수 있다.

A killed or inactivated vaccine may be administered; However, the response to the vaccine may be reduced.

페니토인 또는 포스페니토인의 병용은 경련의 악화, 독성 증강의 위험 또는 세포독성 약물의 효능 상실의 위험이 있으므로 권장되지 않는다.

Concomitant use of phenytoin or phosphenytoin is not recommended due to the risk of worsening of seizures, increased toxicity, or loss of efficacy of cytotoxic drugs.

하기 제제들의 병용은 주의하여 접근해야 한다: 사이클로스포린, 신독성 또는 이독성 약물(예: 아미노글리코사이드, 반코마이신, 카프레오마이신 및 루프 이뇨제를 포함한 이뇨제[증가, 악화 또는 누적된 독성의 위험]).

The concomitant use of the following agents should be approached with caution: cyclosporine, nephrotoxic or ototoxic drugs (e.g., aminoglycosides, vancomycin, capreomycin and diuretics including loop diuretics [risk of increased, exacerbated or cumulative toxicity]).

동시(함께 또는 ≤ 7일 간격으로 제공) 방사선 요법은 피해야 한다.

Simultaneous (given together or ≤ 7 days apart) radiation therapy should be avoided.

D. Selection Criteria

Patients must meet the following general criteria for study enrollment:

서명한 사전 동의서

signed informed consent

사전 동의서에 서명할 당시의 연령

　18세의 여성 및 남성

Age at the time the informed consent was signed

18 years old female and male

연구 프로토콜을 준수할 능력

Ability to comply with research protocols

ECOG 성능 상태 0 또는 1(부록 5 참조)

ECOG performance state 0 or 1 (see Appendix 5)

하기의 연구실에서 정의하는 적절한 혈액 및 말단 기관의 기능

Appropriate blood and end organ function as defined by the following laboratory

Results obtained within 14 days prior to initiation of study treatment (Day 1)

Cycle 1):

1.5 x 109/L(1500/νL). 단, G-CSF 지원 없이 2주 이내, 그리고 다음 이전에:- ANC

1.5 x 109/L (1500/νL). However, within two weeks without G-CSF support, and before:

Day 1 of Cycle 1

0.5 x 109/L(

500//νL)- Lymphocyte count

0.5 x 109/L (

500//νL)

100 x 109/L(

100,000/νL) - - platelet count

100 x 109/L (

100,000/νL) -

No transfusions within 2 weeks before Day 1 of Cycle 1

90 g/L(

9 g/dL)- hemoglobin

90 g/L (

9 g/dL)

To meet the above criteria, the patient will receive a blood transfusion or receive erythropoietic therapy.

can receive

2.5 x 정상 상한치(ULN) - AST, ALT, and ALP

2.5 x Upper Normal Limit (ULN)

1.5 x U, 하기의 경우는 제외함:- Serum bilirubin

1.5 x U, except for:

　3　 lULN인 것으로 공지된 길버트 병 환자가 등록할 수 있다.serum bilirubin levels

Gilbert's disease patients known to be 3 lULN can enroll.

- INR and aPTT 1.5 ULN

This only applied to patients who did not receive therapeutic anticoagulation; Patients on anticoagulant therapy should use a stable dose.

30 mL/분(콕크로프트-가울트 공식을 사용하여 계산)- Creatinine clearance

30 mL/min (calculated using the Cockcroft-Gault formula)

25 g/L(

2.5 g/dL)- Serum albumin

25 g/L (

2.5 g/dL)

・Negative HIV test at screening

Hepatitis B surface antigen (HBsAg) test negative during screening

A positive hepatitis B surface antibody (HBsAb) test at screening, or

HBsAb negative at screening with one of the following

- Total hepatitis B core antibody (HBcAb) negative

- Quantitative hepatitis B virus (HBV) DNA after positive total HBcAb test

< 500 IU/mL

The HBV DNA test is only performed on patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test.

· Hepatitis C virus (HCV) antibody test negative at screening test, or HCV RNA test negative after HCV antibody test positive at screening test.

The HCV RNA test is only performed on patients with a positive HCV antibody test.

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods as defined below and to refrain from egg donation

Women during the treatment period and at least 5 months after the last dose of atezolizumab, 90 days after the last dose of tiragolumab, 1 month after the last dose of nap-paclitaxel, 6 months after the last dose of carboplatin or doxorubicin, or Abstinence should be maintained until the later of 12 months after the last dose of cyclophosphamide or a contraceptive method with a failure rate of <1% per year should be used. Women should refrain from donating eggs during the same period as above.

A woman has no chance of becoming pregnant if she is non-menstrual, has not reached postmenopausal status (without confirmed cause (³ 12 consecutive months of amenorrhea) other than menopause, and has not undergone surgical sterilization (removal of the ovaries and/or uterus). considered to exist

Examples of contraceptive methods that, when used correctly and consistently, have a failure rate of < 1% per year include combined (estrogen and progesterone-containing) hormonal contraception associated with ovulation inhibition, progesterone-only hormonal contraception associated with ovulation inhibition, bilateral tubal occlusion; male infertility; intrauterine device; intrauterine

hormone release system; and sexual abstinence.

The reliability of sexual abstinence should be evaluated with respect to the duration of the clinical study and the desired and general lifestyle of the patient.

Periodic abstinence (eg, calendar, ovulation, symptomatic body temperature, or postovulatory methods) and withdrawal are not acceptable methods of contraception.

Women wishing to become pregnant after discontinuation of study treatment should seek advice on oocyte preservation prior to initiation of study treatment due to the potential for irreversible infertility due to chemotherapy treatment.

For Men: Consent to maintain abstinence (abstain from heterosexual intercourse) or use contraceptive methods, and to refrain from donating sperm, as provided below:

With a female partner of childbearing potential or a pregnant female partner, during treatment and for 90 days after the last dose of tiragolumab, or 6 months after the last dose of nap-paclitaxel, carboplatin, doxorubicin, or cyclophosphamide, whichever is more Until a later date, men must either maintain abstinence or use an additional method of contraception with a failure rate of < 1% per year. Men should refrain from donating sperm during the same period.

The reliability of sexual abstinence should be evaluated with respect to the duration of the clinical trial and the patient's preferred daily lifestyle.

Periodic abstinence (eg, calendar, ovulation, symptomatic body temperature, or postovulatory methods) and withdrawal are not acceptable methods of contraception.

Men wishing to have children after initiation of study treatment should seek advice on sperm conservation prior to beginning study treatment due to the potential for irreversible infertility due to chemotherapy treatment.

· For non-postmenopausal women (non-treatment-induced amenorrhea ³ 12 months) or women who have undergone sterilization, a negative serum pregnancy test result is required within 14 days prior to initiation of study treatment.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other research procedures;

Patients must meet the following cancer-related eligibility criteria:

Histologically documented TNBC (negative HER2, ER and PR status assessed by local testing)

HER2 negative is defined as one of the following by local laboratory assessment (Wolff et al. 2018):

ISH unamplified (HER2 to CEP17 ratio <2.0 or single probe average HER2 gene copy number <4 signal/cell or IHC 0 or IHC 1 + ER and PgR negative defined as <1% of cells expressing hormone receptors in IHC assay do.

Patients with multifocal tumors (one or more individual tumors confined to the same quadrant as the primary tumor) are eligible if one or more foci are sampled, locally identified, and documented as TNBC.

Patients with multiple tumors (multiple tumors comprising one or more separate quadrants) are eligible if all individual lesions are sampled, locally identified, and documented as TNBC.

Documented identifiable tumor PD-L1 assessment via central testing of representative FFPE tumor tissue specimens on paraffin blocks (preferred) or at least 20 unstained slides

Tumor tissue should be of good quality based on total and viable tumor content, and should be assessed for PD-L1 expression as determined using the Ventana (SP142) PD-L1 IHC assay prior to enrollment, with positivity being a central It is defined as ≧1% of the tumor area occupied by infiltrating immune cells expressing PD-L1-expressing tumors of any intensity measured in the laboratory. Patients whose tumor tissue cannot be assessed for PD-L1 expression are not eligible.

If multiple tumor specimens are submitted, patients may be eligible if they have more than one specimen that can be evaluated for PD-L1. Acceptable samples include core-needle biopsies (minimum 3 cores) for deep tumor tissue, or excision, incision, punch or forceps biopsies for skin, subcutaneous or mucosal lesions.

FFPE tumor specimens in paraffin blocks are preferred.

Fine needle aspiration, brushing, cell pellets in pleural effusion, bone metastases, and wash samples are not permitted.

Primary breast tumor size >2 cm in at least one radiographic or clinical measurement

Stage at the time of presentation: cT2-cT4, cN0-cN3 and cM0

Consent of the patient to undergo appropriate surgical management (e.g., including axillary lymph node surgery and partial or total mastectomy) after completion of neoadjuvant therapy

Baseline left ventricular ejection fraction (LVEF) ≥53% measured on echocardiography (ECHO) or multiple gate acquisition (MUGA) scans

E. Exclusion Criteria

Patients meeting any of the following criteria are excluded from study enrollment:

-During study treatment, within 90 days of treatment with tiragolumab, within 5 months of treatment with atezolizumab, within 6 months of treatment with nap-paclitaxel, carboplatin or doxorubicin, or within 12 months of treatment with cyclophosphamide, whichever is more If you are pregnant or lactating until late

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

- Evidence of significant concurrent uncontrolled disease that could affect protocol compliance or interpretation of results, including significant liver disease (e.g., cirrhosis, uncontrolled major seizure disorder, or superior venous syndrome)

- Significant cardiovascular disease, such as New York Heart Association heart disease (Class II or higher), myocardial infarction within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

Patients with known LVEF of 53% are excluded.

Patients with known coronary artery disease or congestive heart failure who do not meet the above criteria.

-Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for infectious complications, bacteremia, or severe pneumonia

-Treatment with oral or IV antibiotics within 2 weeks prior to initiation of study treatment

Patients receiving regular antibiotic prophylaxis (eg, to prevent exacerbation of chronic obstructive pulmonary disease or for tooth extraction) are eligible.

- Major surgery within 28 days prior to initiation of study treatment or the need for major surgical procedures during non-diagnostic studies

The placement of a central venous access catheter (eg, port or the like) is acceptable as it is not considered a major surgical procedure.

- History of severe allergic, hypersensitivity, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

- Known hypersensitivity or allergy to biologics produced from CHO cells or any component of the tiragolumab or atezolizumab formulations

-Including myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis but not limited to, activity or history of autoimmune disease

Patients with a history of autoimmune-mediated hypothyroidism on stable doses of thyroid replacement hormone may be eligible for this study.

Patients with type 1 diabetes mellitus controlled with a stable insulin dosing regimen are eligible for this study.

Patients with eczema, psoriasis, chronic lichen simplex or vitiligo with only dermatological symptoms (eg, no psoriatic arthritis) are allowed if the following conditions are met:

- The rash occupies <10% of the body surface area

- Disease is well controlled at baseline and requires only low titer topical steroids

- No acute exacerbation of an underlying condition requiring ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids in addition to psoralen within the past 12 months

-Prior allogeneic stem cell transplantation or solid organ transplantation

- History of idiopathic pulmonary fibrosis (including pneumonia), drug-induced pneumonia, systemic pneumonia (i.e. bronchiolitis obliterans, latent systemic pneumonia), or evidence of active pneumonia on chest computed tomography (CT) scan at screening

A history of radiation pneumonitis (fibrosis) in the field of radiation is acceptable

- EBV virus capsid antigen (VCA) IgM test positive during screening test

EBV polymerase chain reaction (PCR) testing should be performed as clinically indicated to screen for active or suspected chronic active infection.

Patients with a positive EBV PCR test are excluded.

active tuberculosis

- If the live attenuated vaccine is administered within 4 weeks prior to initiation of the study treatment, or if it is expected that the attenuated live vaccine will be required during the study

Patients must agree not to receive a live, attenuated vaccine (eg, Flumist ^® ) within 28 days prior to initiation of study treatment, during treatment, or within 5 months after administration of the last dose of study treatment.

- Prior treatment with CD137 agonists including anti-CTLA-4 or immune checkpoint blockade, except for anti-PD-1 or anti-PD-L1 therapeutic antibodies

-Treatment with systemic immunostimulants (including but not limited to interferon or IL-2) within 4 weeks prior to initiation of study therapy or within 5 drug elimination half-lives of the drug (whichever is later)

-Systemic immunosuppressants (prednisone,

treatment with, but not limited to, dexamethasone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents, or when systemic immunosuppressants are expected to be required during the study

Patients receiving acute, low-dose, systemic immunosuppressants (eg, single dose of dexamethasone for nausea) can be enrolled in this study.

Inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (eg, fludrocortisone) for patients with orthostatic hypotension, and low-dose adjuvant corticosteroids for adrenal insufficiency may be used.

- History of invasive breast cancer

- Stage IV (metastatic) breast cancer

-Pre-systemic therapy for the treatment and prevention of breast cancer

-Previous therapy with anthracyclines, platinum or taxanes for all malignancies

Remarks: Patients with non-polymorphic LCIS (untreated or treated surgically) are eligible.

-Simultaneous, bilateral invasive breast cancer

-Previous incision and/or excisional biopsy of the primary tumor and/or axillary lymph nodes

-Axillary lymph node amputation prior to initiation of neoadjuvant therapy

-with a negligible risk of metastasis or death (e.g., 5-year overall survival (OS) >90%) History of other malignancies within 5 years prior to screening

- History of cerebrovascular events within 12 months prior to initiation of study treatment

- NCI CTCAE v5.0 Grade 3 Symptomatic Congestive Heart Failure or History of New York Heart Association Class II or greater heart disease

- NCI CTCAE v5.0 Grade 3 Symptomatic Congestive Heart Failure or History of New York Heart Association Class II or higher heart disease

- Angina requiring antianginal medications, severe cardiac arrhythmias not controlled by appropriate medications, severe conduction abnormalities, or clinically significant valvular disease.

- high-risk uncontrolled arrhythmias (i.e., atrial tachycardia with resting heart rate of 100 beats/min, significant ventricular tail arrhythmias [ventricular tachycardia], advanced atrioventricular [AV] block [2nd degree atrioventricular block type 2 [Mobitz 2], or 3 also AV blocking])

- Significant symptoms related to left ventricular dysfunction, arrhythmia, or cardiac ischemia (Grade -2)

- Myocardial infarction within 12 months prior to initiation of study treatment

- uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg)

- Evidence of transmural infarction on ECG

- Requirements for oxygen therapy

-A known allergy or hypersensitivity to a component of the formulation -nab-paclitaxel, cyclophosphamide, doxorubicin or carboplatin

- Known allergy or hypersensitivity to G-CSF or GM-CSF formulations

F. analysis

Safety analysis

To evaluate the safety profile of atezolizumab + nab-pac-carbo + AC versus tiragolumab and atezolizumab + nab-pac + AC, patients were randomized in a 1:1 ratio to one of two groups in Cohort B. do. Formal statistical comparisons of the primary safety endpoints are not performed and safety analyzes are descriptive. Therefore, the credibility calculation was not performed. The sample size is considered sufficient to provide a descriptive safety analysis to evaluate the tolerability of atezolizumab plus nab-pac-carbo-AC to tiragolumab and atezolizumab plus nab-pac-AC. The planned sample size allows to observe adverse events with an actual incidence ≥10% with an acceptable probability across each treatment arm and both combined arms (see Table 66).

Safety assessments include the incidence, nature and severity of adverse events, protocol-essential vital signs, laboratory abnormalities, and other protocol-specific tests considered important for the safety assessment of the study. Adverse events are graded according to NCI CTCAE v5.0.

Safety is assessed by ADA-measured adverse events, changes in laboratory test results, changes in vital signs, exposure to study treatment, and summary of immunogenicity and presented in treatment groups.

Verbose descriptions of adverse reactions correspond to MedDRA terms.

Treatment emergency response (defined as a response that occurs at or after the first dose of study treatment) is summarized in MedDRA terminology, appropriate MedDRA level, and NCI CTCAE v5.0 grade, regardless of relationship to investigator-assessed study drug. If the same adverse event occurs multiple times for each patient, the maximum reported severity is used for the summary.

The following and treatment-related adverse events are summarized separately: Adverse Events Leading to Study Drug Discontinuation, Adverse Events Leading to Dose Reduction or Discontinuation, Grade 3 Adverse Events, Grade 5 Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest .

All deaths and causes of death are summarized.

Relevant laboratory values are summarized by time point, along with identified NCI CTCAE Grade 3 and Grade 4 values where appropriate. NCI CTCAE grade changes are tabulated by treatment group.

Analysis of exposure, adverse events, laboratory and vital signs data

Safety depends on exposure to study treatment, adverse events, changes in laboratory test results, and changes in vital signs and ECGs.

Evaluate through a summary of

Study treatment exposures (eg, duration of treatment, total dose administered, and number of cycles and dose changes) are summarized along with descriptive statistics.

Verbose terms of adverse events correspond to synonymous terms in MedDRA, and the severity of adverse events is graded according to NCI CTCAE v5.0. All adverse events, serious adverse events, adverse events leading to death, adverse events of particular interest, and adverse events leading to study treatment discontinuation (i.e., treatment-related adverse events) occurring at or after administration of the first dose of study treatment These are summarized according to the mapped terms, appropriate synonym levels, and severity ratings. For reactions with variable severity, the highest rating in that summary is used. Deaths and causes of death are summarized.

Relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry, and body temperature) and ECG data are displayed hourly and identified by grade, where appropriate. In addition, tables of changes from selected laboratory tests are used to summarize baseline and post-baseline maximum severity grades. Changes in vital signs and ECG are summarized.

Validity analysis

Efficacy analysis uses an ITT approach, where all enrolled patients, regardless of whether the patient receives any assigned study drug, are included in the analysis, and patients in Cohort B are grouped according to treatment randomized in a 1:1 ratio. do. Analyzes based on subsets of the ITT population may also be performed. Hypothesis analysis is two-sided unless otherwise specified.

The exploratory efficacy goal for Cohort B was to investigate the effectiveness of tiragolumab and atezolizumab plus nab-pac-carbo-AC against tiragolumab and atezolizumab plus nab-pac-AC based on the following endpoints. will be.

-pCR (ypT0/is ypN0), defined as eradication of tumors in both breast and lymph nodes

These efficacy endpoints are established after completion of neoadjuvant therapy and surgery. Patients who miss a pCR assessment are considered not to have achieved pCR.

-EFS, defined as the time from randomization to documented disease recurrence, progression, or death from any cause

Event-free patients at the time of analysis are censored on the last known event-free survival.

Patients without baseline information are censored on the date of randomization.

OS defined as the time from randomization to the date of death from any cause

Patients not reported to have died at the time of analysis are censored on the date of the last known survival. Patients with no post-baseline information are censored on the date of randomization.

Pharmacokinetic analysis

Samples are collected for PK analysis and exposures in this study are compared with exposures obtained in previous studies. Serum concentrations of tiragolumab and atezolizumab and plasma concentrations of nap-paclitaxel, carboplatin, doxorubicin and cyclophosphamide are reported as individual values and summarized by treatment group and cycle (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation).

Individual and median serum tiragolumab and atezolizumab concentrations are plotted by treatment group and day. Tiragolumab and atezolizumab concentration data can be integrated with data from other studies that use established population PK models to derive PK parameters such as clearance, volume of distribution, and AUC as warranted by the data. have. Potential correlations of PK parameters with dose, safety, efficacy, or biomarker outcomes can be investigated.

Immunogenicity assay

Immunogenicity assays included patients with ADA assessments, grouped according to treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients during the treatment and follow-up period will be summarized by treatment group.

The relationship between ADA status and safety, efficacy, and PK endpoints can be analyzed and reported through descriptive statistics.

Biomarker analysis

Although no formal statistical analysis of exploratory biomarkers is performed, the data can be analyzed in the context of this study and in conjunction with data from other studies.

Example 15. A Phase II, Randomized, Double-Blind Study of Atezolizumab + Tiragolumab and Atezolizumab + Placebo as First-Line Treatment in Patients with Recurrent/Metastatic PD-L1-positive Squamous Cell Carcinoma of the Head and Neck

This example was designed to evaluate the efficacy and safety of atezolizumab plus tiragolumab and atezolizumab plus placebo as first-line (1L) treatment in relapsed/metastatic PD-L1-positive squamous cell carcinoma (SCCHN) of the head and neck. A phase II, randomized, double-blind, global study is described. The study consists of the following sections:

Arm A: Patients receive a 1200 mg fixed dose of atezolizumab administered as an IV infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle, followed by a 600 mg fixed dose of tiragoluumab administered to patients each Q3W is administered as an IV infusion on Day 1 of the 21-day cycle.

Arm B: Patients will receive a 1200 mg fixed dose of atezolizumab Q3W as an IV infusion on Day 1 of each 21-day cycle followed by placebo Q3W as an IV infusion on Day 1 of each 21-day cycle.

A. study design

This Phase II, randomized, double-blind, global study was designed to evaluate the efficacy and safety of atezolizumab plus tiragolumab and atezolizumab plus placebo as 1L treatment in relapsed/metastatic PD-L1-positive SCCHN. Eligible patients have recurrent disease unsuitable for topical therapy with curative intent and/or metastatic PD-L1-positive SCCHN (tumor-associated immune cells (TIC) ≥ 5%) and have previously received systemic therapy for relapsed/metastatic disease Male and female patients ≥18 years of age with an Eastern Cooperative Oncology (ECOG) performance status of 0 or 1.

During screening, tumor specimens from each potentially eligible patient are prospectively tested for PD-L1 expression as assessed by a central laboratory using the investigative VENTANA PD-L1 (SP263) companion diagnostic (CDx) assay. Only PD-L1-positive patients with a centrally assessed TIC ≥ 5% are eligible. PD-L1 expression is defined as a low PD-L1 with a TIC of 5%-19% and a high PD-L1 with a TIC ≥20%.

Eligible patients are stratified into human papillomavirus (HPV) status for oropharyngeal cancer (HPV positive oropharyngeal cancer: yes vs. no) and PD-L1 status (PD-L1: low vs. high). Enrollment for each PD-L1 subgroup (PD-L1 low [TIC 5%-19%] and PD-L1 high [TIC ≥ 20%]) is limited to approximately 55% of total planned enrollment (i.e., approximately 66%). patients).

Eligible patients will be randomized in a 2:1 ratio to receive either atezolizumab plus tiragolumab (Arm A) or atezolizumab plus placebo (Arm B).

Arm A: Patients receive a 1200 mg fixed dose of atezolizumab administered as an IV infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle, followed by a 600 mg fixed dose of tiragoluumab administered to patients each Q3W is administered as an IV infusion on Day 1 of the 21-day cycle.

Arm B: Patients will receive a 1200 mg fixed dose of atezolizumab Q3W as an IV infusion on Day 1 of each 21-day cycle followed by placebo Q3W as an IV infusion on Day 1 of each 21-day cycle.

Patients receive tumor assessments at baseline, every 6 weeks (± 7 days) for the first 30 weeks after Day 1 of Cycle 1, and every 9 weeks (± 7 days) after completion of tumor assessments at Week 30. Tumor evaluation is based on loss of clinical benefit, withdrawal of consent, death, or termination of study by sponsor for patients continuing on study treatment after radiological disease progression according to RECIST v1.1 or radiological disease progression according to RECIST v1.1, whichever occurs first. Continue on schedule regardless of treatment delay until it occurs. If progressive disease or loss of clinical benefit is suspected, a scan should be performed at any time at the discretion of the investigator.

Patients who discontinue study treatment (including, but not limited to, clinical decline or toxicity) in the absence of radiologic disease progression per RECIST v1.1 will have their scheduled tumor evaluation scheduled for radiologic disease progression per RECIST v1, withdraw consent Continue at the above-mentioned frequency until death, or end of study by the sponsor, whichever occurs first. In the absence of radiologic disease progression according to RECIST v1.1, tumor evaluation should continue regardless of whether the patient is starting new chemotherapy. The objective response at a single time point is judged by the investigator according to RECIST v1.1.

Serum samples are collected to monitor atezolizumab and tiragolumab PK and detect the presence of antibodies to atezolizumab and tiragolumab. Patient samples, including archival and freshly obtained tumor tissue, plasma and blood samples, are collected for exploratory biomarker evaluation.

Safety assessments include the incidence, nature, and severity of adverse events considered important for the safety assessment of the study, and other protocol-specific tests (eg, laboratory abnormalities).

Survival follow-up information after study treatment discontinuation is collected via phone calls, patient medical records, and/or clinic visits approximately every 3 months until death, follow-up failure, or end of study by the sponsor, whichever occurs first. All patients should be contacted periodically for survival and new anticancer therapy information unless the patient requests withdrawal from survival follow-up (these requests must be documented in the original document and signed by the investigator). If a patient withdraws from survival follow-up, research staff may use public information sources (eg, county records) to obtain information about their survival status.

After an integrated assessment of radiographic data, biopsy results (if available), and clinical status, treatment will continue as long as patients experience clinical benefit as assessed by the investigator in the absence of unacceptable toxicity or worsening of symptoms due to disease progression. can Patients who meet the criteria for disease progression according to RECIST v1.1 but continue to have clinical benefit may continue treatment provided they meet all of the described criteria and provide written informed consent (atezolizumab + tyragolumab or atezoli Zumab + placebo).

B. Dosage and administration

The treatment regimen is summarized in FIG. 23 .

atezolizumab

All patients receive 1200 mg of atezolizumab by IV infusion on Day 1 of each 21-day cycle. Atezolizumab dose is fixed and does not vary with body weight. Atezolizumab infusion is administered according to the guidelines summarized in Table 67.

Tiragolumab and placebo

Following atezolizumab administration and the observation period (see Table 67), patients receive 600 mg tyragolumab/placebo as an IV infusion on Day 1 of each 21-day cycle. The tiragolumab/placebo dose is fixed and does not vary with body weight. Tiragolumab/placebo infusion is administered according to the guidelines summarized in Table 68.

Atezolizumab and Tiragolumab/Placebo

The following rules apply unless atezolizumab or tiragolumab/placebo is permanently discontinued:

-Treatment cycle begins with atezolizumab and tiragolumab/placebo dosing on Day 1 of each 21-day cycle. If one of the study drugs is delayed due to drug-related toxicity, it is recommended that the other study drugs be delayed because the safety profiles for atezolizumab and tiragolumab are similar; However, if deemed appropriate at the investigator's discretion, the cycle may be initiated with the administration of other study drugs.

-If administration of one study drug is delayed due to drug-related toxicity while the other study drug is administered as scheduled, it is recommended that the delayed study drug be administered at the next scheduled infusion (i.e., the next scheduled 21-day cycle).

capacity change

There is no dose adjustment, including dose reduction, for atezolizumab or tiragolumab/placebo in this study.

C. combination therapy

Combination therapy consists of all medications (e.g., prescription drugs, over-the-counter medications, vaccines, herbal or homeopathic remedies, nutritional supplements) taken by the patient in addition to protocol-essential treatment from 7 days before study treatment start to the treatment discontinuation visit.

accepted therapy

Patients are allowed to use the following regimens during the study period:

-prophylactic or therapeutic anticoagulant therapy (eg, stable doses of warfarin or low molecular weight heparin)

- Inactivated influenza vaccination

- Megestrol acetate administered as an appetite stimulant

-mineralocorticoids (eg, fludrocortisone)

- Inhaled or low-dose corticosteroids administered for COPD or asthma

-Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

For patients with no documented radiologic disease progression per RECIST v1.1, it is strongly recommended to maximize supportive care for symptom management and to avoid radiation therapy that impedes evaluation of tumor-targeted lesions.

Treatment may be continued with atezolizumab and tiragolumab/placebo during palliative radiation therapy.

Premedication with antihistamines, antipyretics and/or analgesics may be administered only for the second subsequent infusion of atezolizumab and tiragolumab/placebo, at the discretion of the investigator.

In general, the investigator should manage the patient's treatment (including pre-existing conditions) with adjuvant therapies other than those defined as clinically indicated cautions or contraindicated therapies, in accordance with local standard practice. Patients experiencing infusion-related symptoms may be treated with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice, depending on the symptoms. have. Severe infusion-related events indicated by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation, or dyspnea, as clinically indicated, support supportive care (e.g., supplemental oxygen and 2-adrenergic agonists) ) should be managed.

care

Systemic corticosteroids and TNF-α inhibitors may attenuate the potentially beneficial immunological effects of atezolizumab and/or tiragolumab treatment. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors are routinely administered, alternatives including antihistamines should be considered. If no alternative is possible, systemic corticosteroids and TNF-α inhibitors may be administered at the investigator's discretion.

For the treatment of certain adverse events when associated with atezolizumab and/or tiragolumab therapy, systemic corticosteroids are recommended, at the investigator's discretion.

forbidden therapy

The use of the following combination therapies is contraindicated as follows:

Combination therapies (including, but not limited to, surgery, chemotherapy, hormone therapy, immunotherapy, radiation therapy, and herbal therapy) intended for the treatment of cancer, whether approved by health authorities or experimental, may vary for various periods of time prior to initiation of study treatment. During, depending on the agent, and during study treatment, disease progression is documented and the patient discontinues study treatment except for palliative radiation therapy and topical therapy in certain circumstances.

Investigational therapy is contraindicated within 28 days prior to initiation of study treatment and during study treatment.

- Live attenuated vaccines (eg Flumist ^® ) are contraindicated within 4 weeks prior to initiation of study treatment, during study treatment, 5 months after the last dose of atezolizumab and 90 days after the last dose of tiragolumab/placebo.

-Systemic immunostimulants (including, but not limited to, interferon and IL-2) prior to initiation of study treatment and during study treatment as these agents may potentially increase the risk of autoimmune disease if given in combination with study treatment Contraindicated within 4 weeks or 5 drug elimination half-lives, whichever is longer.

-Systemic immunosuppressants (including, but not limited to, cyclophosphamide, azathioprine, methotrexate and thalidomide) are contraindicated during study treatment as these agents may potentially alter the efficacy and safety of study treatment.

D. Selection Criteria

Patients must meet the following criteria for study entry:

- signed informed consent

-Age at the time of signing the informed consent ≤　18

- Ability to comply with research protocols

-histologic or cytologically confirmed recurrent/metastatic SCCHN (including oropharyngeal, buccal, larynx or hypopharyngeal, considered incurable with topical therapy)

Patients with tumors of primary sites in the nasopharynx or parotid gland, of any histology, are not eligible.

Known results from HPV status testing for oropharyngeal cancer locally judged by -p16 immunohistochemistry (IHC), in situ hybridization or polymerase chain based assays

Note: HPV testing is not required for oral cancer, laryngeal cancer, and hypopharyngeal cancer.

-No previous systemic therapy for metastatic and/or recurrent SCCHN

Patients who have received systemic therapy given as part of a multimodal treatment (eg, concurrent chemoradiation) for locally advanced disease and whose last dose of systemic therapy was 6 months prior to randomization are admitted.

-Measurable disease per RECIST v1.1

Previously irradiated lesions can be considered measurable disease only if progressive disease is clearly documented at the site after irradiation.

- Tumor PD with a TIC of 5%, judged by investigational VENTANA PD-L1 (SP263) CDx analysis and documented through central testing of representative tumor tissue specimens, within previously obtained archival tumor tissue or tissue obtained from biopsies at pre-screening/screening -L1 expression. After approximately 66 patients (55% of total plan enrollment) were enrolled in the PD-L1 subgroups (PD-L1 low (TIC 5%-19%) and PD-L1 high (TIC ≥20%)), their PD - Additional patients in the L1 subgroup are not enrolled.

Confirmed availability of representative tumor specimens on at least 20 slides containing either formalin-fixed paraffin-embedded (FFPE) blocks (preferred) or unstained, freshly excised continuous sections with relevant pathology reports. If only 15-19 slides are available, the patient may still be eligible for the study after receiving Medical Monitor confirmation.

If archival tumor tissue is not available or is judged unsuitable for the required testing, tumor tissue should be obtained from a biopsy performed at the time of pre-screening/screening. A biopsy may be performed at prescreening/screening if the patient's archived biopsy results do not meet the eligibility criteria.

ECOG systemic activity of -0 or 1

-Life expectancy ≥12 weeks

- Adequate blood and terminal organ function, as defined by the following laboratory results, obtained within 14 days prior to randomization:

- ANC ≥1.5 x 10 ⁹ /L (1500/μL), no granulocyte colony stimulating factor adjuvant

- Lymphocyte count ≥ 0.5 x10 ⁹ /L (500/μL)

- Platelet count ≥ 100 x10 ⁹ /L (100,000/μL), no transfusion

- Hemoglobin ≥90 g/L (9 g/dL)

Patients may receive transfusions or receive erythropoietic therapy according to their local SOC to meet this criterion.

- AST, ALT, and ALP ≤ 2.5 x upper limit of normal (ULN), with the following exceptions:

Patients with documented liver metastases: AST and ALT ≤5 x ULN

Patients with documented liver or bone metastases: ALP ≤5 x ULN

- Total bilirubin ≤1.5 x ULN, with the following exceptions:

Known Gilbert's Disease Patients: Total Bilirubin ≤3 xULN

- Creatinine ≤1.5 xULN

- Albumin ≥ 25 g/L (2.5 g/dL)

- For patients not receiving therapeutic anticoagulants: INR and aPTT ≤1.5 x ULN

-For patients receiving therapeutic anticoagulant therapy: stable anticoagulant

-Negative HIV test at screening test

-Negative hepatitis B surface antigen (HBsAg) test during screening

-Hepatitis B surface antibody (HBsAb) positive at screening or HBsAb negative at screening with one of the following:

- Total hepatitis B core antibody (HBcAb) negative

- Quantitative hepatitis B virus (HBV) DNA <500 IU/mL after total HBcAb test positive

HBV DNA testing should only be performed on patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test.

-Negative hepatitis C virus (HCV) antibody test at screening test, or negative HCV RNA test after positive HCV antibody test at screening test.

HCV RNA testing should only be performed on patients with a positive HCV antibody test.

-For women of childbearing age: Consent to maintain abstinence (no intercourse) or use contraception as defined below:

Women should maintain abstinence for the duration of treatment, for 5 months after the last dose of atezolizumab and for 90 days after the last dose of tiragolumab/placebo, or use contraception with an annual failure rate of less than 1%.

The woman is post-menopausal, has not reached post-menopausal status (amenorrhea continues for 12 consecutive months without an identified cause other than menopause), and has not undergone surgery (i.e., removal of the ovaries, fallopian tubes, and/or uterus) or another as determined by the investigator A woman of childbearing age is considered to be of childbearing age unless it is permanent infertility due to cause (eg, absence of Muller's canal). The definition of childbearing age may be adapted to local guidelines or regulations.

Examples of contraceptive methods with an annual failure rate of <1% include bilateral tubal ligation, male sterilization, hormonal contraceptives to suppress ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

The reliability of sexual abstinence should be evaluated with respect to the duration of the clinical trial and the patient's preferred daily lifestyle. Periodic abstinence (eg calendar, ovulation, symptom temperature, post-ovulation method) and extracorporeal ejaculation are not suitable methods of contraception. Information on the reliability of appropriate locally accepted methods of contraception and abstinence as required by local guidelines or regulations is described in the local informed consent form.

-For men: Consent to maintain abstinence (no intercourse) or to use condoms and to refrain from donating sperm, as defined below:

Men with a female partner of childbearing potential or with a pregnant female partner should maintain abstinence or use condoms during tiragolumab/placebo treatment and for 90 days after the last dose of tiragolumab/placebo to avoid embryo exposure. Men should refrain from donating sperm during the same period.

The reliability of sexual abstinence should be evaluated with respect to the duration of the clinical trial and the patient's preferred daily lifestyle. Periodic abstinence (eg, calendar, ovulation, symptom temperature, postovulation method) and extracorporeal ejaculation are not adequate methods of preventing drug exposure. Information on the credibility of abstinence when required by local guidelines or regulations is described in the local informed consent form.

E. Exclusion Criteria

Patients meeting any of the following criteria are excluded from study enrollment:

-diseases suitable for topical treatment with therapeutic intent

-Progressive or recurrent disease within 6 months of last administration of curative systemic therapy for locally advanced SCCHN

- Grade ≤2 unresolved toxicity related to surgery or other previous therapy

-Patients with grade-2 alopecia or neuropathy are allowed.

Patients who underwent major surgery should have recovered sufficiently, including recovery from complications related to interventions.

Patients with managed irreversible toxicity that are not expected to worsen with study drug treatment and may be included after consultation with the Medical Monitor.

-symptomatic, untreated, or active central nervous system (CNS) metastases

Asymptomatic patients with treated CNS lesions are eligible if all of the following criteria are met:

- According to RECIST v1.1, measurable disease must be outside the CNS.

- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

- The patient had not received stereotactic radiotherapy within 7 days prior to randomization, whole brain radiotherapy within 14 days prior to randomization, or neurosurgical resection within 28 days prior to randomization.

- The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Stable dose anticonvulsant therapy is permitted.

- History of meningeal disease

-Uncontrolled tumor-related pain

Patients requiring pain medication must be on a stable regimen at study entry.

Symptomatic lesions that can be treated with palliative radiotherapy (eg, bone metastases or nerve impingement-induced metastases) should be treated prior to enrollment.

The patient must recover from the effects of radiation. The patient must recover from the effects of radiation.

Asymptomatic metastatic lesions (e.g., epidural metastases not currently associated with spinal cord compression) that have the potential to cause functional defects or refractory pain upon further growth should be considered for local treatment if appropriate prior to enrollment.

-Uncontrolled or symptomatic hypercalcemia

-myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, or multiple sclerosis with the exception of Activity or history of autoimmune disease or immunodeficiency, but not limited to:

Patients with a history of autoimmune-related hypothyroidism and taking thyroid replacement hormone are eligible for this study.

Patients with controlled type 1 diabetes mellitus receiving insulin therapy are eligible for the study.

Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only dermatological signs (eg, excluding patients with psoriatic arthritis) are eligible for this study if all of the following conditions are met:

- The rash occupies <10% of the body surface area

- Disease is well controlled at baseline and requires only low titer topical steroids

- No acute exacerbation of an underlying condition requiring ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids in addition to psoralen within the past 12 months

- History of idiopathic pulmonary fibrosis, organic pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonia or interstitial pneumonia, or evidence of active pneumonia on a screening chest computed tomography (CT) scan

A history of radiation pneumonitis (fibrosis) in the field of radiation is acceptable

-active tuberculosis

Significant cardiovascular disease (e.g., New York Heart Association Class II or higher heart disease, myocardial infarction or cerebrovascular accident), unstable arrhythmia, or unstable angina within 3 months prior to study treatment initiation

-Major surgical procedures excluding diagnosis within 4 weeks prior to initiation of study treatment, planned or anticipated need for major surgical procedures during the study

-Malignant tumors with a negligible risk of metastasis or death (e.g., a 5-year OS rate of 90%), such as appropriately treated epithelial carcinoma of the cervix, non-melanoma skin carcinoma, focal prostate cancer, or stage I uterine cancer excluding, history of additional malignancies other than SCCHN within 5 years prior to randomization

-Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

-therapeutic oral or IV antibiotic treatment within 2 weeks prior to initiation of study treatment

Patients receiving prophylactic antibiotics (eg, prophylaxis of urinary tract infections or exacerbations of chronic obstructive pulmonary disease) are eligible for this study.

-Prior allogeneic stem cell transplantation or solid organ transplantation

-Other diseases, metabolic dysfunctions, physical examination findings or clinical laboratory findings that may contraindicate the use of research drugs, may affect the interpretation of results, or put the patient at high risk for complications of treatment

- Expectations of the need for live attenuated vaccine treatment within 4 weeks prior to initiation of study treatment, or during study treatment, within 5 months of the last dose of atezolizumab, or within 90 days of the last dose of tiragolumab/placebo .

-Current treatment of antiviral therapy for HBV or HCV

- Positive Epstein-Barr virus (EBV) virus capsid antigen (VCA) IgM test during screening

EEBV polymerase chain reaction (PCR) testing should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded.

-Treatment with investigational therapy within 28 weeks prior to initiation of study treatment

-Previous treatment with CD137 agonists or immune checkpoint blockade therapy, including anti-CTLA-4, anti-TIGIT, anti-PD-L1 and anti-PD-1 therapeutic antibodies

-Treatment with systemic immunostimulants (including but not limited to interferon or interleukin 2 [IL-2]) within 4 weeks prior to initiation of study treatment or within 5 drug elimination half-lives (whichever is longer)

-treatment with systemic immunosuppression (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-TNF- agents) within 2 weeks prior to initiation of study treatment, or systemic immunity during study treatment Anticipation of the need for inhibitors, with the following exceptions:

- Patients receiving acute, low-dose systemic immunosuppressants or single pulse doses of systemic immunosuppressants (eg, corticosteroids for contrast allergy 48 hours) are eligible for this study after obtaining Medical Monitor confirmation.

- Patients receiving mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose systemic corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for this study.

- History of severe allergic anaphylactic reaction to chimeric or humanized antibodies or fusion proteins

Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation

- Pregnancy or breastfeeding or intention to become pregnant during study treatment, within 5 months of the last dose of atezolizumab, or within 90 days of the last dose of tiragolumab/placebo.

Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

F. evaluation

Patients are closely monitored for safety and tolerability throughout the study. Evaluate patients for toxicity prior to each dose administration; Dosing should be performed only when clinical evaluation and local laboratory test values are acceptable.

Medical history, baseline conditions, concomitant medications, and demographic data

Medical history including clinically significant disease, surgery, history of cancer (including previous cancer therapies and procedures), reproductive status, history of smoking, and abuse of alcohol and drugs is recorded at baseline. In addition, all medications (eg, prescription medications, over-the-counter medications, vaccines, herbal or homeopathic remedies, nutritional supplements) taken by the patient within 7 days prior to initiation of study treatment are recorded. At each subsequent physical examination, an interval medical record is obtained and any changes in medications and allergies are recorded.

Demographic data include age, gender, and self-reported race/ethnicity.

ECOG whole body activity

Performance status is measured using the ECOG Performance Status Scale.

Physical examination

A complete physical examination should be performed at screening and should include evaluation of the head, eyes, ears, nose, and throat, and cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, urogenital, and nervous systems. Any abnormalities identified at baseline should be recorded.

A limited, symptom-oriented physical examination should be performed as clinically indicated at specific post-baseline visits. Changes from baseline abnormalities should be recorded in the patient note. New or worsening clinically significant abnormalities should be recorded as adverse events.

Physical examination

Vital signs include measurements of respiratory rate, pulse rate, systolic and diastolic blood pressure, and body temperature. Abnormalities observed at baseline and new or worsening clinically significant abnormalities at follow-up visits are recorded.

Tumor and Response Assessment

Screening evaluation and subsequent tumor evaluation include CT scans of the chest and abdomen (with oral or IV contrast) and CT scans (with oral or IV contrast) or magnetic resonance imaging (MRI) of the head and neck (skull to base of the clavicle) (with contrast). ) should be included. Contrast CT scans of the pelvis should be performed as clinically indicated or according to local SOC for screening and subsequent response evaluation. If CT scans with contrast media are prohibited (for example, in patients with impaired renal clearance), non-contrast CT scans of the chest may be performed and MRI scans with contrast media (if applicable) of the head and neck, abdomen and pelvis should be done Additional investigations, such as bone scans, should also be performed if clinically indicated at baseline and subsequent response assessments.

Contrast CT scans of the brain or MRI scans with contrast media (if contrast-medium CT is contraindicated) should be performed as clinically indicated to evaluate CNS metastases at screening and subsequent response evaluation. If a CT scan with a contrast agent is performed and the presence of brain metastases is considered ambiguous, an MRI scan of the head is required to confirm or refute the diagnosis of CNS metastases at baseline. Patients with active or untreated CNS metastases are not eligible for this study. Patients with a history of irradiated brain metastases at screening do not need a brain scan at subsequent response assessment unless clinically indicated.

If CT scans for tumor evaluation are performed on a positron emission tomography (PET)/CT scanner, the CT acquisition should be consistent with the standard for full contrast diagnostic CT scans.

Tumor evaluation performed with SOC prior to obtaining informed consent may be used as an alternative to repeating the examination, provided that the scan is of diagnostic quality and performed within 28 days of randomization.

The same radiographic modality (eg, CT scan with contrast medium) and procedure (eg, same contrast medium protocol for CT scan) used during screening should be used for all subsequent tumor evaluations. All known disease sites, including measurable and/or non-measurable disease, are recorded at screening and re-evaluated at each subsequent tumor assessment.

Patients receive tumor assessments at baseline, every 6 weeks (± 7 days) for the first 30 weeks after Day 1 of Cycle 1, and every 9 weeks (± 7 days) after completion of tumor assessments at Week 30. Tumor evaluation is based on loss of clinical benefit, withdrawal of consent, death, or termination of study by sponsor for patients continuing on study treatment after radiological disease progression according to RECIST v1.1 or radiological disease progression according to RECIST v1.1, whichever occurs first. Continue on schedule regardless of treatment delay until it occurs. In addition, if progressive disease or loss of clinical benefit is suspected, a scan should be performed at any time at the discretion of the investigator.

Patients who discontinue study treatment in the absence of radiologic disease progression according to RECIST v.1.1 (including, but not limited to, clinical decline or toxicity) will receive tumor response according to the above schedule, regardless of whether new anticancer therapy is initiated or not. Continue the evaluation. Tumor evaluation continues until radiological disease progression, withdrawal of consent, death, or end of study by the sponsor, whichever occurs first according to RECIST v1.1. Responses are assessed by the investigator for the imaging techniques detailed above using RECIST v1.1. The investigator's assessment of overall tumor response at all time points should be based solely on RECIST v1.1. Assessments should be conducted by the same evaluator if possible to ensure internal consistency throughout the visit.

Investigator's assessment of overall tumor response at all time points is based on RECIST v1.1 only. For patients receiving study treatment after disease progression, tumor evaluation should continue following progression according to RECIST v1.1. This includes ongoing measurement of target lesions, evaluation of non-target lesions, and evaluation of newly identified lesions at all subsequent evaluations.

laboratory, biomarkers, and other biological samples

The following laboratory test samples are sent to the local laboratory at the study site for analysis:

o Hematology: white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count and differential count (neutrophils, eosinophils, basophils, monocytes and lymphocytes).

o Chemical panel (serum or plasma): bicarbonate or total carbon dioxide (if considered local SOC), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total Bilirubin, ALP, ALT, AST and LDH.

o Aggregation: INR and aPTT

o Thyroid function tests: thyroid stimulating hormone, free triiodothyronine (T3) (or total T3 for sites where free T3 has not been administered), and free thyroxine (also known as T4)

- EBV serology, including

o EBV VCA IgM

o EBV VCA IgG or Epstein-Barr Virus Nuclear Antigen (EBNA) IgG

o If clinically indicated: EBV PCR

o HIV serology

- HBV serology consisting of:

o HBsAg, HBsAb and total HBcAb for all patients

o HBV DNA from patients with negative HBsAg and HBsAb tests and positive total HBcAb tests

Patients with positive quantitative HBV DNA at screening (must be ≥500 IU/mL according to eligibility criteria) receive additional HBV DNA testing as outlined in the activity schedule.

o HCV serology: HCV antibody and (if HCV antibody test is positive) HCV RNA

o For SCCHN patients with oropharyngeal involvement: HPV status of tumor tissue as determined by p16 IHC, in situ hybridization or PCR-based analysis

o

pregnancy test.

All women of childbearing potential are tested for serum pregnancy at screening. During study treatment, a urine pregnancy test is performed on Day 1 of each cycle. A urine pregnancy test is also performed at the treatment discontinuation visit. If the urine pregnancy test is positive, it should be confirmed with a serum pregnancy test.

The woman is post-menopausal, has not reached post-menopausal status (amenorrhea continues for 12 consecutive months without an identified cause other than menopause), and has not undergone surgery (i.e., removal of the ovaries, fallopian tubes, and/or uterus) or another as determined by the investigator A woman of childbearing age is considered to be of childbearing age unless it is permanent infertility due to cause (eg, absence of Muller's canal).

o Urinalysis (pH, specific gravity, glucose, protein, ketones and blood); Dipstick Allowed

The following samples are sent for analysis to one or several central laboratories or to the sponsor or designee:

o Serum samples for autoantibody analysis: antinuclear antibody, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody

o Serum samples for C-reactive protein

o Serum samples for atezolizumab and tiragolumab PK assays with validated assays

o Serum samples for ADA evaluation for atezolizumab and tiragolumab with validated assays

o Blood and plasma samples for preliminary research on biomarkers

Blood samples can be processed to obtain peripheral blood mononuclear cells (PBMCs) and other derivatives (eg, RNA, DNA, etc.).

o Archived or freshly collected tumor tissue samples from baseline for evaluation of PD-L1 expression and exploratory studies for biomarkers

A minimum of 20 slides containing representative FFPE tumor specimens in paraffin blocks (preferred) or unstained, freshly excised continuous sections should be submitted along with the relevant pathology report prior to study enrollment. If only 15 to 19 slides are available, the patient may still be eligible for the study after approval by the medical monitor.

Tumor tissue should be of good quality based on total and viable tumor content.

Samples should contain at least 50 viable TCs that preserve cellular context and tissue structure, regardless of needle gauge or retrieval method.

Samples collected via resection, core-needle biopsy (minimum of three cores, embedded in a single paraffin block) or via resection, incision, punch or forceps biopsy are acceptable. Fine needle aspiration (defined as a sample that does not preserve tissue structure and does not produce a cell suspension and/or smear), brushing, cell pellets in pleural effusion, and wash samples are not permitted. Tumor tissue from calcified bone metastases is not acceptable.

A pre-treatment tumor biopsy is recommended if archived tumor tissue is not available or is judged unsuitable for the required testing. A pre-treatment tumor biopsy may be performed if the patient's archival biopsy results do not meet the eligibility criteria.

For preliminary studies of biomarkers, tumor tissue samples obtained at the time of progression, if considered clinically feasible.

A biopsy at the time of progression should be performed within 40 days of progression or before the next chemotherapy, whichever is earlier.

Samples collected via excision, core-needle biopsy (preferably at least 3 cores), or via excision, incision, punch or forceps biopsy are preferred.

NGS may be performed by Foundation Medicine. If conducted by Foundation Medicine, investigators can obtain NGS reports through Foundation Medicine's web portal. Where permitted by local law, investigators may share and discuss results with patients, unless the patient chooses otherwise. NGS reports are generated for research purposes and are not intended to guide future treatment decisions. Results are not provided for samples that do not meet the test criteria.

Exploratory biomarker studies may include, but are not limited to, oncogene alterations, HPV status or gene signatures associated with tumor immunobiology, PD-L1, TIGIT, lymphocyte subpopulations, and T cell receptor repertoire. Studies include extraction of DNA, cell-free DNA or RNA; analysis of mutations and other tumor-specific genomic variants; and genomic profiling through the use of NGS in a comprehensive panel of genes. DNA extracted from blood can be compared to DNA extracted from tissues, and somatic variants can be identified by distinguishing germline variants from somatic variants. NGS methods may include WGS or WES of tissue and blood samples, but WGS or WES of blood samples is only performed by participating institutions.

Refer to the laboratory manual for sampling procedures, storage conditions, and shipping instructions.

Unless the patient specifically consents to the storage of his or her remaining samples for an optional preliminary study, biological samples will be destroyed until the completion of the final clinical study report with the following exceptions:

Serum samples collected for PK or immunogenicity assays may be needed for further immunogenicity characterization and development and validation of PK or immunogenicity assays; Therefore, these samples are discarded within 5 years of completion of the final clinical study report.

· Blood, plasma and PBMC samples collected for biomarker studies will be destroyed within 5 years of completion of the final clinical study report. With the exception of tissue samples that have undergone WGS or WES, they are no longer needed or stored until depleted. However, the storage period is subject to the informed consent form approved by the IRB/EC and applicable laws (eg health authority requirements).

·For enrolled patients, the remaining archived tissue blocks will be returned to the institution upon request or within 18 months of the final clinical study report, whichever occurs first. For unenrolled patients, the remaining archived tissue blocks will be returned to the institution within six weeks of eligibility determination.

If a patient withdraws from the study, samples collected prior to the withdrawal date may continue to be analyzed, unless the patient specifically requests the destruction of the sample or local law requires that the sample be discarded. However, if a sample is tested prior to withdrawal, the results from that test remain part of the overall study data.

Given the complexity and exploratory nature of exploratory biomarker assays, data derived from these assays are generally not made available to study investigators or patients unless required by law (see Foundation Medicine's guideline, which applies only to biopsies obtained at the time of disease progression). excluding reports). The aggregated results of the conducted research can be provided according to the effective sponsorship policy for the publication of research data.

electrocardiogram

ECG is required at screening and as clinically indicated at other time points during the study. ECGs for each patient should be obtained from the same machine whenever possible. Lead placement should be as consistent as possible. ECG recordings should be performed after the patient has been in the supine position for at least 10 minutes.

For safety monitoring purposes, the investigator must review, sign and date all ECG traces. Copies of ECG traces are kept at the institution as part of the patient's permanent study file. Any morphological waveform changes or other ECG abnormalities should be documented in the eCRF.

Clinical Outcome Evaluation

The PRO instrument is completed to more fully characterize the clinical profile of atezolizumab + tiragolumab and atezolizumab + placebo. In addition, the PRO instrumentation allows us to capture each patient's first-hand experience with atezolizumab + tyragolumab and atezolizumab + placebo.

PRO data is collected using the following instruments:

PROMIS^® 아이템 뱅크 v2.0-신체 기능-간편 양식 10b

PROMIS ^® Item Bank v2.0 - Body Functions - Quick Form 10b

PROMIS^® 아이템 뱅크 v1.0-피로도-간편 양식 4a

PROMIS ^® Item Bank v1.0 - Fatigue - Quick Form 4a

PROMIS^® 아이템 뱅크 v1.1-통증 간섭-간편 양식 4a

PROMIS ^® Item Bank v1.1 - Pain Intervention - Quick Form 4a

PROMIS^® 숫자 등급 척도 v1.0-통증 강도 1a

PROMIS ^® Numeric Rating Scale v1.0 - Pain Intensity 1a

Patient's overall impression of Korea (PGI-S)

변화와 그 중요성에 대한 환자의 전체적 인상(PGI-CI)

Patient's overall impression of change and its importance (PGI-CI)

가장 중요한 증상(MIS)

Most important symptom (MIS)

PRO-CTCAE

PRO-CTCAE

PRO questionnaires (ie, PROMIS ^® , PGI-S/PGI-CI, MIS and PRO-CTCAE) are completed at the on-treatment and discontinuation visits.

Data Collection Methods for Evaluation of Clinical Outcomes

The PRO instruments used to characterize the clinical profile of atezolizumab + tiragolumab and atezolizumab + placebo are self-administered in the clinic or administered by an interviewer (if appropriate) at specific time points during the study. PRO data obtained using the PROMIS ^® , PGI-S/PGI-CI, MIS and PRO-CTCAE questionnaires.

In the clinic, the device is put in before the patient is informed of the disease status, prior to performing a non-PRO assessment, and prior to administering the study treatment, unless otherwise specified.

Translated paper PRO questionnaires into the appropriate local language scheduled for administration during the clinic visit should be completed by the patient at the study site prior to other study evaluations and at the beginning of the clinic visit prior to administration of study treatment to avoid possible evaluation bias. The patient completes a paper version of the questionnaire provided by the field staff. Interviewer assessments are permitted but may only be performed by clinic staff for patients unable to complete measurements on their own.

The study staff should review all questionnaires for completeness before the patient leaves the study site.

During clinic visits, PRO instruments should be administered as outlined below:

기구를 투입하기 전에 환자의 건강 상태를 논의해서는 안 된다.

The patient's health status should not be discussed prior to placement of the device.

기관은 시험의뢰자가 제공한 각 기구의 공식 버전을 관리해야 한다. 기구는 프로토콜로부터 복사되어서는 안 된다.

The laboratory shall maintain an official version of each instrument provided by the sponsor. Instruments shall not be copied from the protocol.

기관은 환자가 기구를 완료할 수 있는 충분한 시간을 허용해야 하며, 주기 1 및 2의 1일차에는 15분으로 예정되고 각 후속 주기에는 10분 미만으로 예정된다.

Institutions should allow sufficient time for the patient to complete the instrument, scheduled for 15 minutes on Day 1 of Cycles 1 and 2 and less than 10 minutes for each subsequent cycle.

기관은 산만함과 방해가 최소화된 조용한 장소에서 기구를 관리해야 한다.

The laboratory shall administer the apparatus in a quiet place with minimal distraction and disturbance.

환자는 최선의 능력을 다해 질문에 답하도록 지시 받아야 한다; 정답도 오답도 존재하지 않는다.

Patients should be instructed to answer questions to the best of their ability; There is no right or wrong answer.

현장 직원은 질문을 해석하거나 설명해서는 안 되지만 요청시 질문을 그대로 읽을 수 있다.

Field staff should not interpret or explain questions, but may read them verbatim upon request.

환자는 기구를 완성할 때 다른 사람(예: 가족 또는 친구)의 조언이나 도움을 받아서는 안 된다.

Patients should not seek advice or assistance from others (eg, family or friends) in completing the instrument.

현장 직원은 완성된 모든 도구를 검토하여야 하며 적절한 위치에 명확하게 표시되지 않은 응답을 수정하도록 환자에게 요청해야 한다. 응답이 누락된 경우 현장 직원은 환자에게 해당 항목을 완성하도록 요청하거나 해당 항목을 의도적으로 비워 두었는지 확인해야 한다. 응답이 누락된 경우 현장 직원은 환자에게 해당 항목을 완성하도록 요청하거나 해당 항목을 의도적으로 비워 두었는지 확인해야 한다.

Field staff should review all completed tools and ask the patient to correct responses not clearly marked in the appropriate place. If a response is missing, field personnel should ask the patient to complete the item or ensure that the item is intentionally left blank. If a response is missing, field personnel should ask the patient to complete the item or ensure that the item is intentionally left blank.

Description of Clinical Outcome Assessment Tools

PROMIS ^® Item Bank v2.0 - Body Functions - Quick Form 10b

PROMIS ^® Item Bank v2.0-Body Functions-Simple Form 10b, includes not only instrumental activities of daily life, but also physical activities including functions of the upper extremities (hand movements), lower extremities (walking or mobility) and central regions (neck, back). It consists of 10 questions designed to measure a person's self-reporting ability. All questions are scored on a 1-5 point scale, where 5 corresponds to the patient's highest functional ability and 1 corresponds to the patient's lowest functional ability. The recall period is 7 days.

PROMIS ^® Item Bank v1.0 - Fatigue - Quick Form 4a

The PROMIS ^® Item Bank v1.0-Fatigue-Simple Form 4a consists of four items designed to assess the range of self-reported fatigue symptoms and the patient's ability to perform daily activities. The items on the questionnaire asked the degree of fatigue experienced by the patient in the past 7 days. Items are on a scale of 1-5, with 5 representing the highest degree of fatigue experienced by the patient, and 1 representing the lowest level of fatigue experienced by the patient. The recall period is 7 days.

PROMIS ^® Item Bank v1.1 - Pain Interference - Quick Form 4a

The PROMIS ^® Item Bank v1.1-Pain Intervention-Simple Form 4a consists of 4 questions on a self-reported scale designed to assess the outcome/interference of pain on relevant aspects of a patient's life. All questions are scored on a 1-5 point scale, where 5 corresponds to the highest level of pain interference experienced by the patient, and 1 corresponds to the lowest level of pain interference. The recall period is 7 days.

PROMIS ^® Numeric Rating Scale - v1.0 - Pain Intensity 1a

The PROMIS ^® Numeric Rating Scale-v1.0-Pain Intensity 1a consists of one question on a self-reported scale designed to assess a patient's average pain level.

Questions are scored on a scale of 1-10, where 10 corresponds to “worst pain imaginable” and 1 corresponds to “no pain”. The recall period is 7 days.

Patient's overall impression of severity (PGI-S)

Patient's Global Impression of Severity (PGI-S) is a single-item, self-reported scale used to evaluate a patient's impression of the severity of the overall condition over the past 7 days. The PGI-S uses a 5-point response scale, with 5 being “very severe” and 1 being “none” (introducer Guy et al. 1976).

Patient's overall impression of change and its importance (PGI-CI)

A patient's overall impression of change is a single-item self-reported measure used to evaluate a patient's impression of a change in the patient's condition compared to at the beginning of the study. It uses a 7-point response scale, where 7 corresponds to “very poor” and 1 corresponds to “very improved” (Introducer Guy et al. 1976). In a follow-up question regarding the patient's overall impression of the change, the patient is asked to indicate whether the change experienced is important to him or her, with the answer option being "yes" or "no". or “N/A” if the patient has not experienced any.

Most important symptom (MIS)

The purpose of the Most Significant Symptom questionnaire was to identify the most problematic symptom for the patient in the past 7 days. MIS is based on a severity rating scale of 2.0 or higher on the University of Washington Quality of Life Questionnaire Scale, plus several symptoms related to disease and/or treatment (Rogers et al. 2002). Patients are asked to select up to four of the most troublesome symptoms of the past week.

PRO-CTCAE

PRO-CTCAE is a validated question bank used to characterize the presence, frequency, severity, and/or extent of disturbance of daily functioning of 78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 2015). The PRO-CTCAE included 124 questionnaires rated either dichotomously (to determine presence vs. absence) or on a 5-point scale (to determine frequency, severity, and disturbance of daily functioning). Therapeutic toxicity may be as follows: observable signs (eg, vomiting) or unobservable symptoms.

(eg, nausea). The standard PRO-CTCAE recall period is 7 days.

A subset of the 11 symptoms currently considered most suitable for treatment was selected for this study. Symptoms were selected based on the following previous studies: with atezolizumab + tiragolumab (Rodriguez-Abreu et al. 2020), patient and clinician-reported symptomatic therapeutic toxicity (Hansen et al. 2020), recommendations for symptoms to be measured in head and neck cancer (Cella et al. 2011; Chera et la. 2014)

Blood sample for whole genome sequence or whole exome sequence

At participating sites, blood samples are collected for DNA extraction so that WGS or WES can identify variants that occur specifically in tumors associated with progression to more severe disease states that are predictive of response to study drug. . DNA extracted from blood can be compared to DNA extracted from tissues, and somatic variants can be identified by distinguishing germline variants from somatic variants. The sample may be sent to one or more laboratories for analysis.

The collection and submission of blood samples for WGS or WES is subject to the review and approval of preliminary studies by the respective institutional IRB/EC and, where applicable, the appropriate regulatory body. If an institution has not been granted accreditation for WGS or WES, then these sections of the protocol do not apply to that institution.

Genomics is increasingly providing researchers with information about disease pathobiology. WGS and WES provide comprehensive characterization of the genome and exome, respectively, and use the clinical data collected in this study to monitor efficacy and safety or predict which patients are more likely to respond to drugs or develop adverse events. It can increase the chances of developing new therapeutic approaches or new methods. The data are analyzed in the context of this study, but may also be explored in conjunction with data from other studies. The availability of larger data sets aids in the identification and characterization of important biomarkers and pathways to support future drug development.

Refer to the laboratory manual for sampling procedures, storage conditions, and shipping instructions.

Blood samples collected for WGS or WES should be stored until they are no longer needed or are depleted. However, the storage period is subject to the informed consent form approved by the IRB/EC and applicable laws (eg health authority requirements).

Samples for Research Biosample Repository

A Research Biosample Repository (RBR) is a group of centrally managed facilities used for long-term storage of human biological specimens, including body fluids, solid tissues and their derivatives (eg, DNA, RNA, proteins, peptides). The collection, storage, and analysis of RBR samples could facilitate the rational design of new drugs and the development of diagnostic tests, enabling individualized drug therapy for future patients.

Samples for RBR are collected from patients who have given specific consent to participate in this elective study. RBR samples are analyzed to achieve one or more of the following goals:

Research on the association of biomarkers with efficacy or disease progression

Identification of safety biomarkers associated with susceptibility to adverse events or that may lead to improved monitoring or investigation of adverse events

Promote knowledge and understanding of disease biology and drug safety

Study drug response, including drug effects and drug absorption and treatment processes

Development of biomarkers or diagnostic assays and establishment of performance characteristics of these assays

sample collection

The following samples are stored in RBR and used for research purposes including, but not limited to, studies on atezolizumab, tiragolumab, head and neck cancer or biomarkers related to drug safety.

Residual blood, plasma, PBMC and tumor tissue samples (excluding the remaining stored tissue blocks returned to the site) and procedures medically ordered and performed at the investigator's discretion during the course of the study (e.g., bronchoscopy, esophageal gastroduodenoscopy) Derivatives (e.g., DNA, RNA, proteins, peptides), including residual tissue samples from colonoscopy)

Optional blood samples for DNA extraction collected at any time during the study

Optional stool samples collected prior to dosing on Cycle 1, Day 1 and between Cycle 2, Day 15 and before dosing on Cycle 3, Day 1 These samples may be collected at home.

The sample may be sent to one or more laboratories for whole metagenomic sequencing via WGS, WES or other genomic analysis methods, microbial culture, and microbial community analysis via germline or somatic variants. Genomics is increasingly providing researchers with information about disease pathobiology. WGS and WES provide comprehensive characterization of the genome and exome, respectively, and use the clinical data collected in this study to monitor efficacy and safety or predict which patients are more likely to respond to drugs or develop adverse events. It can increase the chances of developing new therapeutic approaches or new methods.

Data generated from RBR are analyzed in the context of this study, but can also be explored by integrating with data from other studies. The availability of larger data sets aids in the identification and characterization of important biomarkers and pathways to support future drug development.

RBR samples should be stored until they are no longer needed or are depleted. However, the retention period of the RBR is subject to the informed consent form approved by the IRB/EC and applicable laws (eg health authorities requirements).

G. Treatment and patient discontinuation

cessation of treatment

Patients should permanently discontinue study treatment if they experience any of the following:

Unacceptable toxicity associated with the study treatment, including the development of immune-mediated adverse events that the investigator deems unacceptable given the severity of the event and the potential response of the individual patient to treatment.

Any medical condition that could endanger the patient's safety if the patient continues research treatment

Judgment by the investigator or sponsor that discontinuation of treatment is in the best interest of the patient

Use of another non-protocol anticancer therapy

·Pregnant

Radiological disease progression according to RECIST v1.1

Exception: Patients are permitted to continue study treatment after the RECIST v1.1 criteria for advanced disease have been met if all criteria outlined for treatment beyond radiological progression are met.

For patients treated beyond radiological progression in accordance with RECIST v1.1: loss of clinical benefit as determined by the investigator after integrated evaluation of radiological data, biopsy results (if available) and clinical status

The primary reason for discontinuation of study treatment should be documented in the appropriate eCRF. Patients who prematurely discontinue study treatment are not replaced.

Patients return to the clinic for a treatment discontinuation visit ≤30 days after the last dose of study treatment. A visit where the response assessment indicates disease progression may be used as a discontinuation visit, in which case all assessments related to the discontinuation visit must be performed at that time.

If a patient discontinues study treatment for an adverse event considered to be related to the study treatment (including an adverse event of special interest) and the reaction persists for 30 days after the last dose of study treatment, the reaction may cause the event to stabilize or be reversible. The response should be followed until resolution or judgment by the investigator that the absence has occurred.

follow-up evaluation

Tumor Assessment

Patients who discontinue study treatment (including, but not limited to, clinical decline or toxicity) in the absence of radiological disease progression in accordance with RECIST v.1.1, regardless of whether the patient is starting new chemotherapy, are treated with RECIST v1 Tumor response assessments as outlined in the activity schedule should continue until radiological disease progression, withdrawal of consent, death, or termination of the study by the sponsor according to .1, whichever occurs first. If progressive disease is suspected, a scan should be performed at any time at the discretion of the investigator.

Survival and follow-up therapy

After discontinuation of treatment (unless the patient withdraws consent to follow-up or the sponsor terminates the study), follow-up and follow-up of survival via phone, patient records and/or clinic visit approximately every 3 months until patient death Gather information on new anticancer therapies.

Information on follow-up chemotherapy includes systemic therapy (e.g., chemotherapy, targeted therapy, immunotherapy), surgery (e.g., resection of local and/or metastatic disease), and radiation procedures (e.g., radiation therapy for tumor lesions) do.

patient discontinuation

Patients have the right to voluntarily withdraw from the study at any time for any reason. In addition, the investigator has the right to withdraw a patient from the study at any time.

Reasons for a patient to discontinue the study may include, but are not limited to:

환자의 동의 철회

Withdrawal of patient consent

연구 종료 또는 현장 폐쇄

End of study or closure of the site

추적 상실

lost track

시험자 또는 시험의뢰자에 의해 판단에 따라, 프로토콜 요구사항을 준수하지 않는 것으로 정의되는 환자의 비준수

Patient non-compliance, defined as non-compliance with protocol requirements, as judged by the Investigator or Sponsor

Every effort should be made to obtain a reason for the patient to discontinue the study. The main reason for study discontinuation should be documented in the appropriate eCRF. If a patient requests withdrawal from the study (i.e., request withdrawal from any survival follow-up), the request must be documented in the original document and signed by the investigator. Patients who withdraw from the study (ie, follow-up survival) are not replaced.

If a patient withdraws from the study (ie, survival follow-up), research staff may use publicly available sources of information (eg, county records) to obtain information about their survival status.

H. analysis

Validity analysis

Primary efficacy endpoint

The primary efficacy endpoint is the confirmed ORR. A confirmed objective response is defined as two consecutive CR or PR occurrences at 4-week intervals, as judged by the investigator according to RECIST v1.1. Patients who do not meet these criteria, including those without post-baseline tumor assessment, are considered non-responders. Confirmed ORR is defined as the proportion of patients with an identified objective response.

A primary efficacy analysis occurs when all patients are enrolled and a follow-up of at least approximately 5 months is achieved among patients being followed for ORR evaluation.

The primary efficacy analysis population consists of all randomized patients grouped according to their assigned treatment. Estimates of ORR and 95% CI were calculated using the Cloper-Pearson method for each treatment group.

secondary efficacy endpoint

duration of response

DOR is assessed in patients who have achieved an identified objective response as judged by the investigator according to RECIST v1.1. DOR is defined as the time from the first occurrence of an identified objective response to the date of first disease progression or death from any cause, whichever occurs first, as determined by the investigator in accordance with RECIST v1.1. Patients with no progression and no death at the time of analysis are censored on the date of their last tumor assessment. The Kaplan-Meier methodology is used to estimate the median DOR for each treatment arm and generate a Kaplan-Meier curve. The Brookmeyer-Crowley methodology is used to construct a 95% CI for the median DOR for each treatment group.

Progression-free survival, including 6-month progression-free survival

PFS is defined as the time between the date of randomization and the first documented date of disease progression or death, whichever occurs first, as assessed by the investigator according to RECIST v1.1. Patients who have not experienced disease progression or have not died by the data deadline will be censored at the final tumor evaluation. Patients without post-baseline tumor evaluation are censored on the date of randomization.

The Kaplan-Meier methodology is used to estimate the median PFS for each treatment arm and generate a Kaplan-Meier curve. The Brookmeyer-Crowley methodology is used to construct a 95% CI for the median PFS for each treatment group. The PFS rate at 6 months after randomization was estimated using the Kaplan-Meier methodology for each treatment arm with a 95% CI calculated using the standard error derived from the Greenwood formula.

Overall survival including 6-month and 12-month overall survival rates

OS is defined as the time between the date of randomization and death from any cause. Data for patients not reported as dead by the data deadline will be censored on the last confirmed survival date. Data for patients with no post-baseline information are censored on the date of randomization. OS and OS ratios at 6 and 12 months are analyzed using the same method described for PFS.

Patient Reported Results

PROMIS

TTCD for bodily function using Item Bank v2.0-Body Functions-Short Form 10b is defined as the time from the date of randomization to the first clinically significant deterioration. Clinically significant deterioration in identified bodily function is defined as death following an initial clinically meaningful increase above baseline or a clinically significant decrease from baseline that must be maintained for at least two consecutive evaluations. A T-score change >4 is considered clinically significant for a score on the Body Function subscale.

TTCD is assessed in the ITT population. Patients who have not experienced clinically significant deterioration identified by the clinical deadline are censored at the last hour of completing the evaluation. Patients are censored on the date of randomization if no baseline or post-baseline evaluation has been performed. TTCD using the PROMIS scale is analyzed using the same method as the PFS.

척도(통증, 피로 및 신체 기능)의 탐색적 분석은, 요약 통계 및 PROMIS 통증, PROMIS 피로 및 PROMIS 신체 기능 설문지의 사용에 의해 보고되고 PROMIS 채점 매뉴얼에 따라 계산된 ITT 모집단에서의 기준선으로부터의 평균 변화를 포함한다.PROMIS

Exploratory analyzes of the scales (pain, fatigue and body function) were reported by use of summary statistics and the PROMIS Pain, PROMIS Fatigue and PROMIS Body Function Questionnaires and calculated according to the PROMIS Scoring Manual, Mean Change from Baseline in the ITT Population. includes

Summary statistics, including counts and proportions, are presented for PGI-CI, PGI-S and most important symptoms and are exploratory.

The analysis of PRO-CTCAE is exploratory in nature and mainly descriptive, focusing on characterizing the patterns of disease and symptomatic treatment toxicity during this study. The results of these exploratory analyzes are presented separately from other safety analyses. PRO-CTCAE data is analyzed at the item level in accordance with current NCI recommendations for data processing. For each treatment arm, the number (percent) of patients reporting symptoms by category "frequency", "severity", "interference" and "presence" is reported at each assessment.

In addition, the frequency of symptoms is cross-plotted with the severity of symptoms to explore the effects of symptoms when they occur. A summary table is also provided of the percentage of patients in the treatment arm who reported severity of "severe" or "very serious" symptoms during the study.

Safety analysis

The safety analysis population consisted of all randomized patients who received at least one dose of atezolizumab or tiragolumab/placebo.

Safety analyzes are performed in the treatment sector and are based on actual treatment received. Specifically, if a patient is receiving any amount of tyragolumab, at randomization, regardless of the initial treatment assignment, the patient is included in the atezolizumab + tiragolumab arm in the safety analysis.

Drug exposure is summarized, including duration, dose, and dose intensity.

Verbose descriptions of adverse events are mapped to MedDRA synonym terms and graded according to NCI CTCAE v5.0, and severity for CRS is also graded by investigators according to the ASTCT consensus grade scale. All adverse events are summarized by treatment arm and NCI CTCAE grade. CRS is also summarized by treatment category and ASTCT consensus grade. In addition, serious adverse events, immune-mediated adverse events, and adverse events that result in discontinuation or interference with the study treatment are summarized accordingly. Multiple occurrences of the same event are counted once at the maximum severity.

All deaths and causes of death are summarized by treatment category.

Laboratory data with values outside the normal range are identified. Additionally, selected laboratory data, including ADA results, are summarized.

Pharmacokinetic analysis

PK samples of tiragolumab and atezolizumab are collected in this study. Tiragolumab and atezolizumab serum concentration data (minimum serum concentration and maximum serum concentration) are tabulated and summarized.

Descriptive statistics include mean, median, range and standard deviation, where appropriate.

Additional PK analyzes are performed, as appropriate, depending on the availability of data.

Immunogenicity assay

Immunogenicity assays include patients who have undergone an ADA assessment, and patients are classified according to treatment received. The number and proportion of treatment-emergent ADA-positive and ADA-negative patients are summarized by treatment arm.

The relationship between ADA status and safety, efficacy, and PK endpoints can be analyzed and reported through descriptive statistics.

Biomarker analysis

Biomarker analysis is descriptive. Descriptive statistics are used to summarize biomarker subgroups and their relationships to efficacy endpoints; Data can be analyzed in the context of this study and in conjunction with data from other studies.

Interim analysis

When approximately 60 patients are enrolled and have the opportunity to follow up for approximately 5 months or longer, an interim analysis of efficacy is planned and reviewed by the IMC.

Example 16. A Phase Ib/II, Open Label, Multicenter, Randomized Comprehensive Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients with Muscle Invasive Bladder Cancer (MIBC)

The time from diagnosis of muscle invasive bladder cancer (MIBC) to cystectomy is typically 4-8 weeks, providing patients with the opportunity to provide neoadjuvant therapy to improve recurrence rates and OS. The benefit of neoadjuvant chemotherapy is moderate compared to cystectomy alone, with a 5% increase in overall survival (OS) in patients treated with neoadjuvant chemotherapy (Vale et al., Eur Urol , 48: 202-205, 2005). Patients who achieved a pathological complete response (pCR) achieved the greatest benefit when receiving neoadjuvant cisplatin-based chemotherapy, with 80-90% survival at 5-year follow-up; However, up to 50% of patients may have residual high-risk disease (pT2 or higher) at the time of surgery, and the 5-year survival rate is less than 50% (Rosenblatt et al., Eur Urol, 61: 1229-1238, 2011; Bhindi et al. , Eur Urol , 72: 660-664, 2017). Thus, pCR could be a surrogate marker for increased efficacy and survival in neoadjuvant therapy for MIBC.

WO39613 is a Phase Ib/II, open-label, multicenter, randomized, comprehensive study evaluating the efficacy and safety of multiple immunotherapy-based treatments and combinations in patients with cisplatin-incompetent MIBC. The study is designed to have the flexibility to open new therapies, close existing treatment segments that exhibit minimal clinical activity or unacceptable toxicity, or modify patient populations as new treatments become available (e.g., previous chemotherapy or related to biomarker status). Patients are randomly assigned to an experimental group consisting of a control group (atezolizumab (Atezo)) or atezolizumab in combination with tiragolumab (Atezo + Tyra) (Figure 24 and Table 69).

atezo: atezolizumab; MIBC: muscle invasive bladder cancer; Tyra: Tiragolumab. ^a The sponsor may decide to postpone or discontinue enrollment within a given treatment area. Therefore, not all experimental divisions may be opened for registration at the same time. ^b If clinical activity is observed in the trial arm during the preliminary phase, approximately 25 additional patients will be enrolled in the arm during the expansion phase. ^c The rate of randomization depends on the number of experimental arms opened for randomization (e.g., if an arm is added or randomization to an arm is stopped while analysis of results from the preliminary phase is withheld) and the likelihood of being assigned to a control arm is subject to the condition that it does not exceed 35%.

The classification of targets and proposed mechanisms of action for atezolizumab and tiragolumab is summarized in Table 70.

PD-L1 = programmed death ligand 1; TIGIT = T-cell immunoreceptor with Ig and ITIM domains

The specific study objectives and corresponding endpoints are summarized in Table 71.

ADA = anti-drug antibody; CR = complete response; DOR = duration of response; EFS = no symptoms

survival; iRECIST = immune RECIST; MIBC = muscle invasive bladder cancer; NCI CTCAE v4.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0; OS = overall survival; PK = pharmacokinetics; RFS = relapse-free survival.

The objective response at a single time point is determined by the investigator using RECIST v1.1. The overall response according to iRECIST is programmatically calculated by the sponsor based on individual lesion data evaluated by the investigator.

Approximately 150-350 patients are enrolled, divided between MIBC Cohort 1 (PD-L1+) and MIBC Cohort 2 (PD-L1-). Enrollment in the experimental section consists of two phases: a preliminary phase, followed by an expansion phase. All treatment groups are identical for MIBC Cohort 1 (PD-L1+) and MIBC Cohort 2 (PD-L1-) in the preliminary phase. Patients were tested in either MIBC Cohort 1 (PD-L1+) or MIBC Cohort 2 (PD-L1-) after centralized PD-L1 testing on transurethral resection (TURBT) samples of bladder tumors using the VENTANA PD-L1 (SP142) assay. is assigned to Identification of all intensities in tumor-infiltrating immune cells with a PD-L1 immune cell (IC) score of 2 or 3 (IC2/3), covering at least 5% of the tumor area occupied by tumor cells, the relevant intratumoral and adjacent peritumoral stroma Patients corresponding to the presence of possible PD-L1 staining are assigned to MIBC Cohort 1 (PD-L1+). An IC score of 0 or 1 (IC0/1, corresponding to the presence of identifiable PD-L1 staining of any intensity in tumor-infiltrating immune cells covering ≤5% of the tumor area occupied by tumor cells, the relevant intratumoral and adjacent peritumoral stroma ) are assigned to MIBC Cohort 2 (PD-L1-).

In the preliminary phase, up to 30 patients are enrolled in the Artezo + Tyra group and approximately 15 patients are enrolled in all other groups for each MIBC PD-L1 cohort. If clinical activity is observed in the trial arm during the preliminary phase, approximately 25 additional patients will be enrolled in the arm during the expansion phase.

The sponsor may decide to postpone or discontinue enrollment within a given treatment arm. Experimental groups with insufficient clinical activity or unacceptable toxicity will not be expanded. To enable further subgroup analysis, additional patients can be enrolled to ensure a balance between treatment groups with respect to demographic and baseline characteristics, including potential predictive biomarkers.

The randomization rate depends on the number of available trial arms (e.g., if a segment is added or segment enrollment is suspended while the preliminary stage results analysis is pending), provided that the probability of being assigned to a controlled segment does not exceed 35%. follow Randomization takes into account divisional exclusion criteria. Patients are eligible for certain parts if:

Meets any of the exclusion criteria described for that sector.

Patients in the atezolizumab control and experimental groups are treated until there is unacceptable toxicity or loss of clinical benefit, which

After an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical status (eg worsening of symptoms such as pain with disease), the investigator's decision is followed by the investigator's decision. Patients receive up to 1 year of treatment after surgery, followed by 2 years of 3-month follow-up evaluation.

A. Assessment and monitoring

All patients are closely monitored for adverse events throughout the study, and adverse events are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Patients receive tumor assessments every 9 weeks (starting on Day 1 of Cycle 1) for the first 54 weeks and then every 12 weeks thereafter. The response is evaluated by:

Investigators using RECIST v1.1 (Eisenhauer et al., Eur J Cancer, 45: 228-247, 2009). If clinical activity has been demonstrated in the trial sector, the sponsor will

You may be asked to submit a tumor assessment scan for that group.

Baseline tumor tissue samples are collected from all patients, preferably by biopsies performed at the start of the study. If the investigator considers that a biopsy cannot be performed, the archived tumor tissue may be submitted. Tumor tissue is also collected from patients who discontinue Phase 1 due to unacceptable toxicity or loss of clinical benefit, as determined by the investigator (if deemed clinically feasible) by the investigator. These samples as well as blood samples collected during the study are utilized for biomarker studies.

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are obtained at various time points prior to and during study therapy administration.

B. Study End and Study Duration

Study end date is defined as the date the last patient completed the last visit in both phases, including survival follow-up visits by phone or site visit.

The total study duration from screening of the first patient to study termination is approximately 3-5 years.

C. Rationale for Study Design

Research Evidence and Benefit-Risk Assessment

This study was designed to accelerate the expression of cancer immunotherapy (CIT) combinations by identifying early signals and establishing proof-of-concept clinical data in cisplatin-incompetent MIBC patients.

Platinum-based neoadjuvant chemotherapy has been associated with improved OS but is only suitable for a small number of patients. Given the relatively limited treatment options for patients with cisplatin ineligible MIBC and, in addition, the poor prognosis and potential toxicity associated with treatment for locally advanced or metastatic UC, this population appears to be in need of treatment options and therefore suitable for testing new treatment candidates. is considered The currently prevalent CIT approach targets T-cell inhibitory factors such as PD-L1 (programmed death ligand 1)/PD-1 (programmed death-1) to bypass immune evasion mechanisms and promote anti-tumor responses. it will activate

CIT has demonstrated clear clinical efficacy with significant survival benefits observed in several advanced malignancies, and there is evidence that PD-1/PD-L1 checkpoint blockade can generate pCR and sustained responses in UC patients (Powles et al. al., Nat Med, 25: 1706-1714, 2019; Necchi et al., Int J Clin Oncol , 36: 3353-3360, 2018). Although these targets have resulted in surprising clinical therapeutic success for a variety of cancer indications, ongoing research indicates that a sequence of stepwise events is required for generation of an effective anti-tumor immune response (Chen and Mellman, Immunity, 39: 1- 10, 2013). Each event is critical for an effective response, and each is also sensitive to multiple tumor immune evasion mechanisms. Therefore, for the development of cancer immunity spread and CIT field, the need to identify and bypass various factors affecting the absence or avoidance of an effective anticancer immune response becomes important. Combination of atezolizumab with agents targeting different immune evasion mechanisms or novel second-generation CPIs may increase response rates and further reduce disease recurrence rates in this population.

A potential risk in patients with MIBC is associated with adverse events related to study treatment. In most countries, patients wait an average of 4-8 weeks between diagnosis and surgery for urothelial cancer. Participation in this trial that includes preoperative care is not expected to be associated with a participant's surgical delay. Furthermore, atezolizumab did not affect operability or increase surgery-related risks in the ABACUS study (Powles et al., Nat Med, 25: 1706-1714, 2019).

Evidence for perioperative treatment in muscle-invasive bladder cancer

The therapeutic contribution of neoadjuvant therapy and postoperative maintenance therapy is unknown. The WO39613 study is designed to evaluate therapeutic efficacy and to perform extensive biomarker analysis on sequential patient tissues.

IMVigor010 is a phase III randomized study in which patients with MIBC received atezolizumab versus observation as adjuvant therapy after surgical resection and lymphadenectomy. Although this study did not meet the corresponding primary endpoint of disease-free survival benefit with atezolizumab adjuvant therapy in the willing-to-treat population, subgroup analysis and nonclinical data of T3 and T4 patients (Liu et al., Cancer Discov ) , 6: 1382-1399, 2016; Pai et al., Immunity , 50: 477-492, 2019; Hussain et al., J Clin Oncol , 38(15 Suppl.): 5000, 2020), immunotherapy check This suggests that the patient may have to have residual or active disease for point immunotherapy to be effective.

D. Evidence for immunotherapy in patients with muscle-invasive bladder cancer ineligible for cisplatin-based chemotherapy

Approximately 50% of patients with MIBC are not eligible for cisplatin-based neoadjuvant chemotherapy, and there is currently no perioperative systemic therapy recommended for these patients; Cystectomy with bilateral pelvic lymphadenectomy is the standard of care. In addition, less than half of MIBC patients eligible for neoadjuvant chemotherapy will receive it due to personal preference or other comorbidities. Therefore, new therapies are needed to improve outcomes in MIBC patients.

PD-1/PD-L1 checkpoint immunotherapy is approved for all patients who have undergone chemotherapy for mUC and for 1L mUC patients ineligible for platinum-based chemotherapy or cisplatin-based chemotherapy if the tumor is PD-L1+ do. The largest studies investigating the safety and efficacy of PD-1/PD-L1 checkpoint neoadjuvant immunotherapy in patients with MIBC are the ABACUS and PURE-01 studies (Powles et al., Nat Med , 25: 1706-1714, 2019; Necchi et al., Int J Clin Oncol , 36: 3353-3360, 2018).

E. Evidence for pathological complete remission as a primary endpoint

Pathological complete remission (pCR) and pathological downgrade (exploratory endpoint) were validated as surrogate markers of activity in this setting due to their association with sustained remission-free survival (Rosenblatt et al., Eur Urol , 61: 1229). -1238, 2011; Bhindi et al., Eur Urol , 72: 660-664, 2017).

Increased baseline CD8 T cell infiltration and PD-L1+ disease have been shown to increase the potential of pCR as immunotherapy in the neoadjuvant setting (Powles et al., Nat Med , 25: 1706-1714, 2019).

F. Evidence for using atezolizumab as a control

There is no standard of care to provide systemic therapy before or after surgical resection for MIBC patients who are rejected or ineligible for cisplatin-based neoadjuvant chemotherapy.

Because ABACUS and PURE-01 studies showed that PD-1/PD-L1 checkpoint immunotherapy is active and safe in patients with MIBC, and response rates are similar to those historically observed with cisplatin-based chemotherapy, atezolizumab zero was chosen. ABACUS and PURE-01 data show that compared to mUC, MIBCs are generally more inflamed and therefore more likely to benefit from PD-1/PD-L1 checkpoint immunotherapy, which indicates that PD in the IMVigor211 and KN-045 studies This is because -L1 expression was only observed in 25% and 28.5% of patients treated with mUC.

Randomized studies evaluating immunotherapy combinations could identify safe and effective treatments for MIBC patients who are ineligible for cisplatin-based chemotherapy, while at the same time greatly enhancing our understanding of cancer biology and new trials and therapies for all MIBC patients. It can improve the repeatability when designing. This study may include possible future groups and cohorts using immunotherapy combinations for which adequate clinical safety has been demonstrated.

G. Evidence for separate PD-L1+ and PD-L1- cohorts

PD-1/PD-L1 blockade is FDA-approved for patients with PD-L1+ mUC ineligible for 2L mUC and cisplatin-based chemotherapy, but not for MIBC patients. In the ABACUS study, pCR benefit was higher in atezolizumab-treated PD-L1+ (37.1%, n = 13/35) patients than in PD-L1- (24.5%, n = 12/49) disease, although PD-L1-disease Some patients may still benefit from atezolizumab or an immunotherapy combination. The study design allows the sponsor to separately evaluate the effectiveness of atezolizumab and other immunotherapy combinations in these patient subsets and to enroll in groups in each cohort with no evidence of benefit without affecting investigations in other cohorts. can be finished

H. Evidence of investigation into the effect of perioperative treatment on ctDNA in muscle-invasive bladder cancer cohort

Changes in circulating tumor DNA (ctDNA) concentrations over time have the potential to be used to detect disease recurrence (Moding et al., Nat Cancer , 1: 176-183, 2020). ctDNA shed from cancer cells into peripheral blood can be collected non-invasively and tested for the presence of tumor-specific mutations. Several characteristics of UC make them strong candidates for predicting disease recurrence using ctDNA testing.

UC는 높은 체세포 돌연변이율을 나타댄다; 따라서 매우 적은 수의 유전자 또는 표적 영역이 질병 특성을 예측하는 데 매우 유익할 수 있다(Todenhφfer et al., Bladder Cancer, 4: 1929, 2018).

UC indicates a high rate of somatic mutation; Thus, a very small number of genes or target regions can be very beneficial in predicting disease characteristics (Todenhφfer et al., Bladder Cancer , 4: 1929, 2018).

UC에서 전이성 재발은 원래 종양과 돌연변이 분석에서 크게 다르지 않은 클론 기원을 갖는 것으로 관찰되었다(Thomsen et al., Sci Rep, 7: 11702, 2017).

Metastatic recurrence in UC was observed to have a clonal origin that did not differ significantly from the original tumor in mutational analysis (Thomsen et al., Sci Rep , 7: 11702, 2017).

UC에서 쌍을 이루는 종양에 대한 분석을 통해 소수의 서브클론을 확인하여, 최종 치료 후 종방향 ctDNA 테스트의 예후적 잠재력을 강화했다(Lamy et al., Cancer Res, 76: 5894, 2016; Nodentoft et al., Cell Rep, 7: 1649-1663, 2014).

Analysis of paired tumors in UC identified a small number of subclones, enhancing the prognostic potential of longitudinal ctDNA testing after final treatment (Lamy et al., Cancer Res , 76: 5894, 2016; Nodentoft et al. al., Cell Rep , 7: 1649-1663, 2014).

신보조제 화학요법을 받고 방광 절제술을 받은 MIBC 환자 68명으로부터 종방향으로 채취한 샘플에 대해 Natera Signatera ctDNA 분석을 사용하여 분석을 수행했다. 상기 분석은 방광 절제술 후 임의의 시점에서 샘플이 ctDNA 양성인 환자의 전체 재발률이 76%인 반면 방광 절제술 후 ctDNA 음성을 유지한 환자의 경우 0%(21개월 중앙값 추적 관찰)를 보였다(Christiensen et al. J Clin Oncol. 37(18): 1547-1557, 2019).

Analyzes were performed using Natera Signatera ctDNA analysis on samples taken longitudinally from 68 patients with MIBC who underwent cystectomy after neoadjuvant chemotherapy. The analysis showed an overall recurrence rate of 76% for patients with samples positive for ctDNA at any time point after cystectomy, versus 0% (median follow-up for 21 months) for patients who remained ctDNA negative after cystectomy (Christiensen et al. J Clin Oncol. 37(18): 1547-1557, 2019).

These data represent a biomarker selected subpopulation of MIBC patients with high unmet need for urgent treatment options. However, there are currently no data on: 1) the effect of neoadjuvant immunotherapy on ctDNA before and after cystectomy in patients with urothelial cancer; 2) In patients treated with neoadjuvant immunotherapy, maintenance immunotherapy may help prevent recurrence of urothelial cancer after cystectomy; 3) when maintenance immunotherapy reduces the risk of disease recurrence,

Patients treated with neoadjuvant immunotherapy have measurable ctDNA after cystectomy.

As part of this study, ctDNA was measured retrospectively at four time points in all PD-L1+ MIBC patients treated with atezolizumab and atezolizumab plus tiragolumab. 1) before Day 1 of Cycle 1; 2) before cystectomy; 3) 4-6 weeks after cystectomy; and 4) 6 months after cystectomy. The association between event-free survival (EFS) and OS and ctDNA outcome at these time points is investigated. Through these results, the effect of neoadjuvant and the

Know the design of future studies on the value of maintenance therapy. ctDNA investigated at these time points in different segments of the study and clinical activity observed in other segments of the study while awaiting the results of these studies.

The use of this design and ctDNA allows the evaluation of: 1) the effect of neoadjuvant therapy on ctDNA and pathological response; 2) effect of surgery on residual ctDNA after neoadjuvant immunotherapy; and 3) whether maintenance immunotherapy reduces the risk of ctDNA and disease recurrence in postoperative MIBC patients.

Example 17. Materials and Methods for Study WO39613

A. Selection Criteria

Patients must meet all of the following criteria:

연령 ≥ 18세.

Age ≥ 18 years.

조사관의 판단으로, 연구 프로토콜을 준수하는 능력

ability to comply with the study protocol, at the discretion of the investigator

0 또는 1의 ECOG 전신 활동도

ECOG systemic activity of 0 or 1

신보조제 시스플라틴 기반 화학요법을 거부하거나 신보조제 시스플라틴 기반 요법이 적절하지 않은 환자. 본 연구에 대한 시스플라틴 부적격은 크레아티닌 청소율 < 60mL/min 및/또는 등급 ≥ 2 청력 손실 및/또는 등급 ≥ 2 신경병증으로 정의된다.

Patients who refuse neoadjuvant cisplatin-based chemotherapy or for which neoadjuvant cisplatin-based therapy is not appropriate. Cisplatin ineligibility for this study was defined as creatinine clearance < 60 mL/min and/or grade ≥ 2 hearing loss and/or grade ≥ 2 neuropathy.

적합하고 계획된 방광 절제술.

Appropriate and planned cystectomy.

조직학적으로 문서화된 MIBC(pT2-4, N0, M0)로서, TCC 또는 방광의 요로상피 세포 암종이라고도 한다.

Histologically documented MIBC (pT2-4, N0, M0), also called TCC or urothelial cell carcinoma of the bladder.

o Residual disease after TURBT (surgical findings, cystoscopy/endoscopy or radiologic presence).

o Patients with mixed tissue should have a dominant transitional cell pattern.

중앙 테스트를 통해 PD-L1 및 추가 바이오마커 상태를 결정하는 데 적합한 TURBT 표본의 가용성.

Availability of suitable TURBT specimens to determine PD-L1 and additional biomarker status through central testing.

o TURBT specimens must be submitted with the relevant pathology report. Tumor tissue is processed in two different ways (ie, paraffin-fixed tissue and fresh tissue are required for separate biomarker analysis). Tumor tissue of the bladder or upper urinary tract should be of good quality based on total and viable tumor content, and should contain a muscle-invasive component of the tumor (ie, T2 or greater) as confirmed by local pathology review.

o Patients who have additional tissue samples from procedures performed at different times in the course of the MIBC (eg samples from the previous TURBT) may be asked (but not required) to also submit these samples for central testing.

CT 또는 MRI에 의한 N0 또는 M0 질환(등록 후 4주 이내).

N0 or M0 disease by CT or MRI (within 4 weeks of enrollment).

연구 치료 시작 전 14일 이내에 수득한 하기와 같은 실험실 결과로 정의되는 적절한 혈액 및 말단 장기 기능:

Adequate blood and terminal organ function as defined by the following laboratory results obtained within 14 days prior to initiation of study treatment:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10 ⁹ /L (1500/μL) without G-CSF support

- White blood cell (WBC) count ≥ 2.5 x 10 ⁹ /L (2500/μL)

- Lymphocyte count ≥ 0.5 x 10 ⁹ /L (500/μL)

- Platelet count ≥ 100 x 10 ⁹ /L (100,000/μL) without transfusion

- Hemoglobin ≥ 90 g/L (9.0 g/dL)

The patient may be transfused; However, blood transfusions are not permitted within two weeks of being tested for eligibility.

Erythropoietin stimulants may be used in patients with epilepsy or chronic kidney disease with low erythropoietin production.

- AST, ALT and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN)

- Bilirubin ≤ 1.5 x ULN, with the following exceptions:

Known Gilbert's disease patients: bilirubin levels ≤ 3 x ULN

- albumin ≥ 25 g/L (2.5 g/dL)

- Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula)

- For patients not receiving therapeutic anticoagulants:

Partial thromboplastin time (PTT) or aPTT ≤ 1.5 x ULN

Prothrombin time (PT) or International Normalized Ratio (INR) ≤ 1.5 x ULN

스크리닝시 HIV 검사 음성

HIV test negative at screening

o Patients without a prior positive HIV test result will be tested for HIV at screening unless permitted by local regulations.

선별검사시 총 B형 간염 코어 항체(HBcAb) 검사 음성, 또는 선별검사시 총 HBcAb 검사 양성 후 정량적 B형 간염 바이러스(HBV) DNA < 선별검사시 500IU/mL

Quantitative hepatitis B virus (HBV) DNA < 500 IU/mL at screening after negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb at screening

선별 검사시 C형 간염 바이러스(HCV) 항체 검사 음성, 또는 선별 검사시 HCV 항체 검사 양성 후 HCV RNA 검사 음성.

Hepatitis C virus (HCV) antibody test negative at screening test, or HCV RNA test negative after HCV antibody test positive at screening test.

가임 여성의 경우: 금욕 유지(이성간 성교 금지) 또는 피임 방법 사용에 대한 동의 및 난자 기증 자제에 대한 동의

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods and to refrain from egg donation

남성의 경우: 금욕을 유지하기로 동의(이성간 성교 금지) 또는 피임법 사용에 대한 동의 및 정자 기증을 자제에 대한 동의.

For men: Consent to maintain abstinence (no heterosexual intercourse) or consent to use of contraceptive methods and consent to refrain from donating sperm.

B. Exclusion Criteria

Patients meeting any of the following criteria are excluded from study enrollment: Event grades for exclusion criteria are based on NCI CTCAE v4.0.

연구 치료를 시작하기 전에 전신 면역자극제(CTLA-4, 인터페론 및 인터루킨 2를 표적으로 하는 약제를 포함하나 이에 제한되지 않음)를 사용한 사전 치료

Prior treatment with systemic immunostimulants (including but not limited to agents targeting CTLA-4, interferon, and interleukin 2) prior to initiation of study treatment

대조군에 대해서만 적격

Eligible for control group only

이전의 동종 줄기 세포 또는 고형 장기 이식

Previous allogeneic stem cell or solid organ transplantation

연구 치료 시작 전 2주 이내에 전신 면역억제(코르티코스테로이드, 사이클로포스파미드, 아자티오프린, 메토트렉세이트, 탈리도마이드 및 항종양괴사인자-α 제제를 포함하나 이에 제한되지 않음)을 사용한 치료, 또는 연구 치료 동안 전신 면역억제제의 필요성에 대한 예상으로서, 다음 예외를 제외:

Treatment with systemic immunosuppression (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor-α agents) within 2 weeks prior to initiation of study treatment, or during study treatment Anticipation of the need for systemic immunosuppressants, with the following exceptions:

Patients receiving acute, low-dose, systemic immunosuppressants or single pulse doses of systemic immunosuppressants (eg, corticosteroids for contrast allergy 48 hours) are eligible for this study.

Patients receiving mineralocorticoids (eg, fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency were eligible for this study.

연구 치료 시작 전 4주 이내에 약독화 생백신으로 치료, 또눈 아테졸리주맙 치료 중 또는 아테졸리주맙의 마지막 투여 후 5개월 이내에 이러한 백신의 필요성에 대한 예상.

Anticipation of the need for treatment with live attenuated vaccine within 4 weeks prior to initiation of study treatment, during treatment with tonun atezolizumab, or within 5 months after the last dose of atezolizumab.

통제되지 않는 종양 관련 통증. 통증 약제를 필요로 하는 환자는 연구 엔트리에서 안정된 섭생 중에 있어야 한다.

Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry.

중증 근무력증, 근염, 자가면역 간염, 전신성 홍반 루푸스, 류마티스 관절염, 염증성 장 질환, 항인지질항체증후군, 베게너 육아종증, 쇼그렌 증후군, 길랭-바레 증후군, 또는 하기의 예외를 갖는 다발성 경화증을 포함하나 이에 국한되지 않는 자가면역 질환 또는 면역 결핍의 활성 또는 병력:

myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, or multiple sclerosis with the exception of Active or history of autoimmune disease or immunodeficiency that does not include:

Patients with a history of autoimmune-related hypothyroidism and taking thyroid replacement hormone are eligible for this study.

Patients with controlled type 1 diabetes mellitus on stable insulin therapy are eligible for this study.

Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only dermatological signs (eg, excluding patients with psoriatic arthritis) are eligible for this study if all of the following conditions are met:

- The rash should occupy <10% of the body surface area.

- Disease is well controlled at baseline and requires only low potency topical corticosteroids.

- No acute exacerbation of an underlying condition requiring ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids in addition to psoralen within the past 12 months

특발성 폐섬유증, 기질화 폐렴(예: 폐쇄성 세기관지염), 약물 유발성 폐렴 또는 간질성 폐렴의 병력, 또는 선별 흉부 컴퓨터 단층촬영(CT) 스캔 상의 활동성 폐렴의 증거.

A history of idiopathic pulmonary fibrosis, organized pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonia or interstitial pneumonia, or evidence of active pneumonia on a screening chest computed tomography (CT) scan.

적절하게 치료된 자궁경부의 상피암종, 비흑색종 피부암종, 국소 전립선암 또는 I기 자궁암과 같은, 전이 또는 사망의 무시가 가능한 위험(예: 5년 OS 비율 90%)을 갖는 악성 종양을 제외한, 선별검사 전 2년 이내에 UC 이외의 악성 종양의 병력. PSA 재발 없이 치료 목적으로 치료된 국소 전립선암(병기 ≤ pT2c, 글리슨 점수 ≤ 7, 전립선암 진단 시 전립선 특이 항원(PSA) ≤ 20ng/mL로 정의됨) 환자는 자격이 있다. 치료 경험이 없고 적극적인 감시를 받고 있는 기존의 저위험 전립선암(병기 cT1/T2a, 글리슨 점수 ≤ 6, PSA ≤ 10ng/mL로 정의됨) 환자는 자격이 있다.

Except for malignancies with a negligible risk of metastasis or death (e.g., 90% 5-year OS rate), such as appropriately treated epithelial carcinoma of the cervix, non-melanoma skin carcinoma, focal prostate cancer, or stage I uterine cancer. , History of malignancy other than UC within 2 years prior to screening. Patients with regional prostate cancer (defined as stage ≤ pT2c, Gleason score ≤ 7, prostate-specific antigen (PSA) ≤ 20 ng/mL at diagnosis of prostate cancer) treated for therapeutic purposes without PSA recurrence are eligible. Patients with pre-existing low-risk prostate cancer (defined as stage cT1/T2a, Gleason score ≤ 6, PSA ≤ 10 ng/mL) who are treatment-naïve and under active surveillance are eligible.

활동성 결핵(TB)(즉, TB의 징후와 증상이 있음).

Active tuberculosis (TB) (that is, with signs and symptoms of TB).

감염, 균혈증 또는 중증 폐렴의 합병증으로 인한 입원을 포함하나 이에 국한되지 않는 연구 치료 시작 전 4주 이내의 중증 감염, 또는 시험자의 의견상 환자 안전에 영향을 미칠 수 있는 활성 감염.

Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or active infection that, in the opinion of the investigator, could affect patient safety.

연구 치료 시작 전 2주 이내에 치료적 경구 또는 IV 항생제 치료. 예방적 항생제를 투여받는 환자(예를 들어, 요로 감염 또는 만성 폐쇄성 폐질환 악화의 예방)는 본 연구에 적격이다.

Curative oral or IV antibiotic treatment within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (eg, prophylaxis of urinary tract infections or exacerbations of chronic obstructive pulmonary disease) are eligible for this study.

뉴욕심장학회 심장병(Class III 이상), 무작위 배정 전 3개월 이내의 심근경색 또는 뇌혈관 사고, 불안정성 부정맥 또는 불안정형 협심증과 같은 중대한 심혈관 질환.

New York Heart Association heart disease (Class III or higher), myocardial infarction or cerebrovascular accident within 3 months prior to randomization, and serious cardiovascular disease such as unstable arrhythmias or unstable angina.

통제되지 않는 고혈압 (수축기 혈압 > 140 mmHg 및/또는 확장기 혈압 > 95 mmHg으로 정의됨). 이러한 매개변수를 달성하기 위한 항고혈압 요법이 허용된다.

Uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 95 mmHg). Antihypertensive therapy to achieve these parameters is acceptable.

연구 치료 시작 전 28일 이내에 등급 ≥ 3의 출혈 또는 출혈 사건.

Grade ≥ 3 bleeding or hemorrhagic event within 28 days prior to initiation of study treatment.

연구 치료 시작 전 4주 이내에 진단을 위한 것 이외의 주요 외과적 절차, 또는 연구 동안 방광 절제술 또는 신장 요관 절제술 이외의 주요 외과적 절차가 필요할 것으로 예상. 중심 정맥 접근 카테터(예: 포트 또는 이와 유사한 것)의 배치는 주요 수술 절차로 간주되지 않으므로 허용된다.

Expected to require a major surgical procedure other than diagnostic, or a major surgical procedure other than cystectomy or nephroureterectomy during the study within 4 weeks prior to initiation of study treatment. The placement of a central venous access catheter (eg, a port or the like) is acceptable as it is not considered a major surgical procedure.

연구용 약물의 사용을 금하거나, 결과 해석에 영향을 미칠 수 있고, 연구에 참여하는 환자의 능력을 저하시키고, 또는 환자를 치료 합병증으로 인한 고위험에 빠뜨릴 수 있는 기타 질병, 대사 기능장애, 신체 검사 소견 또는 임상 실험실 소견.

Other diseases, metabolic dysfunctions, and physical examination findings that may contraindicate the use of investigational drugs, affect the interpretation of results, impair a patient's ability to participate in the study, or place the patient at high risk for complications of treatment or clinical laboratory findings.

키메라 또는 인간화 항체 또는 융합 단백질에 대한 심각한 알레르기 반응의 병력.

History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins.

중국 햄스터 난소 세포 생성물 또는 재조합 인간 항체에 대한 알려진 과민증.

Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies.

연구 약물 또는 그 부형제(히스티딘, 트레할로스 이수화물 및 폴리소르베이트 20 포함)에 대해 알려진 불내성 또는 과민증.

Known intolerance or hypersensitivity to the study drug or its excipients (including histidine, trehalose dihydrate and polysorbate 20).

사전 투약에 필요한 약물(아세트아미노펜, 라니티딘, 디펜히드라민 및 메틸프레드니솔론)에 대한 알려진 불내성.

Known intolerance to medications required for premedication (acetaminophen, ranitidine, diphenhydramine and methylprednisolone).

연구 기간 동안 임신 또는 수유 중이거나 임신 의도. 가임 여성은 연구 치료 시작 전 14일 이내에 혈청 임신 검사 결과가 음성이어야 한다.

Pregnant, lactating, or intending to become pregnant during the study period. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

Additional exclusion criteria for the atezolizumab + tiragolumab group

Patients meeting any of the following criteria are excluded from the atezolizumab + tiragolumab group:

선별검사 시 활동성 엡스타인-바 바이러스(EBV) 감염 또는 공지되거나 의심되는 만성 활동성 EBV 감염

Active Epstein-Barr virus (EBV) infection at screening or known or suspected chronic active EBV infection

Patients with a positive EBV virus capsid antigen (VCA) IgM test at screening are excluded from this group. EBV polymerase chain reaction (PCR) testing should be performed as clinically indicated to screen for active or suspected chronic active infection. Patients with a positive EBV PCR test are excluded from this group.

C. accepted therapy

Patients are allowed to use the following regimens during the study period:

경구 피임약

pill

호르몬 대체 요법

hormone replacement therapy

예방적 또는 치료적 항응고 요법(예컨대, 안정적인 용량의 와파린 또는 안정적인 용량의 저분자량 헤파린)

Prophylactic or therapeutic anticoagulant therapy (eg, a stable dose of warfarin or a stable dose of low molecular weight heparin)

제도적 기준에 따라 투여되는 예방적 항생제 또는 항바이러스제

Prophylactic antibiotics or antivirals administered according to institutional standards

비활성화 인플루엔자 예방 접종

Inactivated influenza vaccination

식욕 자극제로 투여되는 메게스트롤 아세테이트

Megestrol acetate administered as an appetite stimulant

미네랄로코르티코이드(예컨대, 플루드로코르티손)

Mineralocorticoids (such as fludrocortisone)

만성 폐쇄성 폐질환 또는 천식에 투여되는 코르티코스테로이드

Corticosteroids given for chronic obstructive pulmonary disease or asthma

기립성 저혈압 또는 부신피질 기능부전에 투여된 저용량 코르티코스테로이드

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency

전립선 암에 대한 성선자극호르몬 방출 호르몬 또는 길항제를 이용한 호르몬 요법

Hormone therapy using gonadotropin releasing hormone or antagonist for prostate cancer

하기에 개략된 바와 같은 완화 방사선 요법(예컨대, 공지된 골 전이의 치료 또는 통증의 증상 완화):

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

After 2 cycles of treatment, palliative radiotherapy is allowed as long as it does not interfere with the evaluation of the tumor target lesion (eg, the lesion to be irradiated must not be the only site of measurable disease). Atezolizumab treatment may be continued during palliative radiotherapy.

하기 요약된 국소 요법(예컨대, 수술, 정위 방사선 수술, 방사선요법, 고주파 절제):

Local therapies (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) summarized below:

Patients experiencing mixed reactions requiring topical therapy to control 3 or fewer lesions may still be eligible to continue study treatment after approval from a medical monitor. Patients receiving topical therapy for the target lesion can no longer be evaluated for radiological response, but

Progress can be evaluated continuously.

Prior dosing with antihistamines, antipyretics and/or analgesics may be administered only for the second and subsequent infusions of atezolizumab at the discretion of the investigator.

Patients experiencing infusion-related symptoms may be treated with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice, depending on the symptoms. have. Severe infusion-related reactions presenting with dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation or dyspnea should be managed with adjuvant therapy as clinically indicated (e.g., adjuvant oxygen and β ₂ adrenergic agonists). .

D. Materials and Methods of the Atezolizumab Group

Atezolizumab is administered at an approved dose (TECENTRIQ® US Package Insert; TECENTRIQ® SmPC), a 1200 mg fixed dose (Q3W) every 3 weeks (1200 mg on Day 1 of each 21-day cycle) (Table 72). Antitumor activity was observed over doses ranging from 1 to 20 mg/kg Q3W. In study PCD4989g, the maximally tolerated dose of atezolizumab was not reached and no dose limiting toxicity was observed at any dose. A fixed dose of 1200 mg Q3W (corresponding to a mean weight-based dose of 15 mg/kg Q3W) has been compared with nonclinical studies (Deng et al., MAbs , 8: 593-603, 2016) and available clinical pharmacokinetic, efficacy and safety data. was selected based on

Atezolizumab control patients had unacceptable toxicity or clinical findings as determined by the investigator after an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical condition (e.g., worsening of symptoms such as disease-related pain). Treatment is continued until loss of benefit is achieved. Treatment must be initiated within 7 days of treatment assignment. Patients undergo surgery after cycle 3; Cycle 4 treatment should be resumed 4-6 weeks post surgery.

Administration of atezolizumab is performed in a monitoring setting with trained staff and immediate access to appropriate equipment and medications to manage potentially serious reactions.

Atezolizumab infusion is administered according to the guidelines summarized in Table 73.

D. D. Materials and methods of atezolizumab + tyragolumab cancer

Atezolizumab is administered as described above (see Table 73).

Tiragolumab is administered as a fixed dose of 600 mg IV Q3W (600 mg on Day 1 of each 21-day cycle). Q3W as a 600 mg fixed dose IV was selected based on available clinical PK, efficacy and safety data from the combined Phase Ia/Ib study GO30103 with either single agent tiragolumab or atezolizumab in combination with tiragolumab . In the Phase Ia portion of the study using tyragolumab as a single agent, MTD was not reached and no DLT was observed at dose escalation. clinical

As of the deadline, antidrug antibodies (ADA) to tiragolumab were rare in the Phase Ia or Ib portion across all dose levels. At tiragolumab doses starting at 400 mg, long-term stable disease was observed in patients in the Phase Ia portion of the study. In the Phase Ib portion of the study with atezolizumab in combination with tiragolumab, MTD was not reached. Antitumor activity, as measured by radiological partial response, was observed over tiragoluumab doses ranging up to 600 mg starting at 30 mg in combination with 1200 mg atezolizumab.

Patients in the atezolizumab + tiragolumab arm were considered unacceptable as determined by the investigator after an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms such as disease-related pain). Receive treatment summarized in Table 74 until loss of toxicity or clinical benefit. Patients undergo surgery after cycle 3; Cycle 4 treatment is resumed 4-6 weeks post surgery.

Tiragolumab is administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21-day cycle, as described in Table 75, with a post-infusion observation period. Administration of tiragolumab is performed in a monitoring setting with trained staff and immediate access to appropriate equipment and medications to manage potentially serious reactions.

Example 18. Safety evaluation for study WO39613

A. Safety parameters and definitions

Safety assessments are those considered important for monitoring and recording adverse events, including serious adverse events and adverse events of particular interest, performing protocol-specific safety laboratory assessments, measuring protocol-specific vital signs, and evaluating the safety of a study. Others consist of performing protocol-specific checks.

B. anomalies

According to the International Council for Harmonization of Drug Regulations (ICH) guidelines for clinical trial practices for pharmaceuticals, an adverse event is any adverse medical occurrence in a clinically investigated subject to whom a pharmaceutical product has been administered, regardless of causal attribution. Therefore, the adverse reaction is

It can be any of the following:

의약품에 관련된 것으로 간주되는지 여부와 상관없이, 의약품의 이용과 일시적으로 연관된 임의의 불리하고 의도하지 않은 징후(비정상적인 실험실 결과 포함), 증상 또는 질병.

Any adverse and unintended sign (including abnormal laboratory results), symptom or disease temporarily associated with the use of a drug, whether or not deemed to be drug related.

임의의 새로운 질병 또는 기존 질병의 악화(공지된 장애의 특징, 빈도 또는 중증도에서 악화).

Any new disease or exacerbation of an existing disease (exacerbation in the nature, frequency, or severity of a known disorder).

기준선에서 존재하지 않았던 간헐적 의학적 상태(예컨대, 두통)의 재발.

Recurrence of an intermittent medical condition (eg, headache) that was not present at baseline.

증상과 연관되거나, 또는 연구 치료 또는 병행 치료에서 변화 또는 연구 약물로부터 중단을 야기하는, 실험실 값 또는 다른 임상 시험(예컨대, ECG, 엑스선)에서 임의의 악화.

Any worsening in laboratory values or other clinical trials (eg ECG, X-ray) that is associated with symptoms or that results in a change in study treatment or concomitant treatment or discontinuation from study drug.

연구 치료의 배정에 앞서 일어난 것들을 비롯한, 프로토콜-강제된 개입(예컨대, 생검과 같은 선별 침습성 절차)에 관련된 이상 반응.

Adverse events related to protocol-forced interventions (eg, selective invasive procedures such as biopsies), including those that occurred prior to assignment of study treatment.

serious adverse reactions

A serious adverse event is any adverse event that meets any of the following criteria:

치명적이다(즉, 이상 반응이 실제로 사망을 유발하거나 사망에 이르게 함).

Fatal (ie, the adverse event actually causes or causes death).

생명을 위협한다(즉, 시험자의 관점에서 이상 반응이 환자를 즉각적인 사망 위험에 처하게 함). 이는 더 중증의 형태로 발생했거나 계속되도록 허용된 경우 사망을 초래할 수 있는 임의의 이상 반응을 포함하지 않는다.

Life-threatening (ie, from the investigator's point of view, the adverse event puts the patient at risk of immediate death). It does not include any adverse event that has occurred in a more severe form or could result in death if allowed to continue.

입원 환자로서 입원이 필요하거나 연장된다.

As an inpatient, hospitalization is required or prolonged.

지속적이거나 유의한 장애/정상 생활 불능 상태를 초래한다(즉, 이상 반응으로 인해 정상적인 생활 기능을 수행하는 환자의 능력이 실질적으로 중단됨).

Resulting in persistent or significant disability/disability of life (ie, the adverse event substantially interrupts the patient's ability to perform normal life functions).

연구 치료에 노출된 산모에게서 태어난 신생아/유아의 선천적 기형/선천적 결함이다.

Birth malformations/birth defects in newborns/infants born to mothers exposed to study treatment.

시험자의 판단에 따른 유의한 의학적 사건이다(예컨대, 환자를 위태롭게 할 수 있거나 상기에 나열된 결과 중 하나를 방지하기 위해 의료/외과적 개입이 필요할 수 있음).

A significant medical event at the discretion of the investigator (eg, may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above).

The terms “severe” and “severe” are not synonymous. Severity indicates the intensity of the adverse event (e.g., assessed as mild, moderate or severe, or assessed according to the NCI CTCAE; the adverse event itself may have relatively mild medical significance (e.g., severe headache without further findings)).

Adverse reactions of specific interest

Adverse events of particular interest to the atezolizumab plus tyragolumab group include:

Hy의 법칙에 의해 정의된, 빌리루빈 상승 또는 임상 황달과 함께 ALT 또는 AST 상승을 포함하는, 잠재적인 약물-유발 간 손상 사례.

Potential drug-induced liver injury events, including elevated ALT or AST with elevated bilirubin or clinical jaundice, as defined by Hy's Law.

하기에 정의된, 연구 치료에 의한 것으로 의심되는 감염원의 전파:

Transmission of a suspected infectious agent by study treatment, as defined below:

Any pathogenic or non-pathogenic organism, virus or infectious particle (eg, a prion protein that transmits infectious spongiform encephalopathy) is considered an infectious agent. Transmission of an infectious agent may be suspected from clinical symptoms or laboratory findings indicative of infection in a patient exposed to the drug. This term applies only when contamination of the study treatment is suspected.

폐렴

Pneumonia

대장염

colitis

내분비병증: 당뇨병, 췌장염, 부신 기능 부전 및 뇌하수체염.

Endocrinopathy: diabetes, pancreatitis, adrenal insufficiency, and pituitary insufficiency.

AST 또는 ALT를 포함한 간염 > 10 x 정상 상한.

Hepatitis with AST or ALT > 10 x upper limit of normal.

전신성 홍반성 루푸스.

Systemic lupus erythematosus.

신경학적 장애: 길랭-바레 증후군, 근무력 증후군 또는 중증 근무력증, 수막뇌염.

Neurological Disorders: Guillain-Barré syndrome, myasthenia gravis or myasthenia gravis, meningoencephalitis.

과민증, IRR, 사이토카인 방출 증후군, 인플루엔자 유사 질환, HLH 및 MAS를 암시하는 사건.

Events suggesting hypersensitivity, IRR, cytokine release syndrome, influenza-like disease, HLH and MAS.

신장증

nephritis

안구 독성(예컨대, 포도막염, 망막염 및 시신경염).

Ocular toxicity (eg, uveitis, retinitis and optic neuritis).

근염

myositis

횡문근융해증을 포함한 근병증.

Myopathy, including rhabdomyolysis.

≥ 2등급 심장 장애(예컨대, 심방세동, 심근염, 심낭염).

≥ Grade 2 cardiac disorders (eg, atrial fibrillation, myocarditis, pericarditis).

혈관염

vasculitis

자가 면역 용혈성 빈혈.

Autoimmune hemolytic anemia.

중증 피부 반응(예컨대, 스티븐스-존슨 증후군, 수포성 피부염 또는 독성 표피 괴사).

Severe skin reactions (eg Stevens-Johnson syndrome, bullous dermatitis or toxic epidermal necrosis).

Example 19. Statistical considerations and analysis plan for WO39613 study

The WO39613 study is analyzed based on patient data collected through study discontinuation. Unless otherwise specified, efficacy analyzes are based on an efficacy evaluable population defined as all patients receiving at least one dose of each drug for the assigned treatment regimen, and safety analyzes are based on all patients receiving study treatment. It is based on a population that can be evaluated for safety.

The results of the analysis are summarized in the treatment the patient actually receives. Data are described and summarized according to sample size. Continuous variables are summarized using mean, standard deviation, median, minimum and maximum values. Categorical variables are summarized using counts and percentages. Lists are used instead of tables when the sample size is small.

A. Determination of sample size

WO39613 study was not designed to account for apparent analytical power and type I error for hypothesis analysis.

didn't Instead, this study was designed to obtain preliminary efficacy, safety, and PK data for an immunotherapy-based treatment combination when administered to patients with cisplatin ineligible MIBC. Approximately 150 to 350 patients are randomly assigned to control and experimental groups for the duration of the study.

B. Validity analysis

Primary efficacy endpoint

The primary endpoint is pathological complete response (pCR), defined as the proportion of patients free of residual invasive cancer in completely resected specimens. pCR ratios are calculated for each group with 90% confidence intervals. In addition, the pCR difference between the experimental group(s) and the control group is calculated with a 90% confidence interval. Confidence intervals are estimated by direct probability method or Wald method according to the sample size. Patients with missing or non-existent response assessments are classified as non-responders.

secondary efficacy endpoint

Secondary efficacy endpoints are landmark recurrence-free survival (RFS), landmark event-free survival (EFS), and landmark overall survival (OS) at specific time points (eg, 12, 18, 24 months), respectively. These endpoints are described below. Landmark RFS ratio, landmark EFS ratio, and landmark OS ratio are estimated for each study group using Kaplan-Meier method, and 90% CI is calculated using Greenwood formula .

Exploratory validity endpoints

Exploratory efficacy endpoints were RFS, EFS, OS, and pathologic downstage ratio.

Relapse-free survival (RFS) is defined as the time from Day 1 of the first postoperative cycle to the first reported disease recurrence or death from any cause. For patients with no reported disease recurrence or death, RFS is censored on the day of the last tumor evaluation after surgery.

Event-free survival (EFS) is defined as the time from randomization to the next event (whichever occurs first): inoperable disease progression, assessed by the investigator; local or distant disease recurrence; or death from any cause. Patients who do not experience these events are censored at the time of tumor assessment after the last tumor.

Overall survival (OS) is defined as the time from randomization to death from any cause. not dead

Data for patients are censored from the last known surviving date.

Pathological downstaging is defined as the proportion of patients achieving ≤ pT1pN0 at cystectomy.

The Kaplan-Meier method is used to estimate the median RFS, EFS, and OS for each study group. The Brookmeyer and Crowley methods were used to generate 90% CIs for the median RFS, EFS, and OS for each study group.

C. Safety analysis

Verbose adverse event terms are mapped to thesaurus terms in the Medical Dictionary for Regulatory Activities, and adverse event severity is graded according to NCI CTCAE v4.0.

Safety is assessed through a summary of adverse events, changes in laboratory test results, changes in vital signs and ECGs, and exposure to study drug. Exposure and safety follow-up periods for combination therapy are summarized for each treatment group within each arm.

Treatment-related adverse events occurring after initiation of treatment are summarized. For each patient, the maximum severity reported for each adverse event is used for the summary by severity grade. All treatment-induced adverse events, serious adverse events, adverse events leading to discontinuation of study treatment, ≥ Grade 3 adverse events, deaths and causes of death

Listed and summarized by mapped term, appropriate thesaurus level, and NCI CTCAE severity rating.

Relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry, and body temperature) and ECG data are displayed hourly and identified by grade, where appropriate. Additionally, the baseline and post-baseline maximal severity ratings are summarized using alternate representations of selected laboratory test results. Changes in vital signs are summarized.

D. Pharmacokinetic analysis

Rare samples are collected for PK analysis of atezolizumab (patients receiving at least one dose of atezolizumab) and drugs administered in combination with atezolizumab (patients receiving at least one dose of the drug). Serum or plasma concentrations of various study drugs are reported as individual values and, where appropriate, summarized by treatment group and by cycle and date as data permits (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean variation). Coefficient). Individual and median serum or plasma concentrations of various study drugs are presented by treatment group and by cycle and date. PK data for combination drugs can be compared with historical data available from internal and published previous studies. Concentration data can be integrated with data from other studies using established population PK models to derive PK parameters such as interval, volume of distribution, and area under the curve.

Relationships between PK parameters and safety, efficacy, PK and biomarker endpoints can be analyzed and reported via descriptive statistics.

E. Immunogenicity assay

Immunogenicity is assessed as appropriate for atezolizumab and other study treatments. Immunogenicity assays included all patients who underwent at least one antidrug antibody (ADA) assessment. Patients are grouped according to treatment received, or according to assigned treatment if no treatment was received prior to study discontinuation.

For atezolizumab, the number and proportion of ADA-positive and ADA-negative patients at baseline (baseline prevalence) and after drug administration (post-baseline incidence) are summarized by treatment group. When determining post-baseline incidence rates, if a patient is ADA-negative at baseline or data is missing, but an ADA response occurs after study drug exposure (treatment-induced ADA response), or is ADA positive at baseline and the titer of one or more post-baseline samples is A patient is considered ADA positive if it is at least 0.60-titer units greater than the titer of the sample (treatment-enhanced ADA response). The patient is ADA negative at baseline or data is missing and all samples since baseline are negative, or if the patient is ADA positive at baseline but has no post-baseline samples whose titers are at least 0.60-titer units greater than the titers of the baseline samples ( unaffected), the patient is considered ADA negative.

For other study treatments for which ADA is tested, a positive determination is made according to standard methods established in previous studies of the drug.

The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints was

It can be analyzed and reported through descriptive statistics.

F. Biomarker analysis

Exploratory biomarker analyzes are performed in an effort to understand the association of these biomarkers with response to study drug, taking into account efficacy, safety, PK, immunogenicity, and other biomarker endpoints.

G. Interim analysis

Interim analyzes are performed during the study period, and the earliest interim analyzes are performed when at least one experimental group has completed enrollment in the preliminary phase and the patient has completed postoperative pCR evaluation. Additional interim analyzes may be performed if the sponsor deems it appropriate. The posterior probability can be used to guide further enrollment based on an interim analysis of clinical activity in the experimental group compared to the control group. If the interim analysis suggests that the activity of the experimental group is higher than that of the control group, an additional 25 additional patients can be enrolled in the experimental group (expansion phase) for each MIBC cohort. Final decisions about expansion and termination of Phase 1b clinical trials are made taking into account the overall benefit-risk balance and data as a whole, including time-to-event endpoints and safety data, as well as new external information.

Example 20. Phase Ib/II, open-label, multicenter, randomized comprehensive study evaluating the efficacy and safety of tiragolumab in combination with atezolizumab in patients with metastatic urothelial cell carcinoma (mUC)

WO39613 is a Phase Ib/II, open-label, multicenter, randomized umbrella study evaluating the efficacy and safety of tiragolumab in combination with atezolizumab in patients with locally advanced or metastatic UC who progressed during or after platinum-containing therapy. This study is designed to have the flexibility to open new treatment groups as new treatments become available, close existing treatments with minimal clinical activity or unacceptable toxicity, or modify patient populations (e.g., previous chemotherapy or biologic therapies). with respect to marker status). Eligible patients are initially assigned to one of several treatment groups (see FIG. 25 ). Patients who experience unacceptable toxicity or loss of clinical benefit during Stage 1 may be eligible to continue treatment with another treatment regimen in Stage 2 (see FIG. 25 ).

A. weapon 1

During Stage 1, patients are randomly assigned to either a control group (atezolizumab [Atezo]) or an experimental group consisting of atezolizumab in combination with tyragolumab (Atezo+Tira) (see Figure 25 and Table 76).

atezo = atezolizumab; Tira = tiragolumap. ^a The sponsor may decide to defer or withhold enrollment within a given treatment arm. Therefore, not all experimental groups may be open for enrollment at the same time.

^b If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients will be enrolled in that group during the expansion phase. ^c The rate of randomization depends on the number of experimental groups open for randomization (e.g., if more groups are added or

If randomization of a group is withheld, preliminary analysis of the outcome is withheld), the probability of being assigned to a control group is no more than 35%.

PD-L1 programmed death ligand 1; TIGIT T cell immunoreceptor with Ig and ITIM domains.

Enrollment in the experimental group proceeds in two stages: the preliminary stage and the expansion stage. About 15 patients are enrolled in the preliminary phase. If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients can be enrolled in that group during the expansion phase.

The sponsor may decide to defer or withhold enrollment within a given treatment arm. Experimental groups with insufficient clinical activity or unacceptable toxicity are not expanded. To enable further subgroup analysis, additional patients may be enrolled to ensure balance between treatment groups with respect to demographic and baseline characteristics, including potential predictive biomarkers. The protocol can be modified to add new experimental groups during the study.

Patients are randomly assigned to treatment groups with the exception of the Stage 2 treatment group. In addition, the rate of randomization depends on the number of available experimental groups (e.g., if a group is added or enrollment of a group is withheld, preliminary analysis of results is withheld), and the probability of being assigned to a control group is not greater than 35%. does not Randomization takes into account group exclusion criteria. patient for a specific group

If any of the outlined exclusion criteria are met, the patient is ineligible for that group (see below).

Patients in the atezolizumab control and experimental groups had unacceptable toxicity or toxicity or Treatment is continued until loss of clinical benefit. Criteria for Assessing Response in Solid Tumors, Version 1.1, due to the potential for an initial increase in tumor burden due to immune cell infiltration in the setting of a T cell response (termed pseudoprogression) with cancer immunotherapy (CIT) (eg, atezolizumab). Radiological progression according to (RECIST v1.1) may not represent actual disease progression. In the absence of unacceptable toxicity,

Patients who meet the disease progression criteria per RECIST v1.1 while being treated with CIT drugs may continue on study treatment if all of the following criteria are met:

사용 가능한 모든 데이터를 검토한 후 시험자가 결정한 임상적 이점의 증거.

Evidence of clinical benefit as determined by the investigator after reviewing all available data.

질병의 명백한 진행을 나타내는 증상 및 징후(새로운 또는 악화되는 고칼슘혈증과 같은 실험실 값을 포함함)의 부재.

Absence of symptoms and signs (including laboratory values such as new or worsening hypercalcemia) indicative of apparent progression of the disease.

질병 진행에 기인할 수 있는 ECOG PS 감소의 부재.

Absence of ECOG PS reduction attributable to disease progression.

프로토콜이 허용하는 의료적 개입으로 관리할 수 없는 중요한 해부학적 부위(예컨대, 연수막 질환)에서 종양 진행의 부재.

Absence of tumor progression at critical anatomical sites (eg, leptomeningeal disease) that cannot be managed with medical interventions permitted by the protocol.

B. weapon 2

Patients who experience unacceptable toxicity or loss of clinical benefit as determined by the investigator during Stage 1 may be eligible to receive another treatment combination during Stage 2 if they meet the eligibility criteria (see FIG. 25 ). Treatment groups are assigned by investigators to patients in Stage 2 who are eligible for one or more treatment groups.

Stage 2 treatment should be initiated within 3 months of the patient experiencing loss of clinical benefit or unacceptable toxicity and continued until loss of clinical benefit or unacceptable toxicity as determined by the investigator. Patients are encouraged to begin stage 2 treatment as soon as possible.

The sponsor may decide to withhold or discontinue enrollment in the Stage 2 treatment arm based on review of safety data, preliminary efficacy data, and supporting information (eg, biomarker study data) as appropriate.

C. Rationale for Study Design

Rationale for Patient Population and Atezolizumab Controls

This study enrolls patients with locally advanced or metastatic UC who progressed during or after platinum-containing therapy.

Atezolizumab (Tecentriq) is approved for the treatment of UC in patients who progressed during or after platinum-containing therapy, non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, hepatocellular carcinoma, and melanoma. Approval for secondary treatment in patients with UC who progressed following a previous platinum-containing regimen was based on data from cohort 2 of the ongoing phase II study GO29293 (IMvigor210), followed by

Based on the results of IMvigor210 and phase III study GO29294 (IMvigor211), full approval for the same indication was achieved in Europe. In IMvigor210 cohort 2, 310 patients were enrolled as of July 12, 2017, with an ORR of 16% (95% CI: 13, 21) of a 7% complete response (CR) rate and a median duration of response (DOR) of 24.8 months (95% CI: 13.8, 30.4). According to the safety assessment, 8% of patients had an adverse event that led to treatment discontinuation, and 16% of patients

Treatment-related grade 3 or 4 adverse events were experienced, with the most common adverse events being fatigue, diarrhea, and pruritus. Immune-mediated adverse events occurred in 12% of all patients, and 7% of patients experienced a grade 3 or 4 immune-mediated adverse event (grade 3 or 4 rash [1%], increased ALT [2%], increased blood bilirubin [2%], rhabdomyolysis [1%]). In IMvigor211, as of March 13, 2017, a median OS of 8.6 months, an ORR of 13.4% (10.5, 16.9), and a median DOR of 21.7 months in the purpose of treatment (ITT) group were observed.

Despite the potential of single agent checkpoint inhibitors, only a relatively small proportion of patients experience benefit, highlighting the need for immunotherapeutic combinations. To extend the benefits of atezolizumab to a larger population of patients with inoperable locally advanced and metastatic UC, the multiple combinatorial partners in this study are expected to stimulate the immune system through a variety of mechanisms.

The rationale for stage 2

The advent of immunotherapy marked the first real advance in mUC in 30 years. Despite these advances, substantially more work is needed to extend the benefits to a larger proportion of patients. The key to the ability to advance immunotherapy will lie in a better understanding of the underlying tumor immune environment and how the treatment sequence influences response.

The Stage 2 part of this study may allow some patients to progress to subsequent CIT combinations after disease progression, increasing the scientific understanding of immune escape mechanisms in patients who do not respond or progress to CIT therapy. Critical to a patient's ability to be enrolled in Stage 2 is the ability to undergo a biopsy to assess the immune environment and any changes that may occur during Stage 1 treatment. Participation in Stage 2 gives patients and providers access to treatment options with the potential of a sustained response and improved toxicity profile not attainable with conventional chemotherapy. Stage 2 treatment precludes treatment providing other potentially more standard options; Thus, patients are informed during the Stage 2 consent process that by enrolling in Stage 2, they will forgo a therapy that may have a survival advantage.

Rationale for Artezo + EV and Artezo + SG Groups in Stage 2

Patients may be given the opportunity to receive stage 2 treatment with atezo + EV or atezo + Sg after loss of clinical benefit.

Because of the strong therapeutic response reported in patients previously treated with CPI, receiving single agent enfortumab vedotin, the combination of atezo plus EV was chosen for stage 2. In particular, in a phase I clinical trial of enfortumab vedotin, 8 of 17 patients with metastatic bladder (47%; 95% CI: 23, 72.2) treated with the recommended phase II enfortumab vedotin dose had PR was obtained (Petrylak et al., J Clin Oncol , 35(15 Suppl): 106, 2017). These findings suggest that enfortumab vedotin may provide an advantage in the post-CPI space. The addition of atezolizumab to enfortumab vedotin has the potential to improve response duration. In addition, microtubule perturbation therapy has the potential to induce immunogenic cell death and initiate an anti-tumor immune response.

Because of the strong therapeutic response observed in mUC patients receiving single agent sacituzumab gobitecan on platinum-based therapy and on checkpoint inhibitor therapy, the combination of atezo plus SG was selected for stage 2. In particular, in the Phase II TROPHY-U-01 study, sacituzumab gobitecan exhibited an ORR of 29% in 35 patients, including an ORR of 25.0% in patients with liver metastases (Tagawa et al., J Clin Oncol , 37 (Tagawa et al., J Clin Oncol, 37) 7 Suppl): 3199-3212, 2019). These findings suggest that sacituzumab gobitecan may provide an advantage in the post-CPI space. Combination of atezolizumab with sacituzumab gobitecan in patients who progressed after chemotherapy and immunotherapy may potentiate the antitumor immune response induced from inflammation where atezolizumab is mediated by the antitumor activity of sacituzumab gobitecan. This can provide synergy.

Rationale for Immunotherapy-Based Treatment after Initial Radiological Progression

In immunotherapeutic studies, CR, partial response (PR) and stable disease, respectively, have been shown to occur after radiological evidence of an apparent increase in tumor burden. This initial increase in tumor burden caused by immune cell infiltration in the setting of T cell responses has been termed pseudoprogression (Hales et al., Ann Oncol , 21: 1944-1951, 2010).

In study PCD4989g, evidence of tumor growth and consequent response was observed in several tumor types. In addition, in some responding patients with evidence of radiological progression, biopsies of new lesions or new growth sites of existing lesions showed immune cells and no viable cancer cells. Because of the potential for post-pseudo-progressive response, patients randomly assigned to the immunotherapy-based treatment arm in this study were treated after overt radiological progression according to RECIST v1.1 if the benefit-risk ratio was judged favorable by the investigator.

Combination therapy can be continued. Patients should discontinue treatment if there is unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical status.

The specific study objectives and corresponding endpoints are summarized in Tables 78 and 79.

ADA = anti-drug antibody; CR = complete response; DOR = duration of response; iRECIST = immune RECIST; NCI CTCAE v4.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; RECIST v1.1 = Criteria for Response Evaluation of Solid Tumors, Version 1.1.

ADA = anti-drug antibody; CR = complete response; DOR = duration of response; iRECIST = immune RECIST; NCI CTCAE v4.0 = National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; RECIST v1.1 = Criteria for Response Evaluation of Solid Tumors, Version 1.1.

D. Assessment and monitoring

All patients are closely monitored for adverse events throughout the study, and adverse events are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Patients receive tumor assessments every 9 weeks (starting on Day 1 of Cycle 1) for the first 54 weeks and then every 12 weeks thereafter. the reaction is

The investigator evaluates using RECIST v1.1 (Eisenhauer et al., Eur J Cancer, 45: 228-247, 2009). If clinical activity appears in the experimental group, the sponsor will conduct a tumor assessment scan for that group for evaluation by a central reading facility.

You may request to submit.

Baseline tumor tissue samples are preferably collected from all patients via biopsies performed at the start of the study. If the investigator determines that a biopsy cannot be performed, the archived tumor tissue may be submitted. In addition, (if the investigator determines that it is clinically feasible), tumor tissue is collected from patients who have discontinued Stage 1 due to unacceptable toxicity or loss of clinical benefit as determined by the investigator. These samples and blood samples collected during the study period are used for biomarker studies.

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are obtained at various time points prior to and during administration of study treatment.

E. Study End and Study Duration

Study end is defined as the date the last patient completed the last visit in both arms, including survival follow-up visits performed by phone or site visit.

The total study duration from screening of the first patient to study termination is approximately 3-5 years.

Example 21. WO39613 Materials and Methods for mUC Study

A. Inclusion criteria for stage 1

Patients must meet all of the criteria outlined below to be eligible for Stage 1.

・Age 18 or older at the time of signing the informed consent form

· Life expectancy ≥ 3 months as determined by the investigator.

Histologically reported locally advanced (T4b, any N; or any T, N2-N3) or metastatic UC (M1, stage IV) (TCC or urothelium of the urinary tract including the renal pelvis, ureter, bladder and urethra) Also called cell carcinoma). Patients with mixed tissue should have a dominant transitional cell pattern. Locally advanced bladder cancer is characterized by infiltration of the side walls of the pelvis or adjacent intestines (clinical stage T4b) or bulky

Surgery should not be possible based on nodular metastasis (N2-N3).

Availability of representative tumor specimens suitable for determination of PD-L1 and/or additional biomarker status via central examination. Baseline tumor tissue samples are preferably collected from all patients via biopsies performed at the start of the study.

At least 16 slides containing either formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or unstained, freshly excised serial sections should be submitted with relevant pathology reports. If only 10-15 slides are available, the patient may still be eligible for the study. Tumor tissue should be of good quality based on total and viable tumor content.

Fine needle aspiration, brushing, cell pellets in pleural effusion, bone metastases, and wash samples are not permitted. For core-needle biopsy specimens, a minimum of three cores must be submitted for evaluation. Patients with less than 3 cores available may still be eligible. TURBT specimens should contain a muscle-invasive component (ie, T2 or greater) of bladder tumors confirmed by local pathological review. Specimens obtained during cystectomy/nephrectomy or metastatic spread (ie, specimens from metastatic lesions) are required prior to randomization, unless the TURBT specimen contains a muscle-invasive component.

Disease progression during or after treatment with 1 or less platinum-containing therapies (eg, GC, MVAC, CarboGem) for inoperable, locally advanced or metastatic UC or disease recurrence. The regimen includes at least 2 cycles of platinum-containing therapy.

defined as a patient. Patients who have previously received adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with platinum-containing adjuvant/neoadjuvant therapy are considered line 2 patients. The patient may have previously received no more than 2 treatment regimens (including required platinum-based therapy) for advanced or metastatic UC. The patient must show disease progression during or after all previous therapy(s). Patients with disease progression following chemoradiation should show progression outside the previous radiotherapy port.

B. Inclusion Criteria for Stage 1 and Stage 2

Patients must meet all of the criteria outlined below to be eligible for either Stage 1 or Stage 2.

시험자의 판단으로, 연구 프로토콜을 준수하는 능력.

At the discretion of the investigator, the ability to comply with the study protocol.

0 또는 1의 ECOG PS.

ECOG PS of 0 or 1.

RECIST v1.1에 따른 측정 가능한 질병(적어도 하나의 표적 병변) 이전에 방사선 조사된 병변은 방사선 조사 이후 해당 부위에서 진행성 질병이 명백하게 보고된 경우에만 측정 가능한 질병으로 간주될 수 있다.

Pre-irradiated lesions with measurable disease according to RECIST v1.1 (at least one target lesion) can only be considered measurable disease if progressive disease has been clearly reported at the site after irradiation.

다음 실험실 검사 결과에 의해 정의되는, 연구 치료 개시 전

Prior to initiation of study treatment, as defined by the following laboratory test results:

Adequate blood and terminal organ function achieved within 14 days:

- ANC ≥ 1.5 x 10 ⁹ /L (1500/μL), no granulocyte colony stimulating factor (G-CSF) support.

- Number of WBCs ≥2.5 x 10 ⁹ /L (2500/μL).

- Lymphocyte count ≥0.5 x 10 ⁹ /L (500/μL).

- Platelet count ≥100 x 10 ⁹ /L (100,000/μL), no transfusion.

- Hemoglobin ≥90 g/L (9.0 g/dL).

The patient may receive a blood transfusion; However, transfusions are not permitted within 2 weeks of screening laboratory testing for eligibility.

Erythropoietin stimulants may be used in patients with episodic or chronic kidney disease with low erythropoietin production.

- AST, ALT, and alkaline phosphatase (ALP) ≤2.5 x upper limit of normal (ULN), with the following exceptions:

Patients with reported liver metastases: AST and/or ALT ≤ 5 x ULN

Patients with documented liver or bone metastases: ALP ≤ 5 x ULN.

- Bilirubin ≤ 1.5 x ULN, with the following exceptions:

Known Gilbert's disease patients: bilirubin levels ≤ 3 x ULN.

- Albumin ≥25 g/L (2.5 g/dL).

- Creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula).

- For patients not receiving therapeutic anticoagulants:

PTT or aPTT ≤1.5 x ULN

PT or INR < 1.5 x ULN.

치료적 항응고제를 투여받는 환자의 경우: 연구 치료 개시 전 14일 동안 안정적인 항응고 요법.

For patients receiving therapeutic anticoagulants: stable anticoagulant therapy for 14 days prior to initiation of study treatment.

선별검사 시 HIV 검사 음성. 이전에 HIV 검사 결과가 양성이었던 적이 없는 환자는 현지 규정에 따라 허용되지 않는 한 선별검사 시 HIV 검사를 받는다.

HIV test negative at screening. Patients who have not previously tested positive for HIV are tested for HIV at screening, unless permitted by local regulations.

선별검사 시 총 B형 간염 코어 항체(HBcAb) 검사 음성, 또는 선별검사 시 총 HBcAb 검사 양성 후 정량적 B형 간염 바이러스(HBV) DNA ＜ 500 IU/mL. HBV DNA 검사는 HBcAb 검사가 양성인 환자에게만 시행된다. HCV RNA 검사는 HCV 항체 검사가 양성인 환자에게만 시행된다.

Quantitative hepatitis B virus (HBV) DNA < 500 IU/mL after total hepatitis B core antibody (HBcAb) negative at screening or positive total HBcAb at screening. HBV DNA testing is only performed on patients with a positive HBcAb test. The HCV RNA test is only performed on patients with a positive HCV antibody test.

선별 검사시 C형 간염 바이러스(HCV) 항체 검사 음성, 또는 선별 검사시 HCV 항체 검사 양성 후 HCV RNA 검사 음성. HCV RNA 검사는 HCV 항체 검사 양성인 환자에게만 시행된다.

Hepatitis C virus (HCV) antibody test negative at screening test, or HCV RNA test negative after HCV antibody test positive at screening test. The HCV RNA test is only performed on patients with a positive HCV antibody test.

가임 여성의 경우: 금욕 유지(이성간 성교 금지) 또는 피임 방법 사용에 대한 동의 및 난자 기증 자제에 대한 동의

For women of childbearing potential: Consent to maintain abstinence (no intercourse) or to use contraceptive methods and to refrain from egg donation

남성의 경우: 금욕을 유지하기로 동의(이성간 성교 금지) 또는 피임법 사용에 대한 동의 및 정자 기증을 자제에 대한 동의.

For men: Consent to maintain abstinence (no heterosexual intercourse) or consent to use of contraceptive methods and consent to refrain from donating sperm.

C. Selection criteria for stage 2

Patients must meet all of the following criteria to be eligible for Stage 2:

Atezolizumab control patients: ability to initiate Stage 2 treatment within 3 months of loss of investigator-determined clinical benefit while receiving control treatment.

Patients in the experimental arm during Stage 1: cannot initiate Stage 2 treatment within 3 months of experiencing an investigator-determined unacceptable toxicity or loss of clinical benefit unrelated to atezolizumab while receiving treatment at Stage 1. ability to have.

Availability of tumor specimens from biopsies performed at stage 1 discontinuation.

D. Exclusion Criteria

Patients meeting any of the following criteria will be excluded from enrollment during Stages 1 and 2. Event ratings for exclusion criteria are based on NCI CTCAE v4.0.

Stage 1 exclusion criteria

Patients meeting any of the following criteria are excluded from Stage 1:

Previous treatment with T cell co-stimulation therapy or CPI comprising anti-TLA-4, anti-PD-1 and anti-PD-L1 therapeutic antibodies.

Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, nectin-4 targeting agent, signal regulatory protein α-targeting agent, TIGIT targeting agent, Trop-2 targeting agent, FAP directed therapy, 4-1BB ( CD137) prior treatment with either directed therapy or protocol directed study treatment including treatment with a topoisomerase 1 inhibitor.

연구 치료 개시 전 28일 이내의 임상시험 요법에 의한 치료.

Treatment by investigational regimen within 28 days prior to initiation of study treatment.

연구 치료 개시 전 3주 이내의 화학요법 또는 호르몬 요법을 포함한 임의의 승인된 항암 요법; 다음 예외가 허용됨:

any approved anti-cancer therapy, including chemotherapy or hormone therapy within 3 weeks prior to initiation of study treatment; The following exceptions are allowed:

- Palliative radiotherapy for bone metastases or soft tissue lesions should be completed >14 days prior to baseline imaging.

- Hormone replacement therapy or oral contraceptives

대조군에만 적격

Eligible for control group only

Exclusion Criteria for Stage 1 and Stage 2

Patients meeting any of the following criteria are stage 1 and

Excluded from Stage 2:

선행 동종이계 줄기 세포 이식 또는 고형 장기 이식.

Prior allogeneic stem cell transplantation or solid organ transplantation.

연구 치료 개시 전 4주 또는 약물 반감기의 5배(둘 중 더 긴 것) 이내의 전신 면역자극제(인터페론 및 인터루킨 2를 포함하나 이에 한정되지 않음)를 사용한 치료.

Treatment with systemic immunostimulants (including but not limited to interferon and interleukin 2) within 4 weeks prior to initiation of study treatment or within 5 times the drug half-life, whichever is longer.

연구 치료 개시 전 2주 이내의 전신 면역억제 약물(코르티코스테로이드, 사이클로포스파미드, 아자티오프린, 메토트렉세이트, 탈리도마이드 및 항종양 괴사 인자-α제를 포함하나 이에 한정되지 않음)을 사용한 치료, 또는 연구 치료 동안 전신 면역억제제의 필요성에 대한 예상, 다음은 예외임:

Treatment with systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α agents) within 2 weeks prior to initiation of study treatment, or study Anticipation of the need for systemic immunosuppressants during treatment, with the following exceptions:

Patients receiving an acute low-dose systemic immunosuppressive drug or a single pulsed dose of a systemic immunosuppressive drug (eg, corticosteroids for contrast allergy 48 hours) are eligible for the study.

Patients receiving mineralocorticoids (eg, fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenocortical insufficiency are eligible for study.

연구 치료 개시 전 4주 이내의 약독화 생백신을 사용한 치료, 또는 아테졸리주맙 치료 동안 또는 아테졸리주맙의 마지막 투여 후 5개월 이내의 이러한 백신의 필요성에 대한 예상.

Treatment with live attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of the need for such vaccine during atezolizumab treatment or within 5 months after the last administration of atezolizumab.

조절되지 않는 흉막 삼출, 심낭 삼출, 또는 반복적인 배액 절차가 필요한 복수(매월 1회 또는 더 자주). 유치 카테터(예컨대, PLEURX)의 사용이 허용된다.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (once monthly or more often). Use of an indwelling catheter (eg, PLEURX) is permitted.

통제되지 않는 종양 관련 통증. 통증 약제를 필요로 하는 환자는 연구 엔트리에서 안정된 섭생 중에 있어야 한다. 완화 방사선 요법으로 치료할 수 있는 증상이 있는 병변(예컨대, 골 전이 또는 신경 충돌을 유발하는 전이)은 등록 전에 치료해야 한다. 환자는 방사선의 영향에서 회복되어야 함. 환자는 방사선의 영향에서 회복되어야 함. 추가 성장시 기능적 결함이나 난치성 통증을 유발할 가능성이 있는 무증상 전이성 병변(예컨대, 현재 척수 압박과 관련이 없는 경막외 전이)은

Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions treatable with palliative radiation therapy (eg, bone metastases or metastases causing nerve impingement) should be treated prior to enrollment. The patient must recover from the effects of radiation. The patient must recover from the effects of radiation. Asymptomatic metastatic lesions (e.g., epidural metastases not currently associated with spinal cord compression) that have the potential to cause functional defects or refractory pain upon further growth

Topical treatment should be considered when appropriate prior to enrollment.

조절되지 않거나 증상이 있는 고칼슘혈증(이온화 칼슘 ＞1.5 mmol/L, 칼슘 ＞12 mg/dL 또는 교정된 혈청 칼슘 ＞ULN).

Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12 mg/dL or corrected serum calcium >ULN).

증상이 있거나 치료되지 않았거나 활발히 진행중인 CNS 전이. 치료된 CNS 병변이 있는 무증상 환자는 다음 기준이 모두 충족되는 경우 적격이다:

Symptomatic, untreated, or actively progressing CNS metastases. Asymptomatic patients with treated CNS lesions are eligible if all of the following criteria are met:

- According to RECIST v1.1, measurable diseases must be outside the CNS.

- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

-Patient had not undergone stereotactic radiotherapy within 7 days prior to study treatment initiation, whole brain radiotherapy within 14 days prior to study treatment initiation, or neurosurgical resection within 28 days prior to study treatment initiation.

- The patient has no need for ongoing corticosteroids as therapy for CNS disease. Stable dose anticonvulsant therapy is permitted.

연수막 질환의 병력.

History of leptomeningeal disease.

중증 근무력증, 근염, 자가면역 간염, 전신 홍반성 루푸스, 류마티스 관절염, 염증성 장질환, 항인지질항체 증후군, 베게너 육아종증, 쇼그렌 증후군, 길랭-바레 증후군 또는 다발성 경화증을 포함하나 이에 한정되지 않는 자가 면역 질환 또는 면역 결핍의 활성 또는 병력, 다음은 예외임:

Autoimmune diseases including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome or multiple sclerosis or active or history of immunodeficiency, with the exception of:

Patients with a history of autoimmune-related hypothyroidism and taking thyroid replacement hormone are eligible for the study. Patients with controlled type 1 diabetes on stable insulin therapy are eligible for the study. Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with dermatological signs only (e.g., excluding patients with psoriatic arthritis) are eligible for study if all of the following conditions are met:

- The rash should occupy 10% of the body surface area.

- Disease is well controlled at baseline and requires only low titer topical corticosteroids.

- No acute exacerbation of underlying conditions requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high titers or oral corticosteroids within the past 12 months.

특발성 폐섬유증, 폐색성 기관지염(예컨대, 폐쇄성 세기관지염), 약물 유발성 폐렴 또는 특발성 폐렴의 병력, 또는 선별 흉부 컴퓨터 단층촬영(CT) 스캔에서의 활동성 폐렴의 증거. 방사선 분야에서 방사선 폐렴 (섬유증) 병력은 허용됨

A history of idiopathic pulmonary fibrosis, obstructive bronchitis (eg, bronchiolitis obliterans), drug-induced pneumonia or idiopathic pneumonia, or evidence of active pneumonia on a screening chest computed tomography (CT) scan. A history of radiation pneumonitis (fibrosis) in the field of radiation is acceptable

적절하게 치료된 자궁경부의 상피내암종, 비흑색종 피부암종, 국소 전립선암, 관상피내암종, 또는 병기 I 자궁암과 같은 무시할 수 있는 전이 또는 사망의 위험(예컨대, 5년 전체 생존[OS] 비율 ＞90%)이 있는 악성 종양을 제외한, 선별검사 이전 2년 이내의 UC 이외의 악성 종양의 병력. 전립선 특이적 항원(PSA) 재발 없이 치료 목적으로 치료된 국소 전립선암(병기 ≤pT2c, 글리슨(Gleason) 점수 ≤7 및 전립선암 진단 시 PSA ≤20 ng/mL로 정의됨) 환자는 적격이다. 치료 경험이 없고 능동 감시를 받고 있는 기존의 저위험 전립선암(병기 cT1/T2a, 글리슨 점수 ≤6 및 PSA ≤ 10 ng/mL로 정의됨)이 있는 환자는 적격이다.

Negligible risk of metastasis or death (e.g., 5-year overall survival [OS] ratio > 90%), history of malignancy other than UC within 2 years prior to screening, excluding malignancies with Patients with regional prostate cancer (defined as stage ≤pT2c, Gleason score ≤7 and PSA ≤20 ng/mL at diagnosis of prostate cancer) who have been treated therapeutically without prostate-specific antigen (PSA) recurrence are eligible. Patients with pre-existing low-risk prostate cancer (defined as stage cT1/T2a, Gleason score ≤6 and PSA ≤10 ng/mL) who are treatment-naïve and under active surveillance are eligible.

활동성 결핵(TB)(즉, TB의 징후와 증상이 있음).

Active tuberculosis (TB) (that is, with signs and symptoms of TB).

감염 합병증, 세균혈증 또는 중증 폐렴으로 인한 입원을 포함하나 이에 한정되지 않는 연구 치료 개시 전 4주 이내의 중증 감염, 또는 시험자의 의견에서 환자의 안전에 영향을 미칠 수 있는 임의의 활성 감염.

Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for infectious complications, bacteremia or severe pneumonia, or any active infection that, in the opinion of the investigator, could affect patient safety.

연구 치료 개시 전 2주 이내의 치료적 경구 또는 IV 항생제를 사용한 치료.

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to study treatment initiation.

Patients receiving prophylactic antibiotics (eg, to prevent exacerbation of urinary tract infection or chronic obstructive pulmonary disease) are eligible for study.

뉴욕심장학회 심장 질환(III군 이상), 심근경색증 또는 뇌혈관 장애과 같은 무작위 배정 전 3개월 이내의 유의한 심혈관 질환, 불안정 부정맥 또는 불안정 협심증.

Significant cardiovascular disease, unstable arrhythmia, or unstable angina within 3 months prior to randomization, such as New York Heart Association heart disease (group III or greater), myocardial infarction or cerebrovascular disorder.

조절되지 않는 고혈압(수축기 혈압 > 140 mmHg 및/또는 확장기 혈압 > 95 mmHg으로 정의됨) 이러한 매개변수를 달성하기 위한 항고혈압 요법이 허용된다.

Uncontrolled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >95 mmHg) antihypertensive therapy to achieve these parameters is permitted.

연구 치료 개시 전 28일 이내의 3등급 출혈 또는 출혈 사건.

Grade 3 bleeding or bleeding events within 28 days prior to study treatment initiation.

연구 치료 개시 전 4주 이내의 진단 이외의 주요 외과적 절차, 또는 연구 기간 동안 주요 외과적 절차의 필요성에 대한 예상. 중심 정맥 접근 카테터(예컨대, 포트 또는 이와 유사한 것)의 배치는 주요 수술 절차로 간주되지 않으므로 허용된다.

A major non-diagnosis major surgical procedure within 4 weeks prior to initiation of study treatment, or an estimate of the need for a major surgical procedure during the study period. Deployment of a central venous access catheter (eg, port or the like) is acceptable as it is not considered a major surgical procedure.

임의의 등급의 탈모증 및 ≤2등급 말초 신경병증을 제외한 ≤1등급 이상으로 개선되지 않은 이전 항암 요법의 이상 반응.

Adverse events from previous anticancer therapy that did not improve to ≤Grade 1 or greater, except for alopecia of any grade and ≤Grade 2 peripheral neuropathy.

임상시험용 약물의 사용을 금하거나, 결과 해석에 영향을 미칠 수 있거나, 연구에 참여하는 환자의 능력을 손상시키거나, 또는 치료 합병증으로 인해 환자를 높은 위험에 처하게 할 수 있는 임의의 기타 질병, 대사 기능 장애, 신체 검사 소견 또는 임상 검사 소견.

any other disease that may contraindicate the use of investigational drugs, affect the interpretation of results, impair the patient's ability to participate in the study, or place the patient at high risk for complications of treatment; Metabolic dysfunction, physical examination findings or clinical laboratory findings.

키메라 또는 인간화 항체 또는 융합 단백질에 대한 중증 알레르기 반응의 병력.

History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins.

중국 햄스터 난소 세포 제품 또는 재조합 인간 항체에 대한 공지된 과민증.

Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies.

부형제(히스티딘, 트레할로스 이수화물 및 폴리소르베이트 20을 포함함)의 연구 약물 중 어느 하나에 대한 공지된 불내성 또는 과민증.

Known intolerance or hypersensitivity to any of the study drugs of excipients (including histidine, trehalose dihydrate and polysorbate 20).

사전 투약에 필요한 약물(아세트아미노펜, 라니티딘, 디펜히드라민 및 메틸프레드니솔론) 중 어느 하나에 대한 공지된 불내성.

Known intolerance to any of the medications required prior to dosing (acetaminophen, ranitidine, diphenhydramine and methylprednisolone).

병기 2 진입 환자: 병기 1 동안 아테졸리주맙을 허용할 능력이 없음.

Patients entering Stage 2: Inability to tolerate atezolizumab during Stage 1.

연구 기간 동안 임신 또는 수유 중이거나 임신할 의사가 있는 경우. 가임 여성은 연구 치료 시작 전 14일 이내에 혈청 임신 검사 결과가 음성이어야 한다.

Pregnant, lactating, or intending to become pregnant during the study period. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

병기 2 진입 환자: 동의 시점에 1등급 이상 또는 기준선으로 해결되지 않은 면역요법 관련 이상 반응, 다음은 예외임: 보충 요법으로 적절하게 관리되는 진행 중인 내분비 사건이 있는 환자는 적격이다.

Patients entering Stage 2: Grade 1 or higher at time of consent or unresolved immunotherapy-related adverse events at baseline, with the following exceptions: Patients with ongoing endocrine events adequately managed with supplemental therapy are eligible.

Additional Exclusion Criteria for the Artezo + Tyra group during Stage 1

Patients who meet any of the following criteria are excluded from the atezo+tyra group for stage 1.

선별검사 시 활동성 EBV 감염 및 공지되거나 의심되는 만성 활동성 EBV 감염. 선별검사 시 EBV 바이러스 캡시드 항원 IgM 검사가 양성인 환자는 이 군으로부터 제외된다. 활동성 감염 또는 의심되는 만성 활동성 감염을 선별하기 위해 임상적으로 지시된 대로 EBV 중합효소연쇄반응(PCR) 검사를 수행한다. EBV PCR 검사가 양성인 환자는 이 군으로부터 제외된다.

Active EBV infection at screening and known or suspected chronic active EBV infection. Patients with a positive EBV virus capsid antigen IgM test at screening are excluded from this group. Perform EBV polymerase chain reaction (PCR) testing as clinically indicated to screen for active infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded from this group.

E. accepted therapy

Patients are allowed to use the following regimens during the study period:

경구 피임약

pill

호르몬 대체 요법

hormone replacement therapy

예방적 또는 치료적 항응고 요법(예컨대, 안정적인 용량의 와파린 또는 안정적인 용량의 저분자량 헤파린)

Prophylactic or therapeutic anticoagulant therapy (eg, a stable dose of warfarin or a stable dose of low molecular weight heparin)

제도적 기준에 따라 투여되는 예방적 항생제 또는 항바이러스제

Prophylactic antibiotics or antivirals administered according to institutional standards

비활성화 인플루엔자 예방 접종

Inactivated influenza vaccination

식욕 자극제로 투여되는 메게스트롤 아세테이트

Megestrol acetate administered as an appetite stimulant

미네랄로코르티코이드(예컨대, 플루드로코르티손)

Mineralocorticoids (such as fludrocortisone)

만성 폐쇄성 폐질환 또는 천식에 투여되는 코르티코스테로이드

Corticosteroids given for chronic obstructive pulmonary disease or asthma

기립성 저혈압 또는 부신피질 기능부전에 투여된 저용량 코르티코스테로이드

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency

전립선 암에 대한 성선자극호르몬 방출 호르몬 또는 길항제를 이용한 호르몬 요법

Hormone therapy using gonadotropin releasing hormone or antagonist for prostate cancer

하기에 개략된 바와 같은 완화 방사선 요법(예컨대, 공지된 골 전이의 치료 또는 통증의 증상 완화):

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

After 2 cycles of treatment, palliative radiotherapy is allowed as long as it does not interfere with the evaluation of the tumor target lesion (eg, the lesion to be irradiated must not be the only site of measurable disease). Atezolizumab treatment may be continued during palliative radiotherapy.

하기 요약된 국소 요법(예컨대, 수술, 정위 방사선 수술, 방사선요법, 고주파 절제):

Local therapies (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) summarized below:

Patients experiencing mixed reactions requiring topical therapy to control 3 or fewer lesions may still be eligible to continue study treatment after approval from a medical monitor. Patients receiving topical therapy for the target lesion can no longer be evaluated for radiological response, but

Progress can be evaluated continuously.

Prior dosing with antihistamines, antipyretics and/or analgesics may be administered only for the second and subsequent infusions of atezolizumab at the discretion of the investigator.

Patients experiencing infusion-related symptoms may be treated with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice, depending on the symptoms. have. Severe infusion-related reactions presenting with dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation or dyspnea should be managed with adjuvant therapy as clinically indicated (e.g., adjuvant oxygen and β ₂ adrenergic agonists). .

D. Materials and Methods of the Atezolizumab Group

Atezolizumab is administered at an approved dose (TECENTRIQ® U.S. Package Insert; TECENTRIQ® SmPC), a 1200 mg fixed dose (Q3W) every 3 weeks (1200 mg on Day 1 of each 21-day cycle) (Table 80). Antitumor activity was observed over doses ranging from 1 to 20 mg/kg Q3W. In study PCD4989g, the maximally tolerated dose of atezolizumab was not reached and no dose limiting toxicity was observed at any dose. A fixed dose of 1200 mg Q3W (corresponding to a mean weight-based dose of 15 mg/kg Q3W) has been compared with nonclinical studies (Deng et al., MAbs, 8: 593-603, 2016) and available clinical pharmacokinetic, efficacy and safety data. was selected based on

Atezolizumab control patients had unacceptable toxicity or clinical findings as determined by the investigator after an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical condition (e.g., worsening of symptoms such as disease-related pain). Treatment is continued until loss of benefit is achieved. Treatment must be initiated within 7 days of treatment assignment. Patients undergo surgery after cycle 3; Cycle 4 treatment should be resumed 4 to 6 weeks after surgery.

Administration of atezolizumab is performed in a monitoring setting with trained staff and immediate access to appropriate equipment and medications to manage potentially serious reactions.

Atezolizumab infusion is administered according to the guidelines summarized in Table 81.

F. Materials and Methods of the Atezolizumab + Tiragolumab Group

Atezolizumab is administered as described above (see Table 81).

Tiragolumab is administered as a fixed dose of 600 mg IV Q3W (600 mg on Day 1 of each 21-day cycle). Q3W as a 600 mg fixed dose IV was selected based on available clinical PK, efficacy and safety data from the combined Phase Ia/Ib study GO30103 with either single agent tiragolumab or atezolizumab in combination with tiragolumab . In the Phase Ia portion of the study using tyragolumab as a single agent, MTD was not reached and no DLT was observed at dose escalation. clinical

As of the deadline, antidrug antibodies (ADA) to tiragolumab were rare in the Phase Ia or Ib portion across all dose levels. At tiragolumab doses starting at 400 mg, long-term stable disease was observed in patients in the Phase Ia portion of the study.

observed. In the Phase Ib portion of the study with atezolizumab in combination with tiragolumab, MTD was not reached. Antitumor activity, as measured by radiological partial response, was observed over tiragoluumab doses ranging up to 600 mg starting at 30 mg in combination with 1200 mg atezolizumab.

Patients in the atezolizumab + tiragolumab arm were considered unacceptable as determined by the investigator after an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms such as disease-related pain). Receive treatment summarized in Table 82 until loss of toxicity or clinical benefit. Patients undergo surgery after cycle 3; Cycle 4 treatment is resumed 4-6 weeks post surgery.

Tiragolumab is administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21-day cycle, as described in Table 83, with a post-infusion observation period. Administration of tiragolumab is performed in a monitoring setting with trained staff and immediate access to appropriate equipment and medications to manage potentially serious reactions.

A safety assessment for the WO39613 mUC study was performed as described in Example 18.

Example 22. Statistical considerations and analysis plan for WO39613 mUC study

WO39613 analysis is based on patient data collected through study discontinuation. Unless otherwise specified, efficacy analyzes are based on an efficacy evaluable population defined as all patients receiving at least one dose of each drug for the assigned treatment regimen, and safety analyzes are based on all patients receiving study treatment. It is based on a population that can be evaluated for safety.

The results of the analysis are summarized by the treatment actually received by the patient and, if applicable, by stage (Stage 1 or Stage 2). Data are described and summarized according to sample size. Continuous variables are summarized using mean, standard deviation, median, minimum and maximum values. Categorical variables are summarized using counts and percentages. Lists are used instead of tables when the sample size is small.

A. Determination of sample size

WO39613 study was not designed to account for apparent analytical power and type I error for hypothesis analysis.

Instead, this study was designed to obtain preliminary efficacy, safety, and PK data for an immunotherapy-based treatment combination when administered to patients with locally advanced or metastatic UC who progressed during or after platinum-containing therapy. Approximately 160 to 385 patients are randomly assigned to control and experimental groups for the duration of the study.

B. Validity analysis

Primary efficacy endpoint

The primary endpoint is the objective response rate (ORR) during stage 1 as determined by the investigator according to RECIST v1.1 and defined as above (see Table 78). Patients with missing or non-existent response assessments are classified as non-responders.

ORR, defined as the proportion of patients with CR or PR, is calculated for each group with a 90% CI (Clopper-Pearson direct probability method). In addition, the ORR difference between the experimental group and the control group is calculated as 90% CI. CI is estimated by direct probability method or Wald method according to the sample size.

secondary efficacy endpoint

Secondary efficacy endpoints are progression-free survival (PFS), OS, OS at a specific time point (eg, 12 months), DOR, and disease control during Stage 1 as defined above (see Table 78). PFS, DOR and disease control are determined by the investigator according to RECIST v1.1.

A DOR is derived for evaluable patients with CR or PR.

For patients with no documented disease progression or death during the study phase, PFS and DOR are censored and cleared on the day of the last tumor assessment. Patients still alive at the time of OS analysis are censored on the last day survival is known.

The Kaplan-Meier method is used to estimate the median of PFS, OS, and DOR with 90% CI constructed using Brookmeier and Crowley methods. In addition, the OS ratio at any point in time is estimated using the Kaplan-Meier method with 90% Ci calculated based on Greenwood estimates of variance.

Disease control rate, defined as the proportion of patients with stable disease, PR or CR for 18 weeks is calculated for each treatment arm with an estimated 90% CI using the Klopper-Pearson direct probability method.

Exploratory validity endpoints

Exploratory efficacy endpoints included ORR, PFS, DOR, and disease control during stage 1 as determined by investigators according to iRECIST; and Investigator-determined objective response, PFS, DOR, and disease control during Stage 2 according to RECIST v1.1 and iRECIST. ORR, PFS, DOR and disease control are analyzed using the same method described above. DOR is derived for evaluable patients with CR or PR.

C. Interim analysis

Interim analyzes are performed during the study period, and the earliest interim analyzes are performed when at least one experimental group has completed enrollment in the Stage 1 preliminary stage and patients have been followed for at least 9 weeks. Additional interim analyzes may be performed if deemed appropriate. The posterior probability can be used to guide further enrollment based on an interim analysis of clinical activity in the experimental group compared to the control group. If the interim analysis suggests that the activity of the experimental group is higher than that of the control group, 25 additional patients can be enrolled in the experimental group (expansion phase). Such

Final decisions about expansion and termination of Phase 1b clinical trials are made taking into account the overall benefit-risk balance and data as a whole, including time-to-event endpoints and safety data, as well as new external information.

In addition, analysis is performed after approximately 15 patients have been enrolled in the Stage 2 treatment group and followed for at least 9 weeks. If clinical activity is not observed in the Stage 2 treatment arm, further enrollment in that arm will be discontinued.

D. Other analysis

Safety analysis, pharmacokinetic analysis, immunogenicity analysis and biomarker analysis were performed as described in Example 19.

Example 23. A Phase Ib/II, Open Label, Multicenter, Randomized, Comprehensive Study Evaluating the Efficacy and Safety of Immunotherapy-Based Treatment Combinations in Patients with Locally Advanced or Metastatic Esophageal Cancer

A. Overview of Study Design

YO39609 is a Phase Ib/II, open-label, multicenter, randomized umbrella study evaluating the efficacy, safety, and pharmacokinetics of an immunotherapy-based treatment combination in patients with esophageal cancer. This study was designed to obtain preliminary efficacy, safety, and PK data for an immunotherapy-based treatment combination when administered to patients with esophageal cancer. In addition, the study is designed to have the flexibility to open new treatment groups as new treatments become available, close existing treatments that exhibit minimal clinical activity or unacceptable toxicity, or modify patient populations (e.g., previous anticancer treatments). or with respect to biomarker status).

Esophageal cancer patients who have not previously received systemic treatment for the disease are enrolled in this study. Eligible patients will be randomized to one of three treatment groups. Control patients who experienced disease progression or unacceptable toxicity during Stage 1 may be eligible to continue treatment with another treatment regimen in Stage 2.

Stage 1 treatment

During Stage 1, patients with esophageal cancer are randomly assigned either to a chemotherapy control group (cisplatin + 5-FU) or to one of two experimental groups: tiragolumab and atezolizumab in combination with chemotherapy (atezo + tiragolumab + cisplatin). + 5-FU), or atezolizumab in combination with chemotherapy (Atezo + Cisplatin + 5-FU). Details of the treatment regimen for Stage 1 are provided in Table 84. Details of the treatment regimen for Stage 1 are provided in Table 84.

1L = 1 line; 5-FU = 5-fluorouracil; atezo + atezolizumab; Tira + Tiragolumap. A Randomization ^a The rate of randomization depends on the number of groups open for enrollment (e.g., if a group is added or enrollment of a group is withheld, preliminary analysis of results is withheld), and at any given time 35 % or fewer patients are randomly assigned to the control group. Randomization rates may be altered to increase enrollment in experimental groups exhibiting promising clinical activity. ^b The sponsor may decide to defer or withhold enrollment within a given treatment arm. The experimental group with minimal clinical activity or unacceptable toxicity

does not expand ^c If clinical activity is observed in the experimental group during the preliminary phase,

About 25 additional patients are enrolled in the group during the expansion phase.

Table 85 summarizes the specific study objectives of stage 1 and corresponding endpoints.

ADA = anti-drug antibody; DOR = duration of response; IC = immune cells; IHC = immunohistochemistry; iRECIST = modified RECIST v1.1 for immune-based therapeutics; PFS = progression-free survival; PK = pharmacokinetics; RECIST v1.1 = Response Evaluation Criteria for Solid Tumors, version 1.1; TC = tumor cells; TIGIT = T cell immunoreceptor with Ig and ITIM domains

Note: The overall response at one time point is assessed by the investigator using RECIST v1.1.

The registration of the two experimental groups was performed in the preliminary phase and in the subsequent expansion phase.

It proceeds in two steps.

About 100 to 165 patients are enrolled during Stage 1. Up to approximately 40 patients will be enrolled in the two experimental groups during the preliminary phase to ensure a sufficient number of patients with high TIGIT and PD-L1 expression to facilitate benefit and risk assessment within this subpopulation. If clinical activity is observed in the experimental group during the preliminary phase, approximately 25 additional patients can be enrolled in that group during the expansion phase. The sponsor may decide to defer or withhold enrollment within a given treatment arm.

Experimental groups with minimal clinical activity or unacceptable toxicity are not expanded. The protocol can be modified to add new experimental groups during the study.

Patients in Stage 1 are randomly assigned to treatment groups, and the randomization rate depends on the number of available experimental groups (e.g., if a group is added or enrollment in a group is withheld, preliminary analysis of results is withheld); The probability of being assigned to a control group does not exceed 35%. Randomization rates may be altered to increase enrollment in experimental groups exhibiting promising clinical activity. Randomization takes into account group exclusion criteria. If a patient meets any of the exclusion criteria outlined for a particular group, the patient is ineligible for that group.

Control patients receive treatment until unacceptable toxicity or disease progression according to RECIST v1.1. Patients in the control group had unacceptable toxicity or clinical benefit as determined by the investigator after an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical condition (e.g., worsening of symptoms such as disease-related pain). Treatment is continued until there is loss. Radiological progression according to RECIST v1.1, due to the potential for an initial increase in tumor burden due to immune cell infiltration in the setting of a T-cell response (termed pseudo-progression) with cancer immunotherapy (CIT) (eg, atezolizumab) may not represent actual disease progression. In the absence of unacceptable toxicity, patients who meet disease progression criteria according to RECIST v1.1 while being treated with CIT drugs may continue on study treatment if all of the following criteria are met:

- Evidence of clinical benefit as determined by the investigator after reviewing all available data.

- Absence of symptoms and signs (including laboratory values such as new or worsening hypercalcemia) indicative of apparent progression of the disease.

- Absence of reduced ECOG systemic activity that could be attributed to disease progression.

- Absence of tumor progression in critical anatomical sites (eg, leptomeningeal disease) that cannot be managed with medical interventions permitted by the protocol.

-Patient 's written consent to adjourn other treatment options to continue study treatment at the time of initial disease progression.

Stage 2 treatment

Control patients who experience disease progression according to RECIST v1.1 will be offered the option to receive another treatment combination during Stage 2 if they meet eligibility criteria and Arm 2 is open for enrollment. The stage 2 treatment regimen is atezolizumab plus tiragolumab.

Control patients who experience unacceptable toxicity may be eligible for stage 2 treatment after approval by a medical monitor. Stage 2 treatment must be initiated within 3 months of the patient experiencing disease progression or stage 1 unacceptable toxicity according to RECIST v1.1, and there is no unacceptable toxicity or loss of clinical benefit as determined by the investigator. continues until

Table 86 summarizes the specific study objectives for stage 2 and corresponding endpoints.

ADA = anti-drug antibody; DOR = duration of response; iRECIST = modified RECIST v1.1 for immune-based therapeutics; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; RECIST v1.1 = Criteria for Response Evaluation of Solid Tumors, Version 1.1.

Note: The overall response at one time point is assessed by the investigator using RECIST v1.1.

Stage 2 treatment must be initiated within 3 months of the patient experiencing disease progression or stage 1 unacceptable toxicity according to RECIST v1.1, and there is no unacceptable toxicity or loss of clinical benefit as determined by the investigator. continues until However, patients are encouraged to start stage 2 treatment as soon as possible.

In addition, a referral may decide to discontinue enrollment in the Stage 2 treatment arm, if appropriate, based on review of safety data, preliminary efficacy data, and supporting information (eg, biomarker study data).

B. Study End and Study Duration

Study end is defined as the date the last patient completed the last visit, including survival follow-up visits performed by phone or site visit.

The total study duration from the first patient's screening to the end of the study is approximately 3 to 6 years.

C. Study Design and Patient Population Rationale

This study is designed to accelerate the development of cancer immunotherapy (CIT) combinations by identifying early signs and establishing proof-of-concept clinical data in patients with esophageal cancer.

CIT has shown remarkable success with significant survival benefits observed across several advanced malignancies. Currently, the prevalent CIT approach is to identify and target T cell co-inhibitory surface receptors such as CTLA-4 and PD-L1/PD-1 to bypass immune evasion mechanisms and activate anti-tumor responses. Although these targets have achieved surprising clinical therapeutic success for a variety of cancer indications, ongoing research represents a series of cascading events necessary for the generation of a sustained anti-tumor immune response (Chen and Mellman, Immunity , 39:1-10, 2013). ). Each event is critical for an effective response, each vulnerable to multiple tumor immune evasion mechanisms. Therefore, the need to identify and bypass the various factors involved in tumor immune evasion is of great importance to propagate anti-tumor immune responses and advance the field of CIT, which is most likely achieved through combination therapy.

Esophageal cancer is an unmet disease with a high 5-year survival rate of 5% in the metastatic disease setting and 24% in the locally advanced disease setting. Treatment options for patients with advanced or metastatic esophageal cancer are limited and have a poor prognosis with minimal overall survival benefit. Therefore, there is an ongoing need for more effective and better tolerated treatments for this patient population.

Example 24. Materials and Methods for Studying YO39609

In this setting, approximately 100 to 165 patients with esophageal cancer who have not previously received systemic therapy will be randomized into control and experimental groups for the duration of the YO39609 study.

A. Inclusion criteria for stage 1

Patients must meet all of the following criteria summarized below to be eligible for Stage 1.

Age ≥ 18 years at the time the informed consent was signed.

0 또는 1의 ECOG 전신 활동도

ECOG systemic activity of 0 or 1

조직학적 또는 세포학적으로 확인된 국소 진행성 또는 전이성 질환의 편평세포암종 또는 식도선암종의 진단.

Diagnosis of squamous cell carcinoma or esophageal adenocarcinoma with histologically or cytologically confirmed locally advanced or metastatic disease.

The definitive diagnosis of metastatic esophageal cancer is made by evaluating histopathological data within the context of clinical and radiographic data.

식도암에 대한 이전의 전신 치료 없음, 다음은 예외임:

No prior systemic treatment for esophageal cancer, with the following exceptions:

- For patients treated with chemotherapy in a locally progressive setting: metastasis occurred 6 months after the last dose of chemotherapy.

선암종 환자의 경우: 질병의 초기 진단 시 이전에 수집 및 평가된 종양 조직에서 ISH 음성으로 보고된 HER2 발현의 부재.

For patients with adenocarcinoma: Absence of reported ISH-negative HER2 expression in tumor tissue previously collected and evaluated at the time of initial diagnosis of disease.

- HER2 negative status is determined on the basis of no ISH amplification (ratio of HER2 to CEP17 < 2.0, or single probe average HER2 gene copy number < 4 signals/cell) IHC 0 or IHC 1 + (one or more test results are available) If possible and not all outcomes meet the inclusion criteria definition, all outcomes should be discussed with the medical monitor to establish the patient's eligibility).

시험자가 결정한 기대 수명 ≥ 3개월.

Life expectancy ≥ 3 months as determined by the investigator.

크레아티닌 청소율(CrCl) ≥ 50 mL/분(콕크로프트-골트 공식을 사용하여 계산됨).

Creatinine clearance (CrCl) ≥ 50 mL/min (calculated using Cockcroft-Goldt formula).

IHC에 의한 PD-L1 및 TIGIT 수준 및/또는 후향적 중앙 검사를 통한 추가 바이오마커 상태의 결정에 적합한 대표적인 종양 표본의 가용성.

Availability of representative tumor specimens suitable for determination of PD-L1 and TIGIT levels by IHC and/or additional biomarker status via retrospective central examination.

- Baseline tumor tissue samples are collected from all patients, preferably by biopsy performed at the start of the study. If the investigator determines that a biopsy cannot be performed, if the archival tumor tissue is from a biopsy performed within 6 months prior to enrollment and the patient has not received any chemotherapy since the time of the biopsy, the archival tumor tissue will be removed after approval by the medical monitor. can be submitted

- At least 16 slides containing FFPE tumor specimens in paraffin blocks (preferred) or unstained, freshly excised serial sections should be submitted with the relevant pathology report. If only 10 to 15 slides are available, after approval by the medical monitor, the patient may still be eligible for the study.

B. Inclusion Criteria for Stage 1 and Stage 2

Patients must meet all of the following criteria summarized below to be eligible for Stage 1 and Stage 2.

서명한 사전 동의서

signed informed consent

시험자의 판단으로, 연구 프로토콜을 준수하는 능력.

At the discretion of the investigator, the ability to comply with the study protocol.

RECIST v1.1에 따라 측정 가능한 질병. 이전에 방사선 조사된 병변은 방사선 조사 이후 해당 부위에서 진행성 질환이 명백하게 기록된 경우에만 측정 가능한 질환으로 간주할 수 있다.

Measurable disease according to RECIST v1.1. Previously irradiated lesions can be considered measurable disease only if progressive disease is clearly documented at the site after irradiation.

다음 실험실 검사 결과에 의해 정의되는, 연구 치료 개시 전 14일 이내에 획득한 적절한 혈액 및 종말 기관 기능:

Adequate blood and terminal organ function obtained within 14 days prior to initiation of study treatment, as defined by the following laboratory test results:

- ANC ≥ 1.5 × 10 ⁹ /L (1500/μL), no granulocyte colony stimulating factor support.

- Lymphocyte count ≥ 0.5 × 10 ⁹ /L (500/μL).

- Platelet count ≥ 100 × 10 ⁹ /L (100,000/μL), no transfusion.

- Hemoglobin ≥ 90 g/L (9 g/dL). Patients may receive blood transfusions to meet these criteria.

- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN), with the following exceptions:

Patients with documented liver metastases: AST and ALT ≤ 5 × ULN.

Patients with documented liver or bone metastases: ALP ≤ 5 × ULN.

- Bilirubin ≤ 1.5 × ULN, with the following exceptions:

Known Gilbert's disease patients: bilirubin levels ≤ 3 x ULN.

- Albumin ≥ 25 g/L (2.5 g/dL).

- For patients not receiving therapeutic anticoagulants: INR or aPTT ≤ 1.5 × ULN.

- For patients receiving therapeutic anticoagulants: stable anticoagulant therapy.

선별검사 시 HIV 검사 음성, 다음은 예외임: 선별검사 시 HIV 검사가 양성인 환자는 항레트로바이러스 요법에 안정적이고, CD4 수 ≥ 200/μL이며, 바이러스 부하를 감지할 수 없는 경우 적격이다.

HIV test negative at screening, with the following exceptions: Patients with a positive HIV test at screening are eligible if they are stable on antiretroviral therapy, have a CD4 count ≥ 200/μL, and have no detectable viral load.

선별검사 시 B형 간염 표면 항원(HBsAg) 검사 음성.

Negative hepatitis B surface antigen (HBsAg) test at screening.

선별검사 시 총 B형 간염 코어 항체(HBcAb) 검사 음성, 또는 선별검사 시 총 HBcAb 검사 양성 후 정량적 B형 간염 바이러스(HBV) DNA < 500 IU/mL. HBV DNA 검사는 HBcAb 검사가 양성인 환자에게만 시행된다.

Quantitative hepatitis B virus (HBV) DNA < 500 IU/mL after total hepatitis B core antibody (HBcAb) negative at screening, or positive total HBcAb at screening. HBV DNA testing is only performed on patients with a positive HBcAb test.

선별검사 시 C형 간염 바이러스(HCV) 항체 검사 음성, 또는 선별검사 시 HCV 항체 검사 양성 후 HCV RNA 검사 음성. HCV RNA 검사는 HCV 항체 검사 양성인 환자에게만 시행된다.

Hepatitis C virus (HCV) antibody test negative at screening, or HCV RNA test negative after positive HCV antibody test at screening. The HCV RNA test is only performed on patients with a positive HCV antibody test.

임신 가능성이 있는 여성의 경우: 금욕 유지(이성간 성교 자제) 또는 피임법 사용에 대한 동의 및 난자 기증 자제에 대한 동의.

For women of childbearing potential: Consent to maintain abstinence (abstain from heterosexual intercourse) or to use contraceptives and to refrain from donating eggs.

남성의 경우: 금욕 유지(이성간 성교 자제) 또는 피임법 사용에 대한 동의 및 정자 기증 자제에 대한 동의.

For men: Consent to maintain abstinence (abstain from heterosexual intercourse) or to use contraception and to refrain from donating sperm.

C. Inclusion criteria for stage 2

Patients must meet all of the following criteria summarized below to be eligible for Stage 2.

0, 1 또는 2의 ECOG 전신 활동도

ECOG systemic activity of 0, 1 or 2

병기 1 동안 대조군에 무작위로 배정된 환자: 대조 치료를 받는 동안, 병기 2로의 진입에 대한 의학 모니터 요원의 승인을 얻은 경우, 허용할 수 없는 독성 또는 RECIST v1.1에 따른 질병 진행을 경험한 후 3개월 이내에 병기 2 치료를 개시할 수 있는 능력.

Patients randomized to control group during Stage 1: After experiencing unacceptable toxicity or disease progression per RECIST v1.1, if medical monitor approval is obtained for entry into Stage 2, while receiving control treatment. Ability to initiate Stage 2 treatment within 3 months.

크레아티닌 ≤ 1.5 × ULN 또는 CrCl ≥ 30 mL/분(콕크로프트-골트(Cockcroft-Gault) 공식을 사용하여 계산됨).

Creatinine ≤ 1.5 × ULN or CrCl ≥ 30 mL/min (calculated using the Cockcroft-Gault formula).

허용할 수 없는 독성 또는 RECIST v1.1에 따른 질병 진행으로 인해 병기 1 중단 시 수행된 생검에서 채취된 종양 표본(임상적으로 실현 가능한 것으로 간주되는 경우)의 가용성.

Availability of tumor specimens (if considered clinically feasible) from biopsies performed at stage 1 discontinuation due to unacceptable toxicity or disease progression per RECIST v1.1.

D. Exclusion Criteria

Patients meeting any of the following criteria will be excluded from enrollment during Stages 1 and 2.

Stage 1 exclusion criteria

Patients meeting any of the following criteria are excluded from Stage 1:

·Previous treatment with any of the protocol-directed study treatments.

·Patients with known hearing impairment.

≥ Grade 2 peripheral neuropathy as defined by the NCI CTCAE v4.0 criteria.

Known dihydropyrimidine dehydrogenase deficiency, or thymidylate synthase gene polymorphism that predisposes the patient to 5-FU toxicity.

Exclusion Criteria for Stage 1 and Stage 2

Patients meeting any of the following criteria are excluded from Stage 1 and Stage 2:

내시경 초음파에 의한 식도 누공 또는 T4 분류의 이전 병력 또는 관련 증상과 같은, 임상 평가 또는 영상화에 의한 높은 식도 누공 발생 위험.

High risk of developing an esophageal fistula by clinical evaluation or imaging, such as a previous history of esophageal fistula by endoscopic ultrasound or a previous history of T4 classification or related symptoms.

증상이 있거나, 치료되지 않았거나, 활발히 진행 중인 중추신경계(CNS) 전이. 치료된 CNS 병변이 있는 무증상 환자는 다음 기준이 모두 충족되는 경우 적격이다:

Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated CNS lesions are eligible if all of the following criteria are met:

- According to RECIST v1.1, measurable diseases must be outside the CNS.

- The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

-Patient had not undergone stereotactic radiotherapy within 7 days prior to study treatment initiation, whole brain radiotherapy within 14 days prior to study treatment initiation, or neurosurgical resection within 28 days prior to study treatment initiation.

- The patient does not require continuous corticosteroids as therapy for CNS disease. Stable dose anticonvulsant therapy is permitted.

- Metastasis is limited to the cerebellum or supramial region (ie, no metastasis to the midbrain, pons, medulla or spinal cord).

- There is no evidence of intermediate progression between completion of CNS-directed therapy and initiation of study treatment.

- Asymptomatic patients with newly discovered CNS metastases at screening are eligible for the study after undergoing radiotherapy or surgery without the need to repeat screening brain scans.

선별검사 시 활동성 EBV 감염 및 공지되거나 의심되는 만성 활동성 EBV 감염. EBV IgG 및/또는 엡스타인-바 핵항원(EBNA)에 양성인 환자는 EBV IgM 및/또는 EBV PCR이 음성인 경우에만 적격이다.

Active EBV infection at screening and known or suspected chronic active EBV infection. Patients positive for EBV IgG and/or Epstein-Barr nuclear antigen (EBNA) are eligible only if EBV IgM and/or EBV PCR are negative.

연수막 질환의 병력.

History of leptomeningeal disease.

Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions that can be treated with palliative radiotherapy (eg, bone metastases or metastases causing nerve impingement) should be treated prior to enrollment. The patient must recover from the effects of radiation. The patient must recover from the effects of radiation. Asymptomatic metastatic lesions (e.g., epidural metastases not currently associated with spinal cord compression) that have the potential to cause functional defects or refractory pain upon further growth should be considered for local treatment if appropriate prior to enrollment.

조절되지 않는 흉막 삼출, 심낭 삼출, 또는 반복적인 배액 절차가 필요한 복수(매월 1회 또는 더 자주). 유치 카테터(예컨대, PLEURX®)를 사용하는 환자는 허용된다.

Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (once monthly or more often). Patients using indwelling catheters (eg, PLEURX®) are permitted.

조절되지 않거나 증상이 있는 고칼슘혈증(이온화 칼슘 > 1.5 mmol/L, 칼슘 > 12 mg/dL 또는 교정된 칼슘 > ULN).

Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected calcium > ULN).

중증 근무력증, 근염, 자가면역 간염, 전신 홍반성 루푸스, 류마티스 관절염, 염증성 장질환, 항인지질항체 증후군, 베게너 육아종증, 쇼그렌 증후군, 길랭-바레 증후군 또는 다발성 경화증을 포함하나 이에 한정되지 않는 자가 면역 질환 또는 면역 결핍의 활성 또는 병력, 다음은 예외임:

Autoimmune diseases including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome or multiple sclerosis or active or history of immunodeficiency, with the exception of:

Patients with a history of autoimmune-related hypothyroidism and taking thyroid replacement hormone are eligible for the study.

Patients with controlled type 1 diabetes on stable insulin therapy are eligible for the study.

Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with dermatological signs only (e.g., excluding patients with psoriatic arthritis) are eligible for study if all of the following conditions are met:

- The rash should occupy < 10% of the body surface area.

- Disease is well controlled at baseline and requires only low titer topical corticosteroids.

- No acute exacerbation of underlying conditions requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high titers or oral corticosteroids within the past 12 months.

History of idiopathic pulmonary fibrosis, obstructive bronchitis (eg, bronchiolitis obliterans), drug-induced pneumonia or idiopathic pneumonia, or evidence of active pneumonia on a screening chest computed tomography (CT) scan. A history of radiation pneumonitis (fibrosis) in the field of radiation is acceptable

활동성 결핵.

active tuberculosis.

연구 치료 개시 전 3개월 이내의 유의한 심혈관 질환(예컨대, II군 이상의 뉴욕심장학회 심장 질환, 심근경색증 또는 뇌혈관 장애), 불안정 부정맥 또는 불안정 협심증.

Significant cardiovascular disease within 3 months prior to study treatment initiation (eg, New York Heart Association heart disease greater than or equal to Group II, myocardial infarction or cerebrovascular disorder), unstable arrhythmias, or unstable angina.

연구 치료 개시 전 4주 이내의 진단 이외의 주요 외과적 절차, 또는 연구 기간 동안 주요 외과적 절차의 필요성에 대한 예상.

A major non-diagnosis major surgical procedure within 4 weeks prior to initiation of study treatment, or an estimate of the need for a major surgical procedure during the study period.

적절하게 치료된 자궁경부의 상피내암종, 비흑색종 피부암종, 국소 전립선암, 관상피내암종, 또는 병기 I 자궁암과 같은 무시할 수 있는 전이 또는 사망의 위험(예컨대, 5년 OS 비율 > 90%)이 있는 악성 종양을 제외한, 선별검사 이전 2년 이내의 식도암 이외의 악성 종양의 병력.

Adequately treated, there is a negligible risk of metastasis or death (e.g., 5-year OS rate >90%) History of malignancy other than esophageal cancer within 2 years prior to screening, excluding malignant tumors present.

감염 합병증, 세균혈증 또는 중증 폐렴으로 인한 입원을 포함하나 이에 한정되지 않는 연구 치료 개시 전 4주 이내의 중증 감염.

Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for infectious complications, bacteremia, or severe pneumonia.

연구 치료 개시 전 2주 이내의 치료적 경구 또는 IV 항생제를 사용한 치료.

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to study treatment initiation.

(예컨대, 요로 감염 또는 만성 폐쇄성 폐질환 악화를 예방하기 위해) 예방적 항생제를 투여받는 환자는 연구에 적격이다.

Patients receiving prophylactic antibiotics (eg, to prevent exacerbation of urinary tract infection or chronic obstructive pulmonary disease) are eligible for study.

선행 동종이계 줄기 세포 이식 또는 고형 장기 이식.

Prior allogeneic stem cell transplantation or solid organ transplantation.

임상시험용 약물의 사용을 금하거나, 결과 해석에 영향을 미칠 수 있거나, 또는 치료 합병증으로 인해 환자를 높은 위험에 처하게 할 수 있는 임의의 기타 질병, 대사 기능 장애, 신체 검사 소견 또는 임상 검사 소견.

Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that may contraindicate the use of investigational drugs, affect the interpretation of results, or place the patient at high risk for complications of treatment.

연구 치료 개시 전 4주 이내의 약독화 생백신을 사용한 치료, 또는 아테졸리주맙 치료 동안 또는 아테졸리주맙의 마지막 투여 후 5개월 이내의 이러한 백신의 필요성에 대한 예상.

Treatment with live attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of the need for such vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.

HBV에 대한 항바이러스 요법을 사용한 현재 치료.

Current treatment with antiviral therapy for HBV.

연구 약물 또는 그 부형제 중 어느 하나에 대한 공지된 알레르기 또는 과민증.

Known allergy or hypersensitivity to either the study drug or its excipients.

연구 치료 개시 전 28일 이내의 임상시험 요법에 의한 치료.

Treatment by investigational regimen within 28 days prior to initiation of study treatment.

항 CTLA-4, 항 PD-1, 항 PD-L1 및 항 TIGIT 치료 항체를 비롯한 CD137 작용제 또는 면역 관문 차단 요법을 사용한 이전 치료.

Previous treatment with CD137 agonists or immune checkpoint blockade therapy, including anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-TIGIT therapeutic antibodies.

연구 치료 개시 전 4주 또는 약물 제거 반감기의 5배(둘 중 더 긴 것) 이내의 전신 면역자극제(인터페론 및 인터루킨 2[IL-2]를 포함하나 이에 한정되지 않음)를 사용한 치료.

Treatment with systemic immunostimulants (including but not limited to interferon and interleukin 2 [IL-2]) within 4 weeks prior to initiation of study treatment or within 5 times the drug elimination half-life, whichever is longer.

연구 치료 개시 전 2주 이내의 전신 면역억제 약물(코르티코스테로이드, 사이클로포스파미드, 아자티오프린, 메토트렉세이트, 탈리도마이드 및 항 TNF-α 제제를 포함하나 이에 한정되지 않음)을 사용한 치료, 또는 연구 치료 동안 전신 면역억제제의 필요성에 대한 예상, 다음은 예외임:

treatment with systemic immunosuppressive drugs (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or during study treatment Anticipation of the need for systemic immunosuppressants, with the following exceptions:

- Patients receiving acute low-dose systemic immunosuppressive drugs or single pulse doses of systemic immunosuppressive drugs (eg, corticosteroids for contrast allergy 48 hours) are eligible for study after obtaining approval from the medical monitor.

- Patients receiving mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenocortical insufficiency are eligible for study.

키메라 또는 인간화 항체 또는 융합 단백질에 대한 중증 알레르기 아나필락시스 반응의 병력.

History of severe allergic anaphylactic reaction to chimeric or humanized antibodies or fusion proteins.

중국 햄스터 난소 세포 제품 또는 아테졸리주맙 및 티라골루맙 제제의 임의의 성분에 대한 공지된 과민증.

Known hypersensitivity to any component of the Chinese Hamster Ovary Cell Products or formulations of Atezolizumab and Tiragolumab.

Pregnant, lactating, or intending to become pregnant during study treatment, or within 5 months of the last dose of atezolizumab and within 5 months of the last dose of tiragolumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

E. accepted therapy

Patients are allowed to use the following regimens during the study period:

경구 피임약

pill

호르몬 대체 요법

hormone replacement therapy

예방적 또는 치료적 항응고 요법(예컨대, 안정적인 용량의 와파린 또는 저분자량 헤파린)

Prophylactic or therapeutic anticoagulant therapy (eg, stable doses of warfarin or low molecular weight heparin)

비활성화 인플루엔자 예방 접종

Inactivated influenza vaccination

식욕 자극제로 투여되는 메게스트롤 아세테이트

Megestrol acetate administered as an appetite stimulant

미네랄로코르티코이드(예컨대, 플루드로코르티손)

Mineralocorticoids (such as fludrocortisone)

만성 폐쇄성 폐질환 또는 천식에 투여되는 코르티코스테로이드

Corticosteroids given for chronic obstructive pulmonary disease or asthma

기립성 저혈압 또는 부신피질 기능부전에 투여된 저용량 코르티코스테로이드

Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency

하기에 개략된 바와 같은 완화 방사선 요법(예컨대, 공지된 골 전이의 치료 또는 통증의 증상 완화):

Palliative radiation therapy (eg, treatment of known bone metastases or relief of symptoms of pain) as outlined below:

Palliative radiation therapy is acceptable as long as it does not interfere with the evaluation of tumor target lesions (eg, the lesion to be investigated should not be the only site of measurable disease). Atezolizumab treatment may be continued during palliative radiotherapy.

· Local therapies (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) summarized below:

Patients experiencing mixed reactions requiring topical therapy to control 3 or fewer lesions may still be eligible to continue study treatment after approval from a medical monitor. Patients receiving topical therapy for the target lesion can no longer be evaluated for radiological response, but

Progress can be evaluated continuously.

Prior dosing with antihistamines, antipyretics and/or analgesics may be administered only for the second and subsequent infusions of atezolizumab at the discretion of the investigator.

Patients experiencing infusion-related symptoms may be treated with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent drugs according to local standard practice, depending on the symptoms. have. Severe infusion-related reactions presenting with dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased oxygen saturation or dyspnea should be managed with adjuvant therapy as clinically indicated (e.g., adjuvant oxygen and β ₂ adrenergic agonists). .

F. Dosage and administration

Patients in the following treatment groups were evaluated for unacceptable toxicity or clinical benefit as determined by the investigator after an integrated evaluation of radiographic and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms such as disease-related pain). Receive summarized treatment until loss.

Atezolizumab + Tiragolumab + Cisplatin + 5-fluuracil group

Patients in the atezolizumab + tiragolumab + cisplatin + 5-FU group receive the treatment summarized in Table 87.

5-FU = 5-fluorouracil; ^a Cisplatin treatment is limited after 6 doses. ^b Infusion times of cisplatin and 5-FU may be adjusted according to local standard practice.

Atezolizumab + cisplatin + 5-fluuracil group

Patients in the atezolizumab + cisplatin + 5-FU group receive the treatment summarized in Table 88.

5-FU = 5-fluorouracil; ^a Cisplatin treatment is limited after 6 doses. ^b Infusion times of cisplatin and 5-FU may be adjusted according to local standard practice.

Control (cisplatin + 5-FU)

Cisplatin is administered by IV infusion over 120 minutes at a dose of 80 mg/m2 on Day 1 of the first 6 21-day cycles. 5-FU is administered by continuous IV infusion over days 1 to 5 (120 hours) at a dose of 800 mg/m ² /24 hours starting on Day 1 of each 21-day cycle. Cisplatin treatment is continued for a total of 6 cycles unless unacceptable toxicity develops or the patient discontinues study treatment for any reason. Patients in the cisplatin + 5-FU control group are treated until unacceptable toxicity or disease progression according to RECIST v1.1.

Stage 2 treatment versus control (atezolizumab + tyragolumab)

Patients in the atezolizumab + tyragolumab group receive the treatment summarized in Table 89.

Patients experiencing disease progression according to RECIST v1.1 will be offered the option to receive another treatment combination during Stage 2 of the study if they meet eligibility criteria and Arm 2 is open for enrollment.

In addition, patients who experience unacceptable toxicity may be eligible for treatment during Stage 2 after meeting eligibility criteria and obtaining approval from a medical monitor. Stage 2 treatment should be initiated within 3 months of the patient experiencing disease progression or unacceptable toxicity. If tumor evaluations are performed within 28 days prior to initiation of Stage 2 treatment (i.e., Day 1 of Cycle 1), tumor evaluations performed at or prior to the onset of disease progression or unacceptable toxicity during Stage 1 are the baseline in Stage 2 It can play a role in evaluation. Stage 2 treatment is continued until there is unacceptable toxicity or loss of clinical benefit as determined by the investigator.

Atezolizumab infusion is administered according to the guidelines summarized in Table 90.

Tiragolumab infusions are administered according to the guidelines summarized in Table 91.

G. Safety Assessment Steps

To account for potential overlapping toxicity in the atezolizumab + tiragolumab + cisplatin + 5-FU group, enrollment is withheld after approximately 6 patients have been enrolled for safety evaluation. The safety assessment is based on safety data obtained from at least 6 patients who received at least one dose of treatment (i.e., one dose of each agent for a given combination) and completed safety follow-up for at least one full treatment cycle. . If the combination is judged to be sufficiently safe, registration is resumed in that group.

H. Assessment and monitoring

All patients are closely monitored for adverse events throughout the study, and adverse events are graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Patients receive tumor evaluations every 6 weeks (starting on Day 1 of Cycle 1) for the first 12 months, and then every 6 or 12 weeks thereafter. Response is assessed by the investigator using RECIST v1.1 (Eisenhauer et al., Eur J Cancer , 45: 228-247, 2009). Response to modified RECIST v1.1 (iRECIST) for immune-based therapeutics is determined programmatically by the sponsor based on individual lesion data evaluated by the investigator (Seymour et al., Lancet Oncol , 18: e143-152, 2017). If clinical activity appears in the experimental group, the sponsor may request to submit a tumor assessment scan for that group for evaluation by a central reading facility.

Baseline tumor tissue samples are preferably collected from all patients via biopsies performed at the start of the study. If the investigator determines that a biopsy cannot be performed, the archived tumor tissue may be submitted. In addition, if the investigator determines that it is clinically feasible, the tumor tissue will be staged 1 due to unacceptable toxicity as determined by the investigator, disease progression (control group), or loss of clinical benefit (experimental group) according to RECIST v1.1. collected from patients who discontinued For patients enrolled in the experimental arm in the expansion phase, tumor tissue during treatment 4 weeks after initiation of phase 1 therapy, unless tissue samples have already been collected from at least 15 patients treated with the same CIT combination and are determined to be measurable. Collect samples (if determined clinically feasible). These samples and blood samples collected during the study period are used for biomarker studies.

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and other therapeutic agents, blood samples are obtained at various time points prior to and during administration of study treatment.

Tumor and Response Assessment

Every 6 weeks (± 1 week) for the first 12 months after initiation of treatment, regardless of dose delay, until radiological disease progression according to RECIST v1.1, except for patients who continue treatment after radiological disease progression; Thereafter, tumors are assessed at baseline every 12 weeks (±2 weeks); These patients receive tumor assessments every 8 weeks (±1 weeks) until loss of clinical benefit as determined by the investigator.

Therefore, even if new non-protocol therapy is initiated, tumor evaluation continues according to schedule for patients who discontinue treatment for reasons other than disease progression or loss of clinical benefit. If progressive disease is suspected, the tumor evaluation may be repeated at any time at the investigator's discretion.

Baseline tumor assessment for Stage 2 must be performed within 28 days prior to initiation of Stage 2 treatment (ie, Day 1 of Cycle 1). For patients eligible for Stage 2, if tumor evaluation is performed within 28 days prior to initiation of Stage 2 treatment, unacceptable toxicity or disease (control) or loss of clinical benefit according to RECIST v1.1 during Stage 1 ( Tumor assessments performed at or before the onset of the experimental group) may serve as a baseline assessment of stage 2.

All measurable and evaluable lesions should be evaluated and reported at screening (both Stage 1 and Stage 2). Brain metastases treated with radiation therapy or surgery are not considered measurable or evaluable, but are reported as sites of metastatic disease. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not need to be repeated at screening.

Screening assessments should include CT scans (using oral and/or IV contrast) or magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis. A spiral CT scan of the chest can be obtained, but is not required. If CT scans with contrast agents are contraindicated (i.e., in patients with contrast agent allergy or renal clearance impairment), non-contrast CT scans of the chest may be performed, and MRI scans of the abdomen and pelvis (using IV contrast, if possible) should be performed In addition, if clinically indicated, a bone scan of the neck and a CT scan should be performed. Other methods of assessing measurable disease according to RECIST v1.1 may be used at the discretion of the investigator.

If CT scans for tumor evaluation are performed on a positron emission tomography/CT scanner, the CT acquisition should be consistent with the standard for full-contrast diagnostic CT scans.

All measurable and/or evaluable lesions identified at baseline should be re-evaluated at subsequent tumor assessments. Brain metastases identified at baseline, treated with radiation therapy or surgery, are not considered measurable or evaluable unless disease progression in the brain is suspected (ie, the patient is symptomatic). Therefore, a subsequent CT scan of the head is not required unless clinically indicated. The same radiographic procedure used to evaluate the site of disease at screening should be used for subsequent tumor evaluation (eg, the same contrast agent protocol for CT scans). To facilitate response evaluation according to iRECIST, tumor evaluation should continue after disease progression according to RECIST v1.1 for patients receiving treatment after disease progression. These assessments include continuous measurement of target lesions, assessment of non-target lesions (including monitoring for further deterioration of non-target lesions with clear progression), and evaluation of newly identified lesions at all subsequent assessments (including measurements if lesions are measurable). ) is included. The overall response at one time point is assessed by the investigator using RECIST v1.1.

Biomarker evaluation

Exploratory biomarker studies include the density, localization and activation status of tumor molecular subtypes and genes or gene signatures associated with tumor immunobiology, PD-L1, lymphocyte subpopulations, T cell receptor repertoire, cytokines associated with T cell activation, or ICs; Analysis of that subset may include, but is not limited to, DNA or RNA extraction, analysis of somatic mutations, and use of next-generation sequencing (NGS) (including whole exome sequencing (WES)).

Blood samples for biomarker evaluation are collected at baseline during the study period. Changes in biomarkers in the blood can provide evidence of biological activity of a particular treatment combination. Correlation between surrogate biomarkers in blood (e.g., tumor burden markers, cytokines, chemokines, IC subpopulations, gene expression, and circulating tumor DNA) and drug dose, efficacy, and safety endpoints can help determine whether a patient is from a particular treatment combination. Blood-based biomarkers could be developed to help define future treatments that could predict whether they are more likely to achieve a benefit.

Baseline tumor tissue samples are preferably collected from all patients via biopsies performed at the start of the study. Tumor tissue samples collected at baseline are used for determination of PD-L1 and TIGIT expression and for screening studies for biomarkers. If the investigator determines that it is clinically feasible, tumor tissue is collected from a patient who discontinued during Stage 1 due to unacceptable toxicity as determined by the investigator, disease progression according to RECIST v1.1, or loss of clinical benefit; Analysis of tumor tissue biomarkers associated with resistance, disease progression, and clinical benefit of the study treatment is possible.

If the investigator determines that it is clinically feasible, patients enrolled in the experimental arm during the expansion phase will be treated with Stage 1 unless tissue samples have already been collected during treatment from at least 15 patients treated with the same CIT combination and determined to be evaluable. On-treatment biopsies are taken 4 weeks (± 7 days) after initiation. In an effort to better understand the potential biological changes that occur during treatment with CIT combinations (including immune escape), to provide evidence of pharmacodynamic effects, or to identify a hypothesized mechanism of action, tissue samples are are collected

Tumor samples are evaluated for biomarkers such as tumor infiltrating IC, PD-L1, TIGIT and CD8. Assessment of the tumor microenvironment for treatments within each group, including changes in the number and functional status of tumor infiltrating ICs, can validate the postulated mechanism of action and ensure that appropriate doses and exposures for specific treatment combinations have been achieved.

Tumor tissue and blood samples are analyzed using NGS, including WES, to predict response to study drug, to be associated with progression to a more severe disease state, to be associated with acquired resistance to study drug, or to develop adverse events Identify somatic mutations that are associated with susceptibility to, or that may increase knowledge and understanding of disease biology.

Example 25. Statistical Considerations and Analysis Plan for the YO39609 Study

The final study analysis is based on patient data collected through study discontinuation. Unless otherwise specified, efficacy analyzes are based on an efficacy evaluable population defined as all patients receiving at least one dose of each drug for their assigned treatment regimen, and safety analyzes are based on administration of any amount of study treatment. It is based on a safety evaluable population defined as all patients received.

In addition, results are summarized by stage (Stage 1 or Stage 2) whenever stage 2 treatment is available. In addition, results are summarized by stage (Stage 1 or Stage 2) whenever stage 2 treatment is available. Data are described and summarized according to sample size. Continuous variables are summarized using mean, standard deviation, median, and range. Categorical variables are summarized using counts and percentages. For small sample sizes, a list is used instead of a table.

New baseline values are established for stage 2 efficacy and safety analyses. For assessment of tumor response, a new baseline tumor assessment is established. For other endpoints (eg, changes from baseline in vital signs or laboratory test results), the last unassigned value prior to the patient's first dose during Stage 2 serves as the new baseline.

Determination of sample size

This study was not designed to account for apparent analytical power and Type I error for hypothesis analysis. Instead, this study was designed to obtain preliminary efficacy, safety, and PK data for an immunotherapy-based treatment combination when administered to patients with esophageal cancer.

The study enrolls patients with esophageal cancer who have not previously received systemic therapy in this setting. Approximately 100 to 165 patients are randomly assigned to control and experimental groups for the duration of the study.

G. Validity analysis

Efficacy evaluable population is defined as all patients who received at least one dose of each drug for their assigned treatment regimen. Efficacy endpoints are summarized by actual treatment group.

Primary efficacy endpoint

The primary endpoint is the objective response rate (ORR) during stage 1 based on RECIST v1.1, defined as the proportion of patients with an objective response. Objective response is defined as a complete response or partial response in two consecutive ≥ 4 weeks intervals as determined by the investigator using RECIST v1.1. Patients who do not meet these criteria, including those without a post-baseline tumor assessment, are considered non-responders. ORR and its 95% Ci (Cloper-Pearson method) are summarized. The analysis population for ORR is a population that can be evaluated for effectiveness.

secondary efficacy endpoint

Secondary efficacy endpoints were PFS, OS, OS at specific time points (e.g., 6 and 12 months), duration of response (DOR), disease control during stage 1, objective response and PD in patients with TIGIT positive tumors as defined in Table 77. -The objective response of patients with L1-positive tumors. PFS, DOR and disease control are determined by the investigator according to RECIST v1.1.

A DOR is derived for evaluable patients with a confirmed complete or partial response. For patients with no documented disease progression or death during the study phase, PFS and DOR are censored and cleared on the day of the last tumor assessment. Patients still alive at the time of OS analysis are censored on the last day survival is known.

The Kaplan-Meier method is used to estimate the median of PFS, OS, and DOR with 90% confidence intervals (CI) constructed using Brookmeier and Crowley methods. In addition, the OS ratio at any point in time is estimated using the Kaplan-Meier method with 90% Ci calculated based on Greenwood estimates of variance.

Disease control rate, defined as the proportion of patients with stable disease, partial response, or complete response for ≥ 16 weeks, is calculated for each treatment arm with an estimated 90% CI using the Klopper-Pearson direct probability method.

Exploratory validity endpoints

Exploratory efficacy endpoints were investigator-determined objective response during Stage 1, PFS, DOR, and disease control according to iRECIST, and investigator-determined objective response, PFS, DOR, and disease during stage 2 according to RECIST v1.1 and iRECIST. it is control

H. Safety analysis

The safety analysis includes all patients who received at least one dose of any component of the study treatment. Exposure to study treatment is summarized by actual treatment group, both overall and within each arm.

Verbose terms of adverse events correspond to synonym terms in the Medical Dictionary for Regulatory Activities, and severity of adverse events is graded according to NCI CTCAE v4.0.

Safety is assessed through a summary of adverse events, changes in laboratory test results, changes in vital signs and ECGs, and exposure to study drug. Exposure and safety follow-up periods for combination therapy are summarized for each treatment group within each phase.

Treatment-related adverse events occurring after initiation of treatment are summarized. For each patient, the maximum severity reported for each adverse event is used for the summary by severity grade. All treatment-induced adverse events, serious adverse events, adverse events leading to discontinuation of study treatment, ≥ Grade 3 adverse events, death and cause of death are listed and summarized in terms of mapped, appropriate thesaurus level, and NCI CTCAE severity grade.

Relevant laboratories, vital signs (pulse rate, respiration rate, pulse oximetry, blood pressure and body temperature) and ECG data are displayed hourly and, where appropriate, grades identified. In addition, shift tables from selected laboratory tests are used to summarize baseline and post-baseline maximal severity grades. Changes in vital signs and ECG are summarized.

I. Pharmacokinetic analysis

Rare samples are collected for PK analysis of atezolizumab (patients receiving at least one dose of atezolizumab) and certain drugs administered in combination with atezolizumab (patients receiving at least one dose of the drug) . Serum or plasma concentrations of various study drugs are reported as individual values and, where appropriate, summarized by treatment group and by cycle and date as data permits (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean variation). Coefficient). Individual and median serum or plasma concentrations of various study drugs are presented by treatment group, by cycle, and by date. PK data for combination drugs can be compared with historical data available from internal and published previous studies. Atezolizumab concentration data can be integrated with data from other studies using established population PK models to derive PK parameters such as interval, volume of distribution, and area under the concentration-time curve.

J. Immunogenicity assay

Immunogenicity is assessed as appropriate for atezolizumab and other study treatments. The immunogenicity assay of atezolizumab included all patients who received at least one antidrug antibody (ADA) evaluation. Patients are grouped according to treatment received, or according to assigned treatment if no treatment was received prior to study discontinuation. For atezolizumab, the number and proportion of ADA-positive and ADA-negative patients at baseline (baseline prevalence) and after baseline (post-baseline incidence) are summarized by treatment group. For other study treatments for which ADA is tested, ADA positivity is determined according to standard methods established for previous studies of these drugs. The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints can be analyzed and reported using descriptive statistics.

K. Biomarker analysis

Exploratory biomarker analyzes are performed in an effort to understand the association of these biomarkers with response to study drug, taking into account action and safety endpoints.

L. Interim analysis

Interim analyzes are performed throughout the course of the study, and the earliest (Stage 1) interim analyzes are performed when at least one experimental group has completed enrollment in the preliminary phase and patients have been followed for at least 6 weeks. The posterior probability can be used to guide further enrollment in the treatment group based on an interim analysis of clinical activity in the experimental group compared to the control group. If the interim analysis suggests that the activity of the experimental group is higher than that of the control group, 25 additional patients can be enrolled in the experimental group. In addition, the analysis is performed after approximately 15 patients have been enrolled in the Stage 2 treatment group and followed for at least 6 weeks. If clinical activity is not observed in the Stage 2 treatment arm, further enrollment in that arm will be discontinued.

Example 26. PD-L1 as a predictive biomarker for tiragolumab plus atezolizumab treatment

In a phase Ib study (GO30103; NCT02794571), tiragolumab was well tolerated as monotherapy and in combination with atezolizumab in several solid tumor types. In the randomized Phase II CITYSCAPE study of 1L NSCLC (NCT03563716), the ORR and PFS of tiragolumab plus atezolizumab versus placebo plus atezolizumab in the purpose-to-treat (ITT) population showed clinically meaningful improvements. PD-L1 Tumor Rate Score (TPS) ≥ 50% subgroups showed greater improvement (assessed using PharmDx 22C3 IHC analysis; data cutoff December 2019; median follow-up of 10.9 months).

The value of PD-L1 as a predictive biomarker for tiragolumab plus atezolizumab treatment was found to be consistent across different PD-L1 assays. IHC assessed PD-L1 protein expression for all available patient samples using the pharmDx 22C3 assay (ITT population) and Conformitι Europιenne in vitro diagnostics (CE-IVD0 VENTANA SP263 IHC assay (biomarker evaluable population) The PD-L1 expression level was scored using an algorithm established for each analysis.The baseline characteristics of the BEP and ITT populations were similar to each other (Table 92).

*Not all patients had available tissue samples that could be tested with the SP263 IHC assay.

The prevalence of PD-L1 subgroups was comparable between the two IHC analyzes ( FIG. 26 ). For the PD-L1 22C3 assay, high TPS was classified as TPS ≥ 50%; Low TPS was classified as TPS 1-49%. For the SP263 IHC analysis, high TC was classified as TC ≥ 50%; Low TC was classified as TC 1-49%. Equal ORR and PFS improvement of tiragolumab plus atezolizumab versus atezolizumab alone was in the PD-L1 positive (TC ≥ 1%) subgroup (PFS HR 0.56, 95% CI: 0.34-0.92) as defined by SP263 and PD-L1-positive (TPS ≥ 1%) subgroup defined by 22C3 (Fig. 27a, Fig. 27b, Fig. 28a and Fig. 28b). In addition, comparable ORR and PFS improvements of tiragolumab plus atezolizumab versus atezolizumab alone were in the high-PD-L1 (TC ≥ 50%) subgroup (PFS HR 0.23, 95% CI: 0.10) defined by SP263. −0.53) and high-PD-L1 (TPS > 50%) subgroups defined by 22C3 ( FIGS. 29A, 29B, 30A and 30B).

High PD-L1 expression as assessed by 22C3 or SP263 IHC may be an important predictive biomarker for tiragolumab plus atezolizumab combination therapy.

VII. Other implementations

Some implementations of the technology described herein may be defined according to any one of the numbered implementations of implementation sets A, B, and C.

Embodiment Set A:

1. A method of treating a subject having cancer, comprising:

anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and an evacuation every 3 weeks A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a gold-based chemotherapeutic agent.

2. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 1400 mg to 2000 mg every 4 weeks A method comprising steps.

3. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks A method comprising the step of

4. according to embodiment 2 or embodiment 3,

The method further comprising administering to the subject one or more chemotherapeutic agents.

5. The method according to any one of embodiments 1 to 4,

wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.

6. The method according to any one of embodiments 1 to 5,

The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):

(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);

(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

(d) an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

(e) an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

(f) an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

7. The method according to any one of embodiments 1 to 6,

The anti-TIGIT antagonist antibody has the following light chain variable region framework regions (FR):

(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);

(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);

(c) a FR-L3 sequence comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and

(d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and

The following heavy chain variable region FRs:

(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;

(b) FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);

(c) FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and

(d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

8. The method according to any one of embodiments 1 to 7,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or

(c) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The method according to any one of embodiments 1 to 8,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is tyragolumab.

10. The method according to any one of embodiments 1 to 9,

The method of claim 1, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

11. The method according to any one of embodiments 1 to 10,

The method of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The method according to any one of embodiments 1 to 11,

The method of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The method of embodiment 12,

The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636.

14. The method according to any one of embodiments 1 to 13,

The method of claim 1, wherein the PD-1 axis binding antagonist is atezolizumab.

15. The method according to any one of embodiments 1 to 11,

The method of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The method of embodiment 15,

Said anti-PD-L1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, progolimab, camrelizumab, scintilimab, tislelizumab, torifaliz Mab, dostalimab, retipanrimab, sasanrimab, fenfulimab, CS1003, HLX10, SCT-I10A, zimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21.

17. The method according to any one of embodiments 2 to 16,

A method comprising administering to the subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. according to embodiment 1 or embodiment 17,

The method of claim 1, wherein the non-platinum-based chemotherapeutic agent is a topoisomerase II inhibitor.

19. The method of embodiment 18,

wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331, in particular etoposide; Way.

20. The method of embodiment 18 or embodiment 19,

wherein the topoisomerase II inhibitor is administered at a dose of 100 mg/m2.

21. The method according to any one of embodiments 17 to 20,

The method according to claim 1, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin.

22. The method according to any one of embodiments 17 to 21,

wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration.

23. The method according to any one of embodiments 1-22,

A method comprising a dosing regimen comprising an induction phase and a maintenance phase.

24. The method of embodiment 23,

wherein the induction phase comprises four initial dosing cycles and the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent are administered in each of the four initial dosing cycles.

25. according to embodiment 23 or embodiment 24,

wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent and/or the non-platinum-based chemotherapeutic agent.

26. The method according to any one of embodiments 1 to 25,

wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody.

27. The method according to any one of embodiments 1-26,

wherein said treatment prolongs overall survival of said subject compared to treatment without said anti-TIGIT antagonist antibody.

28. The method according to any one of embodiments 1 to 27,

The method of claim 1, wherein the cancer is lung cancer.

29. The method of embodiment 28,

The method of claim 1, wherein the lung cancer is small cell lung cancer (SCLC), in particular expanded stage SCLC (ES-SCLC).

30. The method of embodiment 28,

wherein the lung cancer is small cell lung cancer (SCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. The method of embodiment 28,

wherein the lung cancer is locally advanced unresectable or metastatic nonsquamous NSCLC.

32. The method of embodiment 28,

The method of claim 1, wherein the lung cancer is resectable lung cancer.

33. The method according to any one of embodiments 1 to 27,

The method of claim 1, wherein the cancer is cervical cancer.

34. The method according to any one of embodiments 1 to 27,

wherein the cancer is early triple negative breast cancer (eTNBC).

35. The method according to any one of embodiments 1 to 27,

The method of claim 1, wherein the cancer is head and neck cancer.

36. The method of any of embodiments 1-27,

wherein the cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. The method according to any one of embodiments 1 to 27,

wherein the cancer is bladder cancer.

38. The method of embodiment 37,

wherein the cancer is urothelial cell carcinoma (UC), in particular metastatic urothelial cell carcinoma (mUC).

39. The method according to any one of embodiments 1 to 27,

The method of claim 1, wherein the cancer is pancreatic cancer, particularly pancreatic ductal cell carcinoma (PDAC).

40. The method according to any one of embodiments 1 to 27,

The method of claim 1, wherein the cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer.

41. A kit comprising an anti TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to the method of any one of embodiments 1-40.

42. The method of embodiment 41,

A kit comprising one or more chemotherapeutic agents.

43. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

The method comprises an anti-TIGIT antagonist antibody and an anti-PD-1 axis binding antagonist according to any one of embodiments 1 to 40.

44. Use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having cancer, comprising:

Use, wherein said treatment is according to the method of any one of embodiments 1 to 40.

45. The method of embodiment 44,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

46. The method of embodiment 44,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single dosage form.

47. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and at least one dosing cycle of a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks A method comprising steps.

48. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and a dose of about 20 mg to about 1600 mg of a PD-1 axis binding antagonist every 2 weeks A method comprising steps.

49. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every 2 weeks and a dose of about 20 mg to about 1600 mg of a PD-1 axis binding antagonist every 2 weeks A method comprising the step of

50. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every 2 weeks and at least one dosing cycle of a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks A method comprising steps.

51. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and at least one dosing cycle of a PD-1 axis binding antagonist at a dose of about 100 mg to about 1000 mg every 6 weeks A method comprising steps.

52. The method according to any one of embodiments 47 to 51,

The method further comprising administering to the subject one or more chemotherapeutic agents.

53. The method of embodiment 52,

A method comprising administering a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent to the subject.

54. A method of treating a subject having cancer, comprising:

Anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, platinum-based chemotherapeutic agent every 3 weeks, and non-vaccine every 3 weeks A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a gold-based chemotherapeutic agent.

55. according to embodiment 53 or embodiment 54,

A method comprising an induction phase and a maintenance phase.

56. of embodiment 55,

wherein the induction and maintenance phases each comprise one or more dosing cycles.

57. according to embodiment 55 or embodiment 56,

wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent.

58. The method according to any one of embodiments 55 to 57,

The method of claim 1, wherein the maintenance phase does not include administration of the non-platinum-based chemotherapeutic agent.

59. The method of embodiment 58,

wherein said maintenance phase comprises one or more dosing cycles of anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks.

60. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and an anti-PD-1 antagonist antibody at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the anti-PD-1 antagonist antibody is pembrolizumab.

61. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein the pembrolizumab is administered at a dose of about 100 mg to about 1000 mg every 6 weeks; Way.

62. A method of treating a subject having cancer, comprising:

Anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and 1 day every 3 weeks of 2 weeks dosing/1 week washout A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an antimetabolite at a dose of about 10 mg/m2 to about 10000 mg/m2 orally in two oral doses.

63. A method of treating a subject having cancer, comprising:

one or more dosing cycles of anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, gemcitabine, and nap-paclitaxel A method comprising administering to the subject a dosing regimen comprising

64. The method of embodiment 52,

wherein the one or more chemotherapeutic agents are gemcitabine and nap-paclitaxel.

65. A method of treating a subject having cancer, comprising:

Anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and about 1 mg/kg to about 35 mg/kg every 3 weeks A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a kg dose of a VEGF antagonist.

66. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) the induction phase is an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks , and at least one dosing cycle of a non-platinum-based chemotherapeutic agent every 3 weeks; and

(b) said maintenance phase comprises at least one additional dosing cycle of said anti-TIGIT antagonist antibody every 3 weeks, said PD-1 axis binding antagonist every 3 weeks, and said non-platinum-based chemotherapeutic agent every 3 weeks, wherein said maintenance wherein the phase does not include administration of the platinum-based chemotherapeutic agent.

67. A method of treating a subject having cancer, comprising:

administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) the induction phase is an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks , and at least one dosing cycle of a non-platinum-based chemotherapeutic agent every 3 weeks; and

(b) the maintenance phase comprises one or more additional dosing cycles of the anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks and wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent.

68. The method of any one of embodiments 56-59, 66 and 67,

wherein the induction phase comprises 4 to 6 dosing cycles.

69. The method of any one of embodiments 53-59 and 66-68,

(a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;

(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel; or

(c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is etoposide.

70. The method according to any one of embodiments 47 to 69,

wherein the cancer is a solid tumor.

71. The method according to any one of embodiments 47 to 70,

wherein the cancer is locally advanced or metastatic.

72. The method according to any one of embodiments 47 to 71,

wherein the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, kidney cancer, melanoma, or ovarian cancer.

73. The method of embodiment 72,

The method of claim 1, wherein the cancer is lung cancer.

74. The method of embodiment 73,

wherein the lung cancer is NSCLC, in particular locally advanced unresectable NSCLC.

75. The method of embodiment 74,

wherein said NSCLC is stage IIIB NSCLC.

76. The method according to any one of embodiments 73 to 75,

wherein the lung cancer is relapsed or metastatic NSCLC.

77. The method of embodiment 76,

The method of claim 1, wherein the NSCLC is stage 3 NSCLC.

78. The method of embodiment 77,

wherein the subject has not been previously treated for stage IV NSCLC.

79. The method of embodiment 73,

wherein the lung cancer is small cell lung cancer (SCLC).

80. A method of treating a subject or population of subjects having lung cancer, the method comprising:

administering to the subject or population of subjects a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor; wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody; Way.

81. A method of treating a population of subjects having lung cancer, comprising:

administering to said subject population a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein wherein said treatment results in a median PFS of the subject population of from about 8.2 months to about 9.2 months.

82. The method of embodiment 80 or embodiment 81,

wherein said treatment prolongs overall survival (OS) of said subject or population of subjects compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody; Way.

83. The method according to any one of embodiments 80 to 82,

wherein the treatment prolongs the PFS of the subject or population of subjects by at least about 2.4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , Way.

84. The method of embodiment 83,

wherein said treatment reduces the PFS of said subject or population of subjects by at least about 3 months to about 4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. How to extend by months.

85. A method of treating a subject or population of subjects having lung cancer, the method comprising:

administering to the subject or population of subjects a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor; , wherein said treatment prolongs OS in said subject as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without said anti-TIGIT antagonist antibody.

86. A method of treating a population of subjects having lung cancer, comprising:

administering to said subject population a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein wherein said treatment results in a median OS in the subject population of about 15.3 months to about 17.6 months.

87. The method according to any one of embodiments 82 to 86,

wherein the treatment prolongs the OS of the subject or population of subjects by at least about 3.3 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , Way.

88. The method according to any one of embodiments 82 to 86,

wherein said treatment reduces the OS of said subject or population of subjects by at least about 3 months to about 5.3 as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. How to extend by months.

89. The method according to any one of embodiments 80 to 88,

wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered in each of four initial dosing cycles.

90. The method according to any one of embodiments 80 to 89,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are further administered in one or more additional cycles after the fourth initial dosing cycle.

91. The method of embodiment 90,

wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of one or more additional dosing cycles.

92. The method according to any one of embodiments 80 to 91,

wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide.

93. The method according to any one of embodiments 80 to 92,

wherein the lung cancer is small cell lung cancer (SCLC).

94. The method of embodiment 93,

wherein the SCLC is an expanded stage SCLC (ES-SCLC).

95. The method of embodiment 94,

The method of claim 1, wherein the subject or subjects is naive for treatment for ES-SCLC.

96. The method according to any one of embodiments 80 to 95,

The method of claim 1, wherein the subject or subjects do not have the presence or history of brain metastases.

97. The method according to any one of embodiments 80 to 96,

The method of claim 1, wherein the lung cancer is not selected for PD-L1 expression.

98. The method according to any one of embodiments 80 to 96,

wherein the lung cancer is selected for PD-L1 expression.

99. The method of embodiment 98,

wherein the lung cancer is selected for PD-L1 expression by a detectable expression level of PD-L1.

100. The method according to any one of embodiments 80 to 99,

wherein the lung cancer is metastatic.

101. The method of embodiment 100,

The method of claim 1, wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal glands.

102. The method of embodiment 100 or embodiment 101,

The method of claim 1, wherein the lung cancer does not metastasize to the brain.

103. The method of any one of embodiments 100-102,

wherein the treatment results in a complete response (CR) or a partial response (PR).

104. The method according to any one of embodiments 80 to 103,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 2 weeks, every 3 weeks, or every 4 weeks.

105. The method of any one of embodiments 80-104,

wherein the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 2 weeks, every 3 weeks, or every 4 weeks.

106. The method of any one of embodiments 80 to 105,

wherein the PD-1 axis binding antagonist, the anti-TIGIT antagonist antibody, the platinum-based chemotherapeutic agent, and the photoisomerase II inhibitor are administered sequentially.

107. The method of embodiment 106,

The PD-1 axis binding antagonist is administered before the anti-TIGIT antagonist antibody, the anti-TIGIT antagonist antibody is administered before the platinum-based chemotherapeutic agent, and the platinum agent is administered before the topoisomerase II inhibitor. , Way.

108. The method according to any one of embodiments 80 to 107,

wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered intravenously.

109. The method according to any one of embodiments 80 to 108,

wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered subcutaneously.

110. A method of treating a subject having SCLC, comprising:

Anti TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle, Atezolizumab at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle, Day 1 of each dosing cycle Carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min, and one dose of etoposide at 100 mg/m2 on each of Days 1, 2, and 3 of each dosing cycle. administering to said subject at least a 21-day dosing cycle, wherein said treatment comprises the subject's PFS and/or compared to treatment with atezolizumab, carboplatin, and etoposide in the absence of said anti-TIGIT antagonist antibody. or extending the OS.

111. A method of treating a subject having SCLC, comprising:

Anti TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg on day 1 of each dosing cycle, atezolizumab at a dose of about 900 mg to about 1500 mg on Day 1 of each dosing cycle, Day 1 of each dosing cycle Carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min, and one dose of etoposide at 100 mg/m2 on each of Days 1, 2, and 3 of each dosing cycle. administering to said subject at least a 21-day dosing cycle, wherein said treatment comprises the subject's PFS and/or compared to treatment with atezolizumab, carboplatin, and etoposide in the absence of said anti-TIGIT antagonist antibody. or extending the OS.

112. The method of embodiment 110 or embodiment 111,

One or more additional 21 doses of anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and atezolizumab at a dose of about 80 mg to about 1600 mg on Day 1 of each additional dosing cycle administering one dosing cycle to the subject, wherein carboplatin and etoposide are omitted from each of the one or more additional dosing cycles.

113. A method of treating a subject or population of subjects having ES-SCLC, comprising:

administering to the subject or population of subjects, four initial dosing cycles followed by one or more additional dosing cycles, wherein:

(a) said four initial dosing cycles are tiragolumab at a dose of about 600 mg on day 1 of each initial dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each initial dosing cycle, each initial dosing cycle Carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of administering poside; and

(b) said one or more additional dosing cycles administering about 600 mg of tiragolumab on day 1 of each additional dosing cycle and about 1200 mg of atezolizumab on day 1 of each additional dosing cycle comprising the steps of

wherein said four initial dosing cycles and said one or more additional dosing cycles are each 21 day dosing cycle, wherein said treatment is compared to treatment with atezolizumab, carboplatin, and etoposide without said tiragolumab to prolong the PFS and/or OS of the subject or population of subjects.

114. A method of treating a subject or population of subjects having cancer, the method comprising:

a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent, and a second chemotherapeutic agent that is a non-platinum-based chemotherapeutic agent; A method comprising administering to

115. The method of embodiment 114,

wherein the lung cancer is not assessed for PD-L1 expression.

116. The method of embodiment 114 or embodiment 115,

The method of claim 1, wherein the subject or subjects is not determined to have a fraction of PD-L1 positive tumor cells greater than or equal to 50%.

117. The method of embodiment 116,

The method of claim 1 , wherein the subject or subjects is not determined to have a fraction of PD-L1 positive tumor cells of less than 50%.

118. The method of embodiment 116 or embodiment 117,

wherein said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein said anti-PD-L1 antibody is SP263 or 22C3.

119. The method according to any one of embodiments 114 to 118,

The method of claim 1 , wherein the subject or subjects do not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormality.

120. The method according to any one of embodiments 114 to 119,

The method of claim 1, wherein said subject or subjects has not received prior systemic therapy for said lung cancer.

121. The method of any one of embodiments 114 to 120,

wherein the lung cancer is locally advanced lung cancer.

122. The method according to any one of embodiments 114 to 121,

wherein the lung cancer is NSCLC, in particular locally advanced unresectable or metastatic nonsquamous NSCLC.

123. The method of embodiment 122,

wherein said nonsquamous NSCLC is stage IV nonsquamous NSCLC.

124. The method according to any one of embodiments 114 to 123,

wherein the dosing regimen includes an induction phase comprising 4 dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent include each dosing cycle of the induction phase. administered on the first day of

125. The method of embodiment 124,

wherein the dosing regimen comprises a maintenance phase after the induction phase, wherein the maintenance phase includes one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the non-platinum chemotherapeutic agent are the maintenance phases. administered on Day 1 of each dosing cycle of the phase.

126. The method of embodiment 125,

wherein the one or more dosing cycles of the maintenance phase do not include administration of the platinum-based chemotherapeutic agent.

127. The method according to any one of embodiments 114 to 126,

The method of claim 1, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed.

128. A method of treating a subject or population of subjects having advanced nonsquamous NSCLC, comprising:

administering to said subject or population of subjects a dosing regimen comprising four 21-day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein said tiragolumab comprises: Administered at a dose of about 600 mg every 3 weeks, the atezolizumab is administered at a dose of about 1200 mg every 3 weeks, and the carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min every 3 weeks. , or the cisplatin is administered at a dose of 75 mg/m2 every 3 weeks, and the pemetrexed is administered at a dose of about 500 mg/m2 every 3 weeks on each day of 4 21-day dosing cycles. , Way.

129. A method of treating a subject or population of subjects having advanced nonsquamous NSCLC, comprising:

To said subject or population of subjects:

(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 4 cycles of induction dosing for pemetrexed at a dose of about 500 mg/m2 per week; and

(ii) one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m ² every 3 weeks wherein the one or more 21-day dosing cycles of the maintenance phase do not include administration of the carboplatin,

wherein the subject or population of subjects has not received prior systemic therapy for advanced nonsquamous NSCLC.

130. A method of treating a subject having advanced nonsquamous NSCLC, comprising:

To the subject:

(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 4 cycles of induction dosing for pemetrexed at a dose of about 500 mg/m2 per week; and

(ii) one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m2 every 3 weeks. administering, wherein at least one 21-day dosing cycle of said maintenance phase does not comprise administration of said carboplatin;

wherein the subject has never received prior systemic therapy for advanced nonsquamous NSCLC.

131. A method of treating a subject with advanced nonsquamous NSCLC, comprising:

administering to the subject a dosing regimen comprising four 21-day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein the tiragolumab is administered every three weeks is administered at a dose of about 600 mg, the atezolizumab is administered at a dose of about 1200 mg every 3 weeks, the cisplatin is administered at a dose of 75 mg/m2, and the pemetrexed is administered in each of 4 21 day dosing cycles. administered at a dose of about 500 mg/m 2 every 3 weeks on day 1 of the method.

132. The method according to any one of embodiments 114 to 131,

wherein the treatment prolongs the PFS of the subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. The method according to any one of embodiments 114 to 132,

wherein said treatment results in a median PFS of a population of subjects from about 12.5 months to about 14.7 months.

134. The method according to any one of embodiments 114 to 133,

wherein the treatment prolongs the OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months.

135. The method according to any one of embodiments 114 to 134,

wherein said treatment results in a median OS in the subject population of about 27.5 months to about 32.0 months.

136. A method of treating a subject having resectable lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks How to.

137. A method of treating a subject having resectable lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks How to.

138. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of said dosing cycles is from about 30 mg to about 1200 mg every three weeks. A method comprising administering as neoadjuvant treatment a TIGIT antagonist antibody and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks.

139. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of said dosing cycles is from about 300 mg to about 800 mg every 3 weeks. A method comprising administering as neoadjuvant treatment a TIGIT antagonist antibody and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks.

140. The method of embodiment 138 or embodiment 139,

At least one of said dosing cycles is administered to said subject as adjuvant treatment with an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 every 3 weeks A method comprising the step of

141. The method of embodiment 140,

At least once in said dosing cycle administering to said subject as adjuvant treatment a dose of about 500 mg to about 700 mg of an anti-TIGIT antagonist antibody every 3 weeks and a dose of about 900 mg to about 1500 of a PD-1 axis binding antagonist every 3 weeks A method comprising the step of

142. The method according to any one of embodiments 138 to 141,

The method of claim 1, wherein the lung cancer is resectable lung cancer.

143. The method according to any one of embodiments 136 to 142,

The method of claim 1, wherein the lung cancer is early stage lung cancer.

144. The method according to any one of embodiments 136 to 143,

The method of claim 1, wherein the lung cancer is stage II, stage 2A, or stage IIIB lung cancer.

145. The method according to any one of embodiments 136 to 144,

wherein the lung cancer does not have epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormalities.

146. The method according to any one of embodiments 136 to 145,

wherein the subject is eligible for R0 resection for therapeutic purposes.

147. The method according to any one of embodiments 136 to 146,

The method of claim 1, wherein the subject has never received prior therapy for lung cancer.

148. The method of embodiment 147,

wherein the prior therapy is immunotherapy, chemotherapy, or radiotherapy.

149. The method according to any one of embodiments 136 to 148,

wherein the subject is eligible for platinum-based chemotherapy.

150. The method of any one of embodiments 136 to 149,

wherein the first dosing cycle is initiated prior to surgery.

151. The method of embodiment 150,

at least 1, 2, 3, or 4 dosing cycles are completed prior to the surgery.

152. The method of embodiment 150 or embodiment 151,

and 4 dosing cycles are completed prior to the surgery.

153. The method according to any one of embodiments 136 to 152,

at least one dosing cycle is initiated after surgery.

154. The method of embodiment 153,

16 dosing cycles are completed after said surgery.

155. The method of any one of embodiments 150 to 154,

wherein the operation is lobectomy, lobectomy, bilobectomy, or pneumonectomy.

156. The method according to any one of embodiments 136 to 155,

The method further comprising radiation therapy.

157. The method of embodiment 156,

The method of claim 1, wherein the radiation therapy is post-surgery radiation therapy.

158. The method according to any one of embodiments 136 to 157,

The method further comprising administering one or more chemotherapeutic agents.

159. The method of embodiment 158,

wherein the one or more chemotherapeutic agents are administered post-surgery.

160. The method of embodiment 159,

The method of claim 1, wherein the one or more chemotherapeutic agents are administered in 4 dosing cycles after the surgery.

161. The method according to any one of embodiments 158 to 160,

wherein the at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

162. The method of embodiment 161:

(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;

(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is gemcitabine;

(c) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel;

(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or

(e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine.

163. The method according to any one of embodiments 136 to 162,

wherein the treatment results in an increase in the major pathological response rate (MPR) compared to the baseline MPR rate.

164. The method of embodiment 163,

The reference MPR ratio is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) the MPR ratio of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

165. The method of any one of embodiments 136 to 164,

wherein the treatment results in an increase in the pathological complete response (pCR) and/or pCR ratio compared to a baseline pCR ratio.

166. The method of embodiment 165,

The reference pCR ratio is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) the pCR ratio of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

167. The method according to any one of embodiments 136 to 166,

wherein said treatment results in an increase in event-free survival (EFS) compared to baseline EFS time.

168. The method of embodiment 167,

The reference EFS time is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) EFS time of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

169. A method of treating a subject having resectable lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 600 mg every 3 weeks and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks How to.

170. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of said dosing cycles is a dose of about 30 mg to about 600 mg every 3 weeks A method comprising administering as neoadjuvant treatment a TIGIT antagonist antibody and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks.

171. A method of treating a subject having resectable lung cancer, comprising:

1 of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent A method comprising administering to the subject one or more dosing cycles.

172. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one of the dosing cycles comprises: anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent A method comprising administering as an adjuvant treatment.

173. A method of treating a subject having resectable lung cancer, comprising:

Anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and: (a) (i) 5 mg/m every 3 weeks a platinum-based chemotherapeutic agent at a dose targeted to achieve an AUC of mL/min or an AUC of 6 mg/mL/min; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m2 every 3 weeks; and (b) (i) an antimetabolite at a dose of about 500 mg/m2 every 3 weeks or about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle; or (ii) administering to the subject one or more dosing cycles of the taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every three weeks.

174. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one of the dosing cycles comprises: To the subject: (a) an anti TIGIT antagonist antibody at a dose of about 30 mg to about 600 mg every 3 weeks; (b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks; (c) at (i) a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m2 every 3 weeks; and (d) administering a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) about 500 mg/m2 every 3 weeks or on days 1 and 8 of each dosing cycle. an antimetabolite at a dose of 1000 mg/m2 or about 1250 mg/m2; or (ii) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every 3 weeks; wherein the treatment is neoadjuvant treatment.

175. A method of treating a subject having resectable lung cancer, comprising:

Tiragolumab at a dose of about 600 mg every 3 weeks, Atezolizumab at a dose of about 1200 mg every 3 weeks, and:

(a)

(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or

(ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks; and

(b)

(i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks or gemcitabine at a dose of about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle; or

(ii) administering to the subject one or more dosing cycles of paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every three weeks.

176. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of tiragolumab, atezolizumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one of the dosing cycles is administered to the subject: (a) tyragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks; (c) administering a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent: (i) achieves an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks a dose of carboplatin targeted to or (ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks or about 1000 on days 1 and 8 of each dosing cycle gemcitabine at a dose of mg/m2 or about 1250 mg/m2; or (ii) paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; wherein the treatment is neoadjuvant treatment.

177. A method of treating a subject having nonsquamous NSCLC, comprising:

administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (a) at least one dosing cycle is about a 600 mg dose of tiragolumab every 3 weeks and 3 weeks administering to the subject as neoadjuvant treatment atezolizumab at a dose of 1200 mg per time; (b) at least one dosing cycle comprising administering to the subject as adjuvant treatment a dose of about 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of atezolizumab every 3 weeks.

178. A method of treating a subject having nonsquamous NSCLC, comprising:

administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment and to the subject: (a) 3 weeks tiragolumab at a dose of about 600 mg each; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a targeted dose to achieve an AUC of 5 mg/mL/min every 3 weeks and pemetrexed at a dose of about 500 mg/m2 every 3 weeks; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and pemetrex at a dose of about 500 mg/m2 every 3 weeks; (II) at least one of said dosing cycles is adjuvant treatment with an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising administering.

179. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment and to the subject: (a) 3 weeks tiragolumab at a dose of about 600 mg each; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles comprises administering as adjuvant treatment a dose of about 30 mg to about 1200 mg of tiragolumab every 3 weeks and a dose of about 80 mg to about 1600 mg of atezolizumab every 3 weeks Including method.

180. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein:

(I) at least one of said dosing cycles is neoadjuvant treatment and to said subject:

(a) tyragolumab at a dose of about 1200 mg every 3 weeks;

(b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and

(c)

(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle;

(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or

(iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks or gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; and

(II) administering to the subject as adjuvant treatment at least one of said dosing cycles is tiragolumab at a dose of about 300 mg to about 800 mg every 3 weeks and atezolizumab at a dose of about 900 mg to about 1500 mg every 3 weeks A method comprising the step of:

181. A method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment and to the subject: (a) 3 weeks tiragolumab at a dose of about 600 mg each; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles comprises administering as adjuvant treatment a dose of about 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of atezolizumab every 3 weeks.

182. A method of treating a subject having resectable squamous NSCLC, comprising:

administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment and to the subject: (a) 3 weeks tiragolumab at a dose of about 600 mg each; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles comprises administering as adjuvant treatment a dose of about 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of atezolizumab every 3 weeks.

183. The method according to any one of embodiments 136 to 182,

A method, wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP263 is determined.

184. The method of embodiment 183,

The method, wherein the detectable protein expression level of PD-L1 is at least 50% of the PD-L1 positive tumor cell fraction.

185. The method of any one of embodiments 73, 114 to 121, and embodiments 136 to 184,

wherein the lung cancer is NSCLC.

186. The method of embodiment 185,

wherein the NSCLC is squamous NSCLC.

187. The method of embodiment 185,

wherein the NSCLC is non-squamous NSCLC.

188. The method of embodiment 72,

The method of claim 1, wherein the cancer is cervical cancer.

189. A method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1, the method comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising steps.

190. A method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1, the method comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method comprising steps.

191. A method of selecting a therapy for a subject having cervical cancer comprising:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) an anti-TIGIT antagonist antibody administered at a dose of about 30 mg to about 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 and 3 selecting a regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist administered at a dose of about 80 mg to about 1600 mg per week.

192. The method of any one of embodiments 189 to 191,

The method of claim 1, wherein the cervical cancer is squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma.

193. The method according to any one of embodiments 189 to 191,

wherein the cervical cancer is stage IVB, metastatic, recurrent, or persistent.

194. The method according to any one of embodiments 189 to 193,

The method of claim 1, wherein the cervical cancer is metastatic and/or recurrent PD-L1 positive cervical cancer.

195. The method of any one of embodiments 189 to 194,

The method of claim 1, wherein the subject or subjects have received at least one line of prior therapy.

196. The method according to any one of embodiments 189 to 195,

The subject or subjects have received two lines of prior therapy.

197. The method according to any one of embodiments 189 to 196,

The method of claim 1, wherein the subject or subjects have received more than two lines of prior therapy.

198. The method according to any one of embodiments 189 to 194,

The method of claim 1, wherein the subject or subjects have not received prior therapy.

199. The method according to any one of embodiments 195 to 198,

wherein the prior therapy is chemotherapy, surgery, and/or radiation therapy.

200. The method according to any one of embodiments 189 and 192 to 199,

wherein said treatment elicits a clinical response.

201. The method of embodiment 200,

wherein the clinical response is an increase in the objective response rate (ORR) of the subject population as compared to a baseline ORR.

202. The method of embodiment 201,

wherein said baseline ORR is the median ORR of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody.

203. The method of embodiment 200,

wherein the baseline ORR is at least about 14.6% to about 26%.

204. The method of embodiment 200,

wherein the clinical response is CR or PR.

205. The method of any one of embodiments 200 to 204,

The clinical response is an increase in progression-free survival (PFS) of the subject compared to a baseline PFS time, an increase in the duration of response (DOR) in the subject compared to a baseline DOR time, or an increase in the subject's progression-free survival (DOR) compared to a baseline OS time. An increase in overall survival (OS).

206. The method of embodiment 205:

(a) said baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline DOR time is the median DOR time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) the baseline OS time is the median OS time of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

207. A method of treating a subject having cervical cancer having a detectable expression level of PD-L1, the method comprising:

A method comprising administering to the subject one or more dosing cycles of a 600 mg dose of anti-TIGIT antagonist antibody every 3 weeks and atezolizumab at a 1200 mg dose every 3 weeks.

208. A method of identifying a subject with cervical cancer who is likely to benefit from therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab, comprising:

(a) providing a tumor sample from the subject;

(a) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(c) one or more dosing cycles of anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks, based on PD-L1 expression on detected tumor cells. identifying the subject as likely to benefit from a therapy comprising

209. A method of selecting a therapy for a subject having cervical cancer comprising:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 A method comprising selecting a regimen comprising one or more dosing cycles of atezolizumab administered as a dose.

210. A method of treating a subject having cervical cancer having a detectable expression level of PD-L1, the method comprising:

A method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

211. A method of treating a subject having cervical cancer comprising:

(a) providing a tumor sample from the subject;

(a) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) one or more dosing cycles of tyrazolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on PD-L1 expression on detected tumor cells. identifying the subject as likely to benefit from therapy; and

(d) administering the therapy to the identified subject.

212. A method of selecting a therapy for a subject having cervical cancer comprising:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) tiragolumab administered at a dose of 600 mg every 3 weeks and a dose of 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 selecting a regimen comprising one or more dosing cycles of atezolizumab administered as

213. A method of treating a subject having metastatic and/or recurrent benign cervical cancer comprising:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) one or more dosing cycles of tyrazolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on PD-L1 expression on detected tumor cells. identifying the subject as likely to benefit from therapy; and

(d) administering the therapy to the identified subject.

214. A method of selecting therapy for a subject with metastatic and/or recurrent cervical cancer comprising:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) tiragolumab administered at a dose of 600 mg every 3 weeks and a dose of 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 selecting a regimen comprising one or more dosing cycles of atezolizumab administered as

215. The method of any one of embodiments 189 to 214,

wherein the subject is identified as likely to benefit from treatment based on PD-L1 expression on the detected tumor cells.

216. The method according to any one of embodiments 189 to 215,

The method of claim 1, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP263.

217. The method according to any one of embodiments 189 to 216,

wherein the detectable expression level of PD-L1 is greater than or equal to 5% of tumor associated immune cells (TICs) in the sample from the subject.

218. The method of any one of embodiments 189 to 215,

The method of claim 1, wherein the PD-L1 expression level is detected using anti-PD-L1 antibody 22C3.

219. The method of any one of embodiments 189 to 216,

wherein the detectable expression level of PD-L1 has a composite positive score (CPS) of 1 or greater in a sample from the subject.

220. The method of embodiment 72, wherein the cancer is breast cancer.

221. A method of treating a subject or population of subjects having breast cancer, comprising:

One or more dosing cycles of tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and nap-paclitaxel at a dose of about 100 mg/m2 of 3 weeks on/1 week off A method comprising administering to the subject or population of subjects a dosing regimen comprising

222. The method of embodiment 220 or embodiment 221,

The method of claim 1, wherein the breast cancer is triple negative breast cancer (TNBC).

223. The method of embodiment 222,

wherein the TNBC is resectable locally advanced or metastatic TNBC.

224. The method of any one of embodiments 220 to 223,

The method of claim 1, wherein the subject has not received prior systemic therapy for metastatic breast cancer.

225. The method of any one of embodiments 220-224,

wherein said treatment results in an ORR in at least about 53% to about 67.5% of the subject population.

226. The method of any one of embodiments 222 to 225,

wherein said treatment results in a median OS in the subject population of about 25.0 months.

227. A method of treating a subject having early stage triple negative breast cancer (eTNBC), comprising:

administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every two weeks and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 20 mg to about 1600 mg every two weeks A method comprising the step of

228. The method of embodiment 227,

The method further comprising administering to the subject one or more chemotherapeutic agents.

229. The method of embodiment 228,

The method of claim 1, wherein the at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The method of embodiment 227,

(a) at least one dosing cycle of said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) The method further comprising administering one or more dosing cycles of

231. The method of embodiment 229 or embodiment 230,

wherein the alkylating agent is cyclophosphamide.

232. The method of embodiment 231,

wherein the cyclophosphamide is administered at a dose of about 600 mg/m2.

233. The embodiment of any one of embodiments 227 to 229, embodiment 231 and embodiment 232,

further administering G-CSF or GM-CSF to the subject.

234. The method of embodiment 230 or embodiment 233,

The G-CSF is pegfilgrastim or filgrastim, the method.

235. The method of embodiment 234,

The G-CSF is pegfilgrastim, the method.

236. The method of embodiment 235,

The method of claim 1, wherein the pegfilgrastim is administered at a dose of about 6 mg.

237. The embodiment of any one of embodiments 228, 229, and embodiments 231 to 236,

further administering to the subject the one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF.

238. The embodiment of any one of embodiments 228, 229, and embodiments 231 to 237,

wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are administered once every week, once every 2 weeks, or once every 3 weeks, respectively.

239. The method of any one of embodiments 229 to 238,

The platinum-based chemotherapeutic agent is administered every 3 weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every 2 weeks, the alkylating agent is administered every 2 weeks, and the G-CSF or GM- The CSF is administered every two weeks.

240. The method of any one of embodiments 229 to 239,

wherein said taxane or said taxane and said platinum-based chemotherapeutic agent are administered during the first 12 weeks of said dosing regimen.

241. The method of any one of embodiments 229-240,

wherein the topoisomerase II inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered for 13 to 19 weeks of a dosing regimen.

242. The method according to any one of embodiments 227 to 241,

The total duration of said dosing regimen is 19 weeks.

243. The method of any one of embodiments 227 to 242,

Neoadjuvant therapy, method.

244. The method according to any one of embodiments 227 to 243,

wherein surgery is performed after said dosing regimen.

245. The method of embodiment 244,

wherein said surgery is performed between 2 and 6 weeks after the last dose of said dosing regimen.

246. The method of embodiment 244 or embodiment 245,

wherein the surgery comprises a mastectomy.

247. The method according to any one of embodiments 244 to 246,

wherein the surgery comprises axillary lymph node surgery.

248. The method of any one of embodiments 229 to 247,

wherein the topoisomerase II inhibitor is doxorubicin.

249. The method according to any one of embodiments 229 to 247,

wherein the taxane is nap-paclitaxel, the platinum-based chemotherapeutic agent is carboplatin, and the topoisomerase II inhibitor is doxorubicin.

250. The method of embodiment 248 or embodiment 249,

The method of claim 1, wherein doxorubicin is administered at a dose of about 60 mg/m2.

251. A method of treating a subject having eTNBC, comprising:

Anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

252. A method of treating a subject having eTNBC, comprising:

Anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-L1 binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

253. A method of treating a subject having eTNBC, comprising:

an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and an anti-PD-L1 antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

254. A method of treating a subject having eTNBC, comprising:

Thiragolumab at a dose of about 300 mg to about 600 mg every 2 weeks and an anti-PD-L1 antagonist antibody at a dose of about 600 mg to about 1200 mg every 2 weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

255. A method of treating a subject having eTNBC, comprising:

anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and atezolizumab at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

256. A method of treating a subject having eTNBC, comprising:

Tiragolumab at a dose of about 300 mg to about 600 mg every two weeks and atezolizumab at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) nap-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen CSF; or

(b)

(i) nap-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen administering to the subject a dosing regimen comprising CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

257. A method of treating a subject having eTNBC, comprising:

Tiragolumab at a dose of about 420 mg every 2 weeks, Atezolizumab at a dose of about 840 mg every 2 weeks, and:

(a)

(i) nap-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen CSF; or

(b)

(i) nap-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen administering to the subject a dosing regimen comprising CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

258. The method of any one of embodiments 220 to 257,

wherein the detectable protein expression level of PD-L1 in a tumor sample from said subject is determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142.

259. The method of embodiment 258,

The method of claim 1, wherein the proportion of tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (ICs) in the tumor sample is at least 1%.

260. The method of any one of embodiments 227 to 259,

wherein the eTNBC is presented as T2-4d TNBC.

261. The method according to any one of embodiments 227 to 260,

wherein the eTNBC is presented as cT2-cT4, cN0-cN3, and cM0 TNBC.

262. The method of any one of embodiments 227 to 261,

wherein the subject has not been previously treated for eTNBC.

263. The method according to any one of embodiments 227 to 262,

wherein the treatment results in a pathological complete response (pCR).

264. The method of any one of embodiments 227 to 263,

wherein the treatment results in an increase in overall survival (OS) or event-free survival (EFS).

265. The method of embodiment 72,

The method of claim 1, wherein the cancer is head and neck cancer.

266. The method of embodiment 265,

The method of claim 1, wherein the head and neck cancer is squamous cell carcinoma (SCCHN) of the head and neck.

267. A method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1, the method comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising steps.

268. A method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1, the method comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method comprising steps.

269. A method of selecting a therapy for a subject or population of subjects with SCCHN comprising:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and 3 weeks based on PD-L1 expression detected for said subject or population of subjects having a detectable expression level of PD-L1 selecting a regimen comprising at least one dosing cycle of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg per time.

270. A method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1, the method comprising:

A method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

271. The method according to any one of embodiments 267 to 270,

wherein the subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

272. The method of any one of embodiments 266 to 271,

wherein the SSCHN is human papillomavirus (HPV) positive.

273. The method according to any one of embodiments 266 to 272,

wherein the SSCHN is HPV negative.

274. The method of embodiment 272 or embodiment 273,

HPV status is determined by p16 IHC, in situ hybridization, or PCR.

275. The method according to any one of embodiments 266 to 274,

wherein the SCCHN is recurrent and/or metastatic SCCHN.

276. The method according to any one of embodiments 265 to 275,

The method of claim 1, wherein the subject or subjects have not received prior therapy.

277. The method of embodiment 276,

wherein said prior therapy is prior systemic therapy for recurrent and/or metastatic disease.

278. The embodiment of any one of embodiments 265-268 and embodiments 270-277,

wherein said treatment results in CR or PR.

279. The method according to any one of embodiments 265 to 268 and 270 to 277,

wherein the treatment results in an increase in the objective response rate (ORR) of the subject population as compared to a baseline ORR.

280. The method of embodiment 279,

wherein said baseline ORR is the median ORR of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody.

281. The method of embodiment 279 or embodiment 280,

wherein the baseline ORR is at least about 19% to about 36%.

282. The method of any one of embodiments 265-268 and 270-281,

wherein the treatment is associated with an increase in progression-free survival (PFS) of the subject or subject population as compared to a baseline PFS time, an increase in the duration of response (DOR) of the subject or subject population compared to a baseline DOR time, or a baseline OS time and as compared to cause an increase in overall survival (OS) of the subject or population of subjects.

283. The method of embodiment 282:

(a) said baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline DOR time is the median DOR time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) the baseline OS time is the median OS time of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

284. The method of embodiment 282,

wherein the baseline DOR time is at least about 6.7 months to about 23.4 months.

285. The method of embodiment 282,

wherein the baseline OS time is at least about 11.6 months to about 14.9 months.

286. A method of treating a subject having SCCHN having a detectable expression level of PD-L1, the method comprising:

administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks How to.

287. A method of treating a subject having SCCHN having a detectable expression level of PD-L1, the method comprising:

A method comprising administering to the subject one or more dosing cycles of a dose of about 1200 mg of the PD-1 axis binding antagonist every 3 weeks and a dose of about 600 mg of an anti TIGIT antagonist antibody every 3 weeks.

288. A method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

administering to the subject one or more dosing cycles of a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks , Way.

289. A method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

A method comprising administering to the subject one or more dosing cycles of atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks.

290. A method of treating a subject having SCCHN having a detectable expression level of PD-L1, the method comprising:

A method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

291. A method of treating a subject with SCCHN comprising:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) administering the subject to one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks. identifying as a person likely to benefit from; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

292. A method of treating a subject having SCCHN comprising:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) administering the subject to a regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks. identifying as and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

293. A method of treating a subject having SCCHN comprising:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) subjecting the subject to one or more dosing cycles of atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks. identifying as a probable person; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

294. A method of treating a subject having SCCHN comprising:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks. ; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

295. A method of selecting a therapy for a subject with SCCHN comprising:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and about 30 every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 selecting a regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of mg to about 1200 mg.

296. A method of selecting a therapy for a subject with SCCHN comprising:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a dose of about 1200 mg of a PD-1 axis binding antagonist every 3 weeks and a dose of about 600 mg of anti every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 A method comprising selecting a regimen comprising at least one dosing cycle of the TIGIT antagonist antibody.

297. A method of selecting a therapy for a subject with SCCHN comprising:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and about 30 mg to about every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 A method comprising selecting a regimen comprising one or more dosing cycles of tiragolumab at a dose of 1200 mg.

298. A method of selecting a therapy for a subject with SCCHN comprising:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 A method comprising selecting a regimen comprising one or more dosing cycles.

299. The method according to any one of embodiments 267 to 298,

wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1 determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody SP263.

300. The method of embodiment 299,

The detectable protein expression level of PD-L1 is in the tumor sample:

(a) at least 5%;

(b) at least 5% and less than 20%; or

(c) at least 20% tumor-associated immune cells (TICs).

301. would benefit from a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks A method of identifying a subject having SCCHN as a probable person, comprising:

detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the protein expression level of PD-L1 with a TIC of at least 5% is and identifying the subject as likely to benefit from the therapy.

302. would benefit from a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks A method of identifying a subject having SCCHN as a probable person, comprising:

detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the TIC of PD-L1 is greater than or equal to 5% and less than 20%. The method of claim 1, wherein the protein expression level identifies the subject as likely to benefit from the therapy.

303. would benefit from a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks A method of identifying a subject having SCCHN as a probable person, comprising:

detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the protein expression level of PD-L1 having a TIC of at least 20% is identifying the subject as likely to benefit from the therapy.

304. The method of any one of embodiments 301 to 303,

wherein the subject is identified as likely to benefit from the therapy and the method further comprises administering the therapy to the subject.

305. The method of any one of embodiments 301 to 304,

wherein the TIC is determined using a Ventana SP263 IHC assay.

306. The method of any one of embodiments 267 to 305,

wherein the subject or population of subjects is identified as likely to benefit from treatment based on PD-L1 expression on the detected tumor cells.

307. The method of embodiment 72,

The method of claim 1, wherein the cancer is liver cancer.

308. The method of embodiment 307,

wherein the liver cancer is hepatocellular carcinoma (HCC).

309. A method of treating a subject or population of subjects having hepatocellular carcinoma (HCC), comprising:

A method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject or population of subjects has not received prior systemic therapy for HCC. .

310. The method of embodiment 309,

The method of claim 1, further comprising administering a VEGF antagonist to the subject or population of subjects.

311. A method of treating a subject or population of subjects having HCC, comprising:

A method comprising administering to the subject or population of subjects one or more dosing cycles of an anti TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist.

312. The method of embodiment 310 and embodiment 311,

The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks.

313. The method of any one of embodiments 309 to 312,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks.

314. The method of embodiment 313,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 800 mg every 3 weeks.

315. The method of any one of embodiments 309 to 314,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks.

316. The method of any one of embodiments 309 to 315,

The method of claim 1, wherein the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 1600 mg every 3 weeks.

317. The method of any one of embodiments 309 to 316,

The method of claim 1, wherein the PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every 3 weeks.

318. The method of embodiment 310 or embodiment 311,

The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks.

319. The method of embodiment 318,

The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 10 mg/kg every two weeks.

320. The method of embodiment 319,

The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg, about 7.5 mg/kg, or about 10 mg/kg every two weeks.

321. The method of any one of embodiments 309 to 311 and 318 to 320,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every two weeks.

322. The method of any one of embodiments 309 to 311 and embodiments 318 to 321, wherein the PD-1 axis binding antagonist is administered at a dose of about 20 mg to about 1600 mg every two weeks. .

323. according to embodiment 309 to embodiment 311,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 200 mg to about 2000 mg every 4 weeks.

324. The method according to any one of embodiments 309 to 311 and 323,

The method of claim 1, wherein the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 4 weeks.

325. The embodiment of any one of embodiments 309 to 311, 323, and 324,

The method of claim 1, wherein the PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every 4 weeks.

326. The method of any one of embodiments 309 to 325,

wherein the HCC is locally advanced or metastatic HCC.

327. The method of any one of embodiments 309 to 326,

wherein the HCC is unresectable HCC.

328. The method of any one of embodiments 309 to 327,

The subject or subjects are determined to have adequate liver function.

329. The method of embodiment 328,

wherein said adequate liver function is characterized by Child-Pugh class A.

330. The method of any one of embodiments 309 to 329,

wherein the subject or HCC tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

331. The method of any one of embodiments 309 to 330,

and administering to the subject or population of subjects at least four dosing cycles.

332. The method of embodiment 331,

and administering to the subject or population of subjects at least 16 dosing cycles.

333. A method of treating a subject or population of subjects having HCC, comprising:

administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and bevacizumab at a dose of about 15 mg/kg every 3 weeks. A method comprising steps.

334. The method of any one of embodiments 311 to 333,

The method of claim 1, wherein the subject or subjects have not received prior systemic treatment for HCC.

335. The method of any one of embodiments 309 to 334,

wherein said treatment results in a median PFS in the subject population of at least about 5.6 months to at least about 6.83 months.

336. The method of embodiment 72,

wherein the cancer is bladder cancer.

337. The method of embodiment 336,

wherein the bladder cancer is muscle invasive bladder cancer (MIBC).

338. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising the steps of, wherein the subject is ineligible for treatment with a platinum-based chemotherapeutic agent.

339. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method comprising the steps of, wherein the subject is ineligible for treatment with a platinum-based chemotherapeutic agent.

340. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising the steps of, wherein the treatment is perioperative treatment.

341. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method comprising the steps of, wherein the treatment is perioperative treatment.

342. The method of any one of embodiments 338 to 341,

The method of claim 1, wherein the subject or subjects have a creatinine clearance of less than 60 mL/min.

343. The method of any one of embodiments 338 to 342,

The method of claim 1, wherein the subject or subjects have a hearing loss of grade 2 or greater.

344. The method of any one of embodiments 338 to 343,

The method of claim 1 , wherein the subject or subjects have grade 2 or greater neuropathy.

345. The method of any one of embodiments 338 to 344,

The method of claim 1, wherein the subject or subjects refused treatment with a platinum-based chemotherapeutic agent.

346. The method according to any one of embodiments 338 or 342 to 345,

The method of claim 1, wherein the platinum-based chemotherapeutic agent is cisplatin.

347. The method of any one of embodiments 338 to 346,

wherein the MIBC is surgically feasible.

348. The method of embodiment 347,

The method further comprising surgery.

349. The method of embodiment 348,

at least one dosing cycle is initiated prior to the surgery.

350. The method of embodiment 348 or embodiment 349,

at least 1, 2, or 3 dosing cycles are completed prior to the surgery.

351. The method of any one of embodiments 348 to 350,

at least one dosing cycle is initiated between 4 and 6 weeks post surgery.

352. The method of embodiment 351,

1 to 17 dosing cycles are completed after said surgery.

353. The method of any one of embodiments 348 to 352,

wherein the surgery is cystectomy and/or lymphadenectomy.

354. The method of any one of embodiments 338 to 353,

wherein the treatment results in a pathological complete response (pCR).

355. The method of any one of embodiments 338 to 354,

wherein the treatment is an increase in relapse-free survival (RFS) of the subject or subjects as compared to a baseline RFS time, an increase in the event-free survival (EFS) of the subject or subjects compared to a baseline EFS time, or an increase in the event-free survival (EFS) of the subject or subjects as compared to a baseline OS time. causing an increase in OS of the subject or subjects.

356. The method of embodiment 355:

(a) said baseline RFS time is the median RFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline EFS time is the median EFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) the baseline OS time is the median OS time of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

357. The method of any one of embodiments 338 to 356,

wherein the treatment results in pathological downstaging.

358. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising the steps of, wherein the subject is cisplatin ineligible.

359. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising the steps of, wherein the treatment is perioperative treatment.

360. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the subject is cisplatin ineligible.

361. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the treatment is perioperative treatment.

362. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks and atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks; , wherein the subject is cisplatin ineligible.

363. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks and atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks; , wherein the treatment is perioperative treatment.

364. A method of treating a subject or population of subjects having MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks, wherein the subject or subjects have cisplatin ineligible, method.

365. A method of treating a subject or population of subjects having MIBC, comprising:

administering to said subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks, wherein said treatment comprises perioperative treatment In, way.

366. The method of any one of embodiments 338-365,

wherein said treatment results in an ORR in at least about 13.4% to about 15% of the subject population.

367. The method of any one of embodiments 338 to 366,

wherein said treatment results in a median OS in the subject population of at least about 7.9 months to about 8.6 months.

368. The method of any one of embodiments 338 to 367,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142 is determined.

369. The method of embodiment 368,

The method of claim 1, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction in which the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC) is 5% or more.

370. The method of embodiment 336,

wherein the bladder cancer is urothelial cell carcinoma (UC).

371. The method of embodiment 370,

wherein the UC is metastatic urothelial cell carcinoma (mUC).

372. A method of treating a subject or population of subjects having mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or subject. A method comprising administering to a population.

373. A method of treating a subject or population of subjects having mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks to the subject or subject. A method comprising administering to a population.

374. A method of treating a subject or population of subjects having mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or subject. A method comprising administering to a population, wherein the subject has not received prior cancer immunotherapy.

375. A method of treating a subject or population of subjects having mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or subject. A method comprising administering to a population, wherein the treatment is a second line treatment.

376. The method of any one of embodiments 372, 372, and 375,

The method of claim 1, wherein the subject or subjects have not received prior therapy.

377. The method according to any one of embodiments 372 to 374,

wherein the treatment is a second line treatment.

378. The method of any one of embodiments 372 to 377,

wherein the mUC progresses during or after platinum containing therapy.

379. The method according to any one of embodiments 372 to 378,

The method further comprising administering a second dosing regimen to the subject or subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity.

380. The method of embodiment 379,

wherein the second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist and an antibody-drug conjugate (ADC).

381. The method of embodiment 380,

The method of claim 1, wherein the ADC is (a) enfortumab vedotin or (b) sacituzumab gobitecan.

382. The method of embodiment 381,

(a) enfortumab vedotin is administered at a weekly dose of 1.25 mg/kg on a 2-week dosing/week break, or (b) sacituzumab gobitecan is administered at 10 mg/week on a 2-week dos/week break Administered in kg dose.

383. The method of embodiment 381 or embodiment 382,

(a) enfortumab vedotin is administered at a dose of 1.25 mg/kg on days 1 and 8 of each 21-day cycle, or (b) sacituzumab gobitecan is administered on day 1 of each 21-day cycle and at a dose of 10 mg/kg on day 8.

384. A method of treating a subject or population of subjects having mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks; A method comprising administering to

385. A method of treating a subject or population of subjects having mUC, comprising:

administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of tyragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks and atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks A method comprising steps.

386. A method of treating a subject or population of subjects having mUC, comprising:

A method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

387. A method of treating a subject or population of subjects having mUC, comprising:

administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein:

(a) said first dosing regimen comprises at least one dosing cycle of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks comprising; and

(b) said second dosing regimen comprises one or more dosing cycles of the PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and (i) Enfortumab vedotin is administered for 2 weeks. administered at a weekly dose of 1.25 mg/kg with a weekly break of one week, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg with a two-week dosing/1 week off, wherein the second dosing regimen is wherein said subject or population of subjects is administered to said subject or population of subjects after experiencing disease progression or unacceptable toxicity during said first dosing regimen.

388. A method of treating a subject or population of subjects having mUC, comprising:

administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein:

(a) said first dosing regimen comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks including; and

(b) said second dosing regimen comprises one or more dosing cycles of the PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, (i) Enfortumab vedotin is administered for 2 weeks / administered at a weekly dose of 1.25 mg/kg with a one-week break, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg with a two-week dosing/week break, wherein the second dosing regimen is The method of claim 1, wherein the method is administered to the subject after the subject experiences disease progression or unacceptable toxicity during the first dosing regimen.

389. A method of treating a subject or population of subjects having mUC, comprising:

administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein:

(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; and

(b) said second dosing regimen comprises at least one dosing cycle of atezolizumab at a dose of about 1200 mg every 3 weeks, and (i) enfortumab vedotin is administered at 1.25 weekly doses of 2 weeks on/1 week off. is administered in a mg/kg dose, or (ii) sacituzumab gobitecan is administered at a weekly 10 mg/kg dose of 2 weeks dosing/1 week off, wherein the second dosing regimen is such that the subject administers the first dose The method is administered to the subject after experiencing disease progression or unacceptable toxicity during therapy.

390. The method of any one of embodiments 372 to 389,

wherein said treatment results in an ORR in at least about 13.4% to at least about 31% of the subject population.

391. The method of any one of embodiments 372 to 390,

wherein said treatment results in a median OS of the subject population of about 7.9 months to about 16.3 months.

392. The method of embodiment 72,

The method of claim 1, wherein the cancer is pancreatic cancer.

393. A method of treating a subject or population of subjects having pancreatic cancer, the method comprising:

Tiragolumab at a dose of about 420 mg on days 1 and 15 of each 28-day dosing cycle, atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle, each 28 days. Gemcitabine at a dose of about 1000 mg/m2 on days 1, 8, and 15 of the dosing cycle, and at a dose of about 125 mg/m2 on days 1, 8, and 15 of each 28-day dosing cycle. A method comprising administering to the subject or population of subjects a dosing regimen comprising at least one 28-day dosing cycle of nap-paclitaxel.

394. The method of embodiment 392 or embodiment 393,

The method of claim 1, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

395. The method of embodiment 394,

wherein the PDAC is a metastatic PDAC.

396. The method of any one of embodiments 392 to 395,

The method of claim 1, wherein the subject or subjects have not received prior systemic therapy for metastatic PDAC.

397. The method of any one of embodiments 392 to 396,

wherein said treatment results in an ORR in at least about 41.7% to about 46.7% of the subject population.

398. The method of any one of embodiments 392 to 397,

wherein said treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nap-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

399. The method of any one of embodiments 392 to 398,

wherein said treatment results in a median PFS in the subject population of at least about 5.5 months to about 7 months.

400. The method of any one of embodiments 392 to 399,

wherein said treatment results in a median OS in the subject population of at least about 8.5 months to about 10.6 months.

401. The method of embodiment 72,

wherein the cancer is esophageal cancer.

402. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

One or more times 21 of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. A method comprising administering to the subject or population of subjects a dosing regimen comprising one dosing cycle.

403. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

One or more 21 doses of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle 21 A method comprising administering to the subject or population of subjects a dosing regimen comprising one dosing cycle.

404. A method of treating a subject or population of subjects having esophageal cancer, the method comprising:

One or more times 21 of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. A method comprising administering to the subject or population of subjects a dosing regimen comprising one dosing cycle, wherein the subject has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

405. A method of treating a subject or population of subjects having esophageal cancer, the method comprising:

One or more times 21 of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. A method comprising administering to the subject or population of subjects a dosing regimen comprising one dosing cycle, wherein the subject has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

406. The method of embodiment 402 or embodiment 403,

The method of claim 1, wherein the subject or subjects has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. The method of embodiment 404 or embodiment 406,

wherein said subject or subjects experienced disease progression or unacceptable toxicity during said prior treatment.

408. The method of embodiment 402 or embodiment 403,

The 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

409. The method of embodiment 408,

wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses.

410. The method of any one of embodiments 404 to 409,

The method of claim 1, wherein the platinum-based chemotherapeutic agent is cisplatin.

411. The method of embodiment 410,

The method of claim 1 wherein cisplatin is administered at a dose of about 80 mg/m2 on Day 1 of each dosing cycle.

412. The method of any one of embodiments 404 to 411,

The method of claim 1, wherein the non-platinum-based chemotherapeutic agent is an antimetabolites.

413. The method of embodiment 412,

wherein the antimetabolite is 5-fluorouracil.

414. The method of embodiment 413,

5-fluorouracil is administered at a dose of about 800 mg/m2/24 hours on days 1-5 of each 21-day cycle.

415. The method of any one of embodiments 404 to 414,

The method of claim 1, wherein the esophageal cancer is advanced or metastatic esophageal cancer.

416. The embodiment of any one of embodiments 402, 403, 408, and 409,

The method of claim 1, wherein the subject or subjects has not received prior treatment for metastatic esophageal cancer.

417. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

Anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle, a dose of about 80 mg to about 1600 mg of PD-1 axis binding antagonist on Day 1 of each dosing cycle, One or more 21 doses of a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on Day 1, and a non-platinum-based chemotherapeutic agent at a dose of about 800 mg/m2/24 hours on days 1-5 of each 21-day cycle. A method comprising administering to the subject or population of subjects a dosing regimen comprising one dosing cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses.

418. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

Anti-TIGIT antagonist antibody at a dose of about 600 mg on day 1 of each dosing cycle, a dose of about 1200 mg of PD-1 axis binding antagonist on day 1 of each dosing cycle, about 80 mg/day on day 1 of each dosing cycle a dosing regimen comprising one or more 21-day dosing cycles of cisplatin at an m2 dose, and 5-fluorouracil at a dose of about 800 mg/m2/24 hour on days 1-5 of each 21-day cycle to the subject or subject administering to a population, wherein cisplatin is omitted from the dosing regimen after 6 doses.

419. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

Tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle, cisplatin at a dose of about 80 mg/m2 on day 1 of each dosing cycle and administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of 5-fluorouracil at a dose of about 800 mg/m2/24 hours on days 1-5 of each 21-day cycle. wherein cisplatin is omitted from the dosing regimen after 6 doses.

420. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

administering a first dosage regimen and a second dosage regimen to the subject or population of subjects, wherein:

(a) said first dosing regimen comprises at least one 21-day dosing cycle of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses; ; and

(b) said second dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and PD- at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle. A method comprising at least one 21 day dosing cycle of a uniaxial binding antagonist.

421. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

administering a first dosage regimen and a second dosage regimen to the subject or population of subjects, wherein:

(a) said first dosing regimen comprises a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on Day 1 of each dosing cycle and 800 mg/m2/24 hour dose on Days 1-5 of each 21-day cycle. at least one 21-day dosing cycle of a non-platinum-based chemotherapeutic agent, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses; and

(b) said second dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and PD- at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle. A method comprising at least one 21 day dosing cycle of a uniaxial binding antagonist.

422. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

administering a first dosage regimen and a second dosage regimen to the subject or population of subjects, wherein:

(a) said first dosing regimen is cisplatin at a dose of about 80 mg/m2 on day 1 of each dosing cycle and 5-fluoro at a dose of 800 mg/m2/24 hours on days 1-5 of each 21 day cycle one or more 21-day dosing cycles of lauracil, wherein cisplatin is omitted from said dosing regimen after 6 doses; and

(b) said second dosing regimen is one or more 21 day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle A method comprising

423. The method of any one of embodiments 402 to 422,

wherein the treatment results in an ORR in at least about 14% of the subject population.

424. The method according to any one of embodiments 47 to 423,

The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):

HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);

HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

A method comprising an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

425. The method of embodiment 424,

Anti-TIGIT antagonist antibodies have the following light chain variable region framework regions (FR):

FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);

FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);

FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and

FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

426. The method of embodiment 424,

The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs:

(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;

FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);

FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and

FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

427. The method of embodiment 426,

X1 is E, the method.

428. The method of embodiment 426,

X1 is Q; the method.

429. The method of any one of embodiments 424 to 428,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or

(c) a VH domain as in case (a) and a VL domain as in case (b).

430. The method of any one of embodiments 424 to 429,

The anti-TIGIT antagonist antibody is:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and

(b) A method comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19.

431. The embodiment of any one of embodiments 424 to 427, 429, and 430,

The anti-TIGIT antagonist antibody is:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and

(b) A method comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19.

432. The method of any one of embodiments 424 to 427 and embodiments 429 to 431,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and

(b) a light chain comprising the amino acid sequence of SEQ ID NO:34.

433. The method of any one of embodiments 424 to 432,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

434. The method of any one of embodiments 424 to 433,

wherein the anti-TIGIT antagonist antibody is a human antibody.

435. The method of any one of embodiments 424 to 434,

wherein the anti-TIGIT antagonist antibody is a full length antibody.

436. The method of any one of embodiments 424 to 427 and embodiments 429 to 436,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is tyragolumab.

437. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, embodiment 421, and embodiment any one of embodiments 424 to 436,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is tiragolumab, bivostolimab, ethigilumab, EOS084448, SGN-TGT or TJ-T6.

438. The method of embodiment 437,

wherein the anti-TIGIT antagonist antibody has prototypical Fc-mediated effector function.

439. according to embodiment 437 or embodiment 438,

wherein the anti-TIGIT antagonist antibody has enhanced Fc-mediated effector function.

440. The method of any one of embodiments 437 to 439,

wherein the anti-TIGIT antagonist antibody is SGN-TGT.

441. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, and embodiment 421 according to any one of embodiments,

wherein the anti-TIGIT antagonist antibody is dombanalimab, BMS-986207, ASP8374 or COM902.

442. The embodiment of any one of embodiments 424 to 431, and embodiment 441,

wherein the anti-TIGIT antagonist antibody has no Fc mediated effector function.

443. The method according to any one of embodiments 47 to 442,

wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

444. The method of embodiment 443,

wherein the IgG class antibody is an IgG1 subclass antibody.

445. of embodiment 444,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is tiragolumab, bivostolimab, etigilimab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, dombanalimab or BMS-986207.

446. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, and embodiment 421,

wherein the IgG class antibody is an IgG4 subclass antibody.

447. The method of embodiment 446,

wherein the anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. The method of any one of embodiments 424 to 434,

wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, bis-Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab')2 fragment, Way.

449. The method of any one of embodiments 424 to 448,

wherein the anti-TIGIT antagonist antibody is a monospecific antibody.

450. The method of any one of embodiments 424 to 448,

wherein the anti-TIGIT antagonist antibody is a multispecific antibody.

451. The method of embodiment 450,

wherein the multispecific antibody is a bispecific antibody.

452. The method of any one of embodiments 424 to 451

The method of claim 1, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

453. The method of embodiment 452,

The method of claim 1, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

454. The method of embodiment 453,

wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

455. The method of embodiment 454,

wherein the PD-L1 binding antagonist inhibits PD-L1 from binding to PD-1, B7-1, or both PD-1 and B7-1.

456. The method according to any one of embodiments 453-455,

The method of claim 1, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The method of embodiment 456,

The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636.

458. The method of embodiment 457,

The method of claim 1, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

459. The method of embodiment 456,

The anti-PD-L1 antagonist antibody has the following HVRs:

HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);

HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);

HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22);

HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);

HVR-L2 comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and

A method comprising HVR-L3 comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25).

460. The method of embodiment 459,

The anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or

(c) a VH domain as in case (a) and a VL domain as in case (b).

461. The method of embodiment 460,

The anti-PD-L1 antagonist antibody comprises:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and

(b) A method comprising a VL domain comprising the amino acid sequence of SEQ ID NO:27.

462. The method of embodiment 461,

The anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 28; and

(b) A method comprising a light chain comprising the amino acid sequence of SEQ ID NO:29.

463. The method according to any one of embodiments 459 to 462,

The method of claim 1, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

464. The method of any one of embodiments 459 to 463,

The method of claim 1, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

465. The method of embodiment 463 or embodiment 464,

wherein the anti-PD-L1 antagonist antibody is a full length antibody.

466. The method according to any one of embodiments 459 to 464,

The method of claim 1, wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab')2 fragments.

467. The method according to any one of embodiments 459 to 465,

wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

468. The method of embodiment 467,

wherein the IgG class antibody is an IgG1 subclass antibody.

469. The method of embodiment 452,

The method of claim 1, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. The method of embodiment 469,

wherein the PD-1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

471. The method of embodiment 470,

wherein the PD-1 binding antagonist inhibits PD-L1 from binding to PD-L1, PD-L2, or both PD-L1 and PD-L2.

472. The method according to any one of embodiments 469 to 471,

The method of claim 1, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The method of embodiment 472,

Said anti-PD-L1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, progolimab, camrelizumab, scintilimab, tislelizumab, torifaliz Mab, dostalimab, retipanrimab, sasanrimab, fenfulimab, CS1003, HLX10, SCT-I10A, zimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21.

474. The method according to any one of embodiments 469 to 471,

The method of claim 1, wherein the PD-1 binding antagonist is an Fc fusion protein.

475. The method of embodiment 474,

The Fc fusion protein is AMP-224, the method.

476. The embodiment of any one of embodiments 80-112, 114-127, and embodiments 309-312,

and administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 30 mg to about 1200 mg every three weeks.

477. Embodiment 51, Embodiment 54, Embodiment 60, Embodiment 62, Embodiment 63, Embodiment 65-67, Embodiment 80-112, Embodiment 114-127, Embodiment 136- Embodiment 140, embodiment 169-174, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301, embodiment 302, embodiment 303, embodiment 313, embodiment 315, embodiment 338, embodiment 340, embodiment 358 to embodiment 361, embodiment 372, embodiment 384, embodiment 387, embodiment 388, embodiment 402 to The embodiment of any one of embodiments 404, 417, 420, 421, and 476,

and administering said anti-TIGIT antagonist antibody to said subject at a dose of about 600 mg every 3 weeks.

478. Embodiment 51, Embodiment 54, Embodiment 60, Embodiment 62, Embodiment 63, Embodiment 65-67, Embodiment 80-112, Embodiment 114-127, Embodiment 136- Embodiment 140, embodiment 169-174, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301, embodiment 302, Embodiment 303, Embodiment 309, Embodiment 313, Embodiment 315, Embodiment 338, Embodiment 340, Embodiment 358 to Embodiment 361, Embodiment 372, Embodiment 384, Embodiment 387, Embodiment 388, The embodiment of any one of Embodiments 402 to 404, Embodiment 417, Embodiment 420, Embodiment 421, and Embodiment 476,

administering said anti-TIGIT antagonist antibody to said subject or population of subjects in stepwise doses based on the body weight of said subject, wherein said subject has a body weight of:

(a) weighing 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks;

(b) greater than 15 kg and less than or equal to 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or

(c) greater than 40 kg, wherein the anti TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks.

479. The embodiment of any one of embodiments 47, 48, 77, 78, 82, and 83,

and administering said anti TIGIT antagonist antibody to said subject or population of subjects at a dose of about 700 mg to about 1000 mg every 4 weeks.

480. The embodiment of any one of embodiments 47, 48, 59, 67, 323, and 479,

and administering the anti-TIGIT antagonist antibody to the subject at a dose of about 840 mg every 4 weeks.

481. The embodiment of any one of embodiments 49, 50, and 104,

and administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of about 300 mg to about 600 mg every two weeks.

482. The embodiment of any one of embodiments 49, 50, 227, 251 to 253, 255, and 481,

and administering the anti-TIGIT antagonist antibody to the subject at a dose of about 420 mg every two weeks.

483. The method according to any one of embodiments 47 to 482,

wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose.

484. The embodiment of any one of embodiments 54, 62, 63, 65-67, 80-109, and 27-2698,

and administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of about 900 mg to about 1500 mg every three weeks.

485. embodiment 54, embodiment 60, embodiment 62, embodiment 63, embodiment 65-67, embodiment 80-112, embodiment 114-127, embodiment 136-140, Embodiment 169 to embodiment 172, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301 to embodiment 303, embodiment 309, embodiment 311, embodiment 313, embodiment 315, embodiment 338, embodiment 340, embodiment 358 to embodiment 361, embodiment 372 to embodiment 375, embodiment 384, embodiment 387, embodiment 388, The embodiment of any one of Embodiments 402 to 405, Embodiment 417, Embodiment 420, Embodiment 421, and Embodiment 484,

administering the PD-1 axis binding antagonist to the subject at a dose of about 1200 mg every 3 weeks.

486. The embodiment of any one of embodiments 47, 50, 80-109, and embodiment 324,

The method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist at a dose of about 1400 mg to about 2000 mg every 4 weeks.

487. The embodiment of any one of embodiments 47, 50, 59, 67, 324, and 479,

administering the PD-1 axis binding antagonist to the subject at a dose of about 1680 mg every 4 weeks.

488. according to embodiment 48, embodiment 49, embodiment 80-109, and embodiment 481,

and administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of about 600 mg to about 1200 mg every two weeks.

489. The embodiment of any one of embodiments 48, 49, 80 to 109, 227, 251 to 253, and 481,

administering the PD-1 axis binding antagonist to the subject at a dose of about 840 mg every two weeks.

490. The method according to any one of embodiments 47 to 489,

The method of claim 1, wherein the dose of the PD-1 axis binding antagonist is a fixed dose.

491. The method of embodiment 60 or embodiment 61,

A method comprising administering to the subject pembrolizumab at a fixed dose of about 200 mg every 3 weeks or 400 mg every 6 weeks.

492. The embodiment of any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191,

The length of each of said one or more dosing cycles is 21 days.

493. The embodiment of any one of embodiments 47, 59, 67, 80 to 109, and embodiments 309 to 311,

The length of each of the one or more dosing cycles is 28 days.

494. The embodiment of any one of embodiments 49, 80 to 109, and embodiments 309 to 311,

The length of each of the one or more dosing cycles is 14 days.

495. The method according to any one of embodiments 47 to 494,

and administering said anti TIGIT antagonist antibody to said subject or population of subjects on about Day 1 of each of said one or more dosing cycles.

496. The method according to any one of embodiments 47 to 495,

and administering the PD-1 axis binding antagonist to the subject or population of subjects on about Day 1 of each of the one or more dosing cycles.

497. according to embodiment 321 or embodiment 493,

and administering said anti-TIGIT antagonist antibody to said subject on about day 15 of each of said one or more dosing cycles.

498. The method of embodiment 322 or embodiment 493,

and administering the PD-1 axis binding antagonist to the subject on about day 15 of each of the one or more dosing cycles.

499. The method according to any one of embodiments 47 to 498,

administering to the subject or population of subjects the PD-1 axis binding antagonist prior to the anti TIGIT antagonist antibody or the anti TIGIT antagonist antibody prior to the PD-1 axis binding antagonist.

500. The method of embodiment 499,

a first observation period following administration of said PD-1 axis binding antagonist or said anti-TIGIT antagonist antibody.

501. The method of embodiment 500,

The method of claim 1, wherein the first observation period is from about 30 minutes to about 60 minutes in length.

502. The method of embodiment 500 or embodiment 501,

a second observation period following administration of said anti-TIGIT antagonist antibody or said PD-1 axis binding antagonist.

503. The method of embodiment 502,

and the second observation period is between about 30 minutes and about 60 minutes in length.

504. The method of any one of embodiments 47 to 503,

administering the PD-1 axis binding antagonist to the subject or population of subjects concurrently with the anti-TIGIT antagonist antibody.

505. The method of any one of embodiments 47 to 504,

and administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist intravenously to the subject or population of subjects.

506. The method of embodiment 505,

administering the PD-1 axis binding antagonist to the subject or population of subjects as an intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes.

507. The method of embodiment 505 or embodiment 506,

and administering said anti-TIGIT antagonist antibody to said subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes.

508. The method of any one of embodiments 47-114 and 116-507,

A method, wherein the level of PD-L1 expression in the subject or a tumor sample obtained from subjects is determined.

509. The method of embodiment 508,

wherein the subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

510. The method of embodiment 509,

wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1.

511. The method of embodiment 510,

The method of claim 1, wherein the detectable protein expression level of PD-L1 is determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody suitable for staining.

512. The method of embodiment 511,

wherein said anti-PD-L1 antibody suitable for staining is said anti-PD-L1 antibody SP263, SP142, 22C3 or 28-8.

513. The method of embodiment 511 or embodiment 512,

wherein the detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a PalmDx 28-8 IHC assay. .

514. The embodiment of any of embodiments 47 to 109, 188, 220 to 265, and embodiments 307 to 423,

A method, wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP263 is determined.

515. The embodiment of any one of embodiments 47 to 220, 265 to 338, and embodiments 370 to 423,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142 is determined.

516. The embodiment of any one of embodiments 47 to 113, 136 to 187, and 220 to 423,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 22C3 is determined.

517. The method of any one of embodiments 47 to 114 and embodiments 116 to 423,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 28-8 is determined.

518. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% of tumor associated immune cells (TICs) in the tumor sample.

519. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 5% and less than 20% in the tumor sample.

520. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 10% in the tumor sample.

521. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 20% in the tumor sample.

522. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 10% and less than 50% in the tumor sample.

523. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 50% in the tumor sample.

524. The embodiment of any one of embodiments 514, 516, and 517,

The method of claim 1, wherein the detectable protein expression level of PD-L1 is greater than or equal to 1% of the PD-L1 positive tumor cell fraction.

525. The embodiment of any one of embodiments 514, 516, and 517,

The method of claim 1, wherein the detectable protein expression level of PD-L1 is greater than or equal to 30% in the fraction of PD-L1 positive tumor cells.

526. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 1% and less than 50% of a fraction of PD-L1-positive tumor cells in the tumor sample.

527. The embodiment of any one of embodiments 514, 516, and 517,

The method, wherein the detectable protein expression level of PD-L1 is at least 50% of the PD-L1 positive tumor cell fraction.

528. The method of embodiment 515,

wherein the PD-L1-positive tumor cell fraction is a proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (ICs).

529. The method of embodiment 515,

The method of claim 1, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is at least 1%.

530. The method of embodiment 515,

The method of claim 1, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is at least 5%.

531. The method of embodiment 516,

The method of claim 1, wherein the detectable protein expression level of PD-L1 has a composite positive score (CPS) of 1 or more.

532. The method of embodiment 516,

The method, wherein the detectable protein expression level of PD-L1 has a CPS of 10 or more.

533. The method of embodiment 516,

The method, wherein the detectable protein expression level of PD-L1 has a CPS of 20 or more.

534. The method of any one of embodiments 528 to 530,

wherein the IHC assay is a Ventana SP142 IHC assay.

535. The method of embodiment 509,

wherein the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1.

536. The method of embodiment 535,

The detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH or a combination thereof.

537. The method according to any one of embodiments 47 to 423,

wherein the treatment results in an increase in overall survival (OS) of the subject compared to baseline OS time and/or an increase in progression free survival (PFS) in the subject compared to baseline PFS time.

538. The method of embodiment 537:

(a) said baseline OS time is the median OS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without an anti-PD-1 axis binding antagonist; and/or

(b) the baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without an anti-PD-1 axis binding antagonist.

539. The embodiment of any one of embodiments 52, 158, and 228,

The method of claim 1, wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents.

540. The method of embodiment 539,

The method of claim 1, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. The method of embodiment 69, embodiment 92, embodiment 127, embodiment 131, embodiment 249, and embodiment 540,

wherein the carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min or AUC=6 mg/ml/min.

542. The method of embodiment 69, embodiment 127, embodiment 162, embodiment 164, embodiment 166, embodiment 168, and embodiment 540,

wherein the cisplatin is administered at a dose of about 75 mg/m2 or 80 mg/m2.

543. The method of any one of embodiments 539 to 542,

The method of claim 1, wherein the one or more non-platinum-based chemotherapeutic agents are antimetabolites, taxanes, or topoisomerase II inhibitors.

544. The method of embodiment 62, embodiment 173, embodiment 174, and embodiment 543,

wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. The embodiment of any one of embodiments 69, 127, 162, and 544,

The method of claim 1, wherein the pemetrexed is administered at a dose of about 500 mg/m2.

546. The embodiment of any one of embodiments 63, 64, 162, 398, and 544,

wherein the gemcitabine is administered at a dose of about 1000 mg/m2 or about 1250 mg/m2.

547. The method of embodiment 544,

The method of claim 1, wherein the antimetabolite is capecitabine.

548. The method of embodiment 544 or embodiment 547,

wherein the capecitabine is administered at a dose of about 1250 mg/m2.

549. The embodiment of any one of embodiments 173, 174, 229, 230, 239, 240, and 543 to 548,

The method of claim 1, wherein the taxane is paclitaxel or nap-paclitaxel.

550. The method of any one of embodiments 69, 162, and 549,

wherein the paclitaxel is administered at a dose of about 175 mg/m2 or about 200 mg/m2.

551. The embodiment of any one of embodiments 63, 64, 249, 398, and 549,

wherein the nap-paclitaxel is administered at a dose of about 100 mg/m2.

552. The embodiment of any one of embodiments 80-91, 229, 230, 239, 241, 251, 255, and 543-551. ,

wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331.

553. The embodiment of any one of embodiments 69, 92, and 552,

wherein the etoposide is administered at a dose of about 100 mg/m2.

554. The method of any one of embodiments 543 to 553,

The one or more chemotherapeutic agents are each administered once every week, once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, twice every 4 weeks, or 3 times every 4 weeks. , Way.

555. The method of any one of embodiments 543 to 554,

The method of claim 1, wherein the one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles.

556. The method of any one of embodiments 544 to 555,

wherein the gemcitabine is administered three times every four weeks.

557. The method according to any one of embodiments 544 to 556,

wherein the gemcitabine is administered on days 1, 8, and/or 15 of one or more dosing cycles.

558. The method of any one of embodiments 544 to 557,

wherein the capecitabine is administered daily for 2 weeks.

559. The method according to any one of embodiments 544 to 558,

wherein the capecitabine is administered on days 1 to 14 of one or more dosing cycles.

560. The method of any one of embodiments 549 to 559,

wherein the nap-paclitaxel is administered 3 times every 4 weeks.

561. The method of any one of embodiments 549 to 560,

wherein said nap-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles.

562. The method of any one of embodiments 552 to 561,

The method of claim 1, wherein the etoposide is administered on days 1 to 3 every 3 weeks.

563. The method of any one of embodiments 552 to 562,

wherein the etoposide is administered on days 1-3 of one or more dosing cycles.

564. The method of any one of embodiments 543 to 563,

wherein said one or more chemotherapeutic agents are administered prior to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

565. The method of any one of embodiments 543 to 564,

wherein said one or more chemotherapeutic agents are administered after said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

566. The method of any one of embodiments 543 to 565,

The method of claim 1, wherein the one or more chemotherapeutic agents are administered intravenously or orally.

567. The embodiment of any one of embodiments 65, 310, and 311,

The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks.

568. The method of embodiment 312 or embodiment 567,

The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 10 mg/kg to about 20 mg/kg every 3 weeks.

569. according to embodiment 318 and embodiment 568,

The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 15 mg/kg every 3 weeks.

570. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 569,

The method of claim 1, wherein the VEGF antagonist is an anti-VEGF antibody.

571. The method of embodiment 570,

The method of claim 1, wherein the anti-VEGF antibody comprises a VH domain and a VL domain of bevacizumab.

572. The method of embodiment 570 or embodiment 571,

The anti-VEGF antibody is bevacizumab, the method.

573. The embodiment of any one of embodiments 65, 310 to 312, and embodiments 318 to 320,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the VEGF antagonist is bevacizumab.

574. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 573,

and administering the VEGF antagonist to the subject on Day 1 of one or more dosing cycles.

575. The method of any one of embodiments 318 to 320,

and administering the VEGF antagonist to the subject on day 15 of one or more dosing cycles.

576. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 575,

The method of claim 1, wherein the VEGF antagonist is administered intravenously.

577. The method of embodiment 576,

wherein the VEGF antagonist is administered to the subject as an intravenous infusion over 90 ± 15 minutes.

578. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 577,

A method comprising administering to the subject the PD-1 axis binding antagonist prior to the VEGF antagonist, and the VEGF antagonist prior to the anti-TIGIT antagonist antibody.

579. The method of embodiment 578,

A method comprising a first observation period after administration of the PD-1 axis binding antagonist, a second observation period after administration of the VEGF antagonist, and a third observation period after administration of the anti-TIGIT antagonist antibody.

580. The method of embodiment 579,

wherein the first observation period, the second observation period, and the third observation period are each from about 30 minutes to about 120 minutes in length.

581. Embodiment 113, Embodiment 128, Embodiment 129 to Embodiment 131, Embodiment 175 to Embodiment 182, Embodiment 210 to Embodiment 214, Embodiment 221, Embodiment 256, Embodiment 257, Embodiment 270, Embodiment 289, Embodiment 290, Embodiment 293, Embodiment 294, Embodiment 297, Embodiment 298, Embodiment 333, Embodiment 362 to Embodiment 365, Embodiment 385, Embodiment 386, Embodiment 389, Embodiment 393, embodiment 419, and embodiment 422 according to any one of embodiments,

wherein tiragolumab and atezolizumab are bound to an IV bag prior to administration.

582. The method of any one of embodiments 47-581, wherein the subject is a human.

583. Embodiment 47-190, Embodiment 192-208, Embodiment 210-211, Embodiment 213, Embodiment 215-268, Embodiment 270-294, and Embodiment 299 A kit comprising a PD-1 axis binding antagonist and/or anti TIGIT antagonist antibody for treating a subject having cancer according to the method of any one of embodiments to embodiment 582.

584. Embodiment 47-190, Embodiment 192-208, Embodiment 210-211, Embodiment 213, Embodiment 215-268, Embodiment 270-294, and Embodiment 299 A kit comprising a PD-1 axis binding antagonist for use in combination with an anti TIGIT antagonist antibody to treat a subject having cancer according to the method of any one of embodiments to embodiment 582.

585. The method of embodiment 584,

The kit further comprising an anti-TIGIT antagonist antibody.

586. The method of any one of embodiments 583 to 585,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is tyragolumab.

587. The method according to any one of embodiments 583 to 586,

The method of claim 1, wherein the PD-1 axis binding antagonist is atezolizumab.

588. Embodiment 47 to embodiment 190, embodiment 192 to embodiment 208, embodiment 210 to embodiment 211, embodiment 213, embodiment 215 to embodiment 268, embodiment 270 to embodiment 294, and embodiment 299 A kit comprising an anti TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to the method of any one of embodiments to embodiment 582.

589. The method of embodiment 588,

A kit, further comprising a PD-1 axis binding antagonist.

590. The method of embodiment 588 or embodiment 589,

The kit, wherein the PD-1 axis binding antagonist is atezolizumab.

591. The method of any one of embodiments 588 to 590,

The method of claim 1, wherein the anti-TIGIT antagonist antibody is tyragolumab.

592. The method according to any one of embodiments 583 to 591,

A kit, further comprising one or more chemotherapeutic agents.

593. The method of embodiment 592,

wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents.

594. The method of embodiment 593,

wherein the at least one platinum-based chemotherapeutic agent is carboplatin or cisplatin.

595. The method of embodiment 593 or embodiment 594,

wherein the at least one non-platinum-based chemotherapeutic agent is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

596. The method of embodiment 595,

wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

597. The method of embodiment 595 or embodiment 596,

wherein the taxane is paclitaxel or nap-paclitaxel.

598. The method according to any one of embodiments 595 to 597,

wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331.

599. The method of any one of embodiments 583 to 598,

A kit, further comprising a VEGF antagonist.

600. The method of embodiment 599,

The VEGF antagonist is an anti-VEGF antibody, kit.

601. The method of embodiment 600,

The anti-VEGF antibody is bevacizumab, the kit.

602. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having cancer, comprising:

The method includes embodiments 47 to 190, 192 to 208, 210 to 211, 213, 215 to 268, 270 to 294, and embodiments An anti TIGIT antagonist antibody and an anti PD-1 axis binding antagonist according to any one of 299 to embodiment 582.

603. Use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject or population of subjects having cancer, comprising:

Embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-implementation Use according to the method of any one of Example 582.

604. The method of embodiment 603,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

605. The method of embodiment 603,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single dosage form.

Implementation Set B:

1. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 500 mg to about 700 mg every 3 weeks. and wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 900 mg to about 1500 mg every 3 weeks, wherein said treatment is a platinum-based chemotherapeutic agent every 3 weeks and a non-platinum-based chemotherapy every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, further comprising the use of an agent.

2. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti TIGIT antagonist antibody is administered at a dose of about 700 mg to about 1000 mg every 4 weeks. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for use, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 1400 mg to 2000 mg every 4 weeks.

3. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 300 mg to about 600 mg every two weeks. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist formulated for use, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 600 mg to about 1200 mg every two weeks.

4. according to embodiment 2 or embodiment 3,

wherein said treatment further comprises the use of one or more chemotherapeutic agents.

5. The method according to any one of embodiments 1 to 4,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.

6. The method according to any one of embodiments 1 to 5,

The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):

(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);

(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

(d) an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

(e) an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

(f) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

7. The method according to any one of embodiments 1 to 6,

The anti-TIGIT antagonist antibody has the following light chain variable region framework regions (FR):

(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);

(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);

(c) FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and

(d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and

The following heavy chain variable region FRs:

(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;

(b) FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);

(c) FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and

(d) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, further comprising FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

8. The method according to any one of embodiments 1 to 7,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or

(c) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The method according to any one of embodiments 1 to 8,

wherein said anti-TIGIT antagonist antibody is tyragolumab; an anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

10. The method according to any one of embodiments 1 to 9,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

11. The method according to any one of embodiments 1 to 10,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The method according to any one of embodiments 1 to 11,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The method of embodiment 12,

The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

14. The method according to any one of embodiments 1 to 13,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is atezolizumab.

15. The method according to any one of embodiments 1 to 11,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The method of embodiment 15,

Said anti-PD-L1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, progolimab, camrelizumab, scintilimab, tislelizumab, torifaliz Mab, dostalimab, retipanrimab, sasanrimab, fenfulimab, CS1003, HLX10, SCT-I10A, zimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, For use which is HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21 Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists.

17. The method according to any one of embodiments 2 to 16,

wherein said treatment further comprises the use of an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. according to embodiment 1 or embodiment 17,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the non-platinum-based chemotherapeutic agent is a topoisomerase II inhibitor.

19. The method of embodiment 18,

wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331, in particular etoposide; Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

20. The method of embodiment 18 or embodiment 19,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said topoisomerase II inhibitor is formulated for administration at a dose of 100 mg/m2.

21. The method according to any one of embodiments 17 to 20,

wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

22. The method according to any one of embodiments 17 to 21,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration.

23. The method according to any one of embodiments 1-22,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. The method of embodiment 23,

wherein the induction phase comprises 4 initial dosing cycles and the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and non-platinum-based chemotherapeutic agent are administered in each of the four initial dosing cycles. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for

25. according to embodiment 23 or embodiment 24,

wherein said maintenance phase does not include administration of said platinum-based chemotherapeutic agent and/or non-platinum-based chemotherapeutic agent.

26. The method according to any one of embodiments 1 to 25,

wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

27. The method according to any one of embodiments 1-26,

wherein said treatment prolongs overall survival of said subject as compared to treatment without said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

28. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is lung cancer.

29. The method according to any one of embodiments 1 to 28,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said lung cancer is small cell lung cancer (SCLC), in particular diastolic SCLC (ES-SCLC).

30. The method of embodiment 28,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said lung cancer is small cell lung cancer (SCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. The method of embodiment 28,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is locally advanced unresectable or metastatic nonsquamous NSCLC.

32. The method of embodiment 28,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is resectable lung cancer.

33. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is cervical cancer.

34. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is early triple negative breast cancer (eTNBC).

35. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is head and neck cancer.

36. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is bladder cancer.

38. The method of embodiment 37,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cancer is urothelial cell carcinoma (UC), in particular metastatic urothelial cell carcinoma (mUC).

39. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cancer is pancreatic cancer, in particular pancreatic ductal cell carcinoma (PDAC).

40. The method according to any one of embodiments 1 to 27,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer.

41. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

The method comprises an anti TIGIT antagonist antibody formulated for administration at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist formulated for administration of a dose of about 900 mg to about 1500 mg every 3 weeks. An anti TIGIT antagonist antibody and PD- for use comprising administering to the subject a dosing regimen comprising at least one dosing cycle of a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks uniaxial binding antagonists.

42. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

The method comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis binding antagonist formulated for administration of a dose of about 1400 mg to about 2000 mg every 4 weeks. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising administering to the subject a dosing regimen comprising one or more dosing cycles.

43. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

The method comprises an anti TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis binding antagonist formulated for administration at a dose of about 600 mg to about 1200 mg every two weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising administering to the subject a dosing regimen comprising one or more dosing cycles of

44. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

(a) the method comprises an anti TIGIT antagonist antibody formulated for administration at a dose of about 500 mg to about 700 mg every 3 weeks, PD-1 formulated for administration of a dose of about 900 mg to about 1500 mg every 3 weeks administering to the subject a dosing regimen comprising one or more dosing cycles of an axis-binding antagonist, a platinum-based chemotherapeutic agent every three weeks, and a non-platinum-based chemotherapeutic agent every three weeks; (b) the method comprises an anti-TIGIT antagonist antibody formulated for administration of a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis formulated for administration of a dose of about 1400 mg to about 2000 mg every 4 weeks. administering to the subject a dosing regimen comprising one or more dosing cycles of the binding antagonist; or (c) the method comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every two weeks and a PD- formulated for administration at a dose of about 600 mg to about 1200 mg every two weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising administering to the subject a dosing regimen comprising one or more dosing cycles of the uniaxial binding antagonist.

45. The method of embodiment 44,

The anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist.

46. The method of embodiment 44,

The anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

47. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 200 mg to about 2000 mg every 4 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-1 axis binding antagonist is formulated for administration of a dose of about 80 mg to about 2000 mg every 4 weeks.

48. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 200 mg to about 2000 mg every 4 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-1 axis binding antagonist is formulated for administration of a dose of about 20 mg to about 1600 mg every two weeks.

49. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every two weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-1 axis binding antagonist is formulated for administration of a dose of about 20 mg to about 1600 mg every two weeks.

50. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every two weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-1 axis binding antagonist is formulated for administration of a dose of about 80 mg to about 2000 mg every 4 weeks.

51. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-1 axis binding antagonist is formulated for administration of a dose of about 100 mg to about 1000 mg every 6 weeks.

52. The method according to any one of embodiments 47 to 51,

wherein said treatment further comprises the use of one or more chemotherapeutic agents.

53. The method of embodiment 52,

wherein said treatment further comprises the use of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

54. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the use of a chemotherapeutic agent.

55. according to embodiment 53 or embodiment 54,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the method comprises an induced phase and a maintenance phase.

56. The method of embodiment 55,

wherein said induction phase and maintenance phase each comprise at least one dosing cycle.

57. according to embodiment 55 or embodiment 56,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent.

58. The method according to any one of embodiments 55 to 57,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said maintenance phase does not include administration of said non-platinum-based chemotherapeutic agent.

59. The method of embodiment 58,

The maintenance phase is one or more dosing cycles of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 200 mg to about 2000 mg every 4 weeks and a dose of about 80 mg to about 2000 mg of the PD-1 axis binding antagonist every 4 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising:

60. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein the anti-PD-1 antagonist antibody is formulated for administration of a dose of about 80 mg to about 1600 mg every three weeks, wherein the anti-PD-1 antagonist antibody is pembrolizumab. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists.

61. Tiragolumab and pembrolizumab for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of tiragolumab and pembrolizumab in a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein said pembrolizumab is about 100 mg to about 1000 mg every 6 weeks. A method formulated for administration of a dose.

62. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks. of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and orally about 10 mg/m2 twice daily every 3 weeks of dosing for 2 weeks/1 week off. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising the use of a dose of from to about 10000 mg/m2 of the antimetabolite.

63. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks. An anti-TIGIT antagonist antibody and PD for use, wherein the PD-1 axis binding antagonist comprises the use of a dose of about 80 mg to about 1600 mg every 3 weeks, gemcitabine, and nap-paclitaxel. -1 axis binding antagonists.

64. The method of embodiment 52,

wherein said at least one chemotherapeutic agent is gemcitabine and nap-paclitaxel.

65. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks. is formulated for administration of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and a dose of about 1 mg/kg to about 35 mg/kg of a VEGF antagonist every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

66. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) the induction phase is an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, 3 weeks comprising at least one dosing cycle of a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks; and

(b) said maintenance phase comprises at least one additional dosing cycle of said anti-TIGIT antagonist antibody every 3 weeks, said PD-1 axis binding antagonist every 3 weeks, and said non-platinum chemotherapeutic agent every 3 weeks, wherein said maintenance An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, wherein the group does not include administration of said platinum-based chemotherapeutic agent.

67. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) the induction phase is an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, 3 weeks comprising at least one dosing cycle of a platinum-based chemotherapeutic agent every 3 weeks, and a non-platinum-based chemotherapeutic agent every 3 weeks; and

(b) the maintenance phase is an anti-TIGIT antagonist antibody formulated for administration at a dose of about 200 mg to about 2000 mg every 4 weeks and PD-1 formulated for administration of a dose of about 80 mg to about 2000 mg every 4 weeks. an anti-TIGIT antagonist antibody and PD-1 axis binding for use comprising one or more additional dosing cycles of the axis binding antagonist, wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent antagonist.

68. The method of any one of embodiments 56 to 59, embodiment 66, and embodiment 67,

wherein said induction phase comprises 4 to 6 dosing cycles.

69. The method of any one of embodiments 53-59 and 66-68:

(a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;

(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel; or

(c) said platinum-based chemotherapeutic agent is carboplatin or cisplatin and said non-platinum-based chemotherapeutic agent is etoposide.

70. The method according to any one of embodiments 47 to 69,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is a solid tumor.

71. The method according to any one of embodiments 47 to 70,

wherein the cancer is locally advanced or metastatic; an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

72. The method according to any one of embodiments 47 to 71,

wherein said cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, kidney cancer, melanoma, or ovarian cancer. uniaxial binding antagonists.

73. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is lung cancer.

74. The method of embodiment 73,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is NSCLC, in particular locally advanced unresectable NSCLC.

75. The method of embodiment 74,

wherein said NSCLC is stage IIIB NSCLC.

76. The method according to any one of embodiments 73 to 75,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is relapsed or metastatic NSCLC.

77. The method of embodiment 76,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said NSCLC is stage IV NSCLC.

78. The method of embodiment 77,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject has not previously been treated for stage IV NSCLC.

79. The method of embodiment 73,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is small cell lung cancer (SCLC).

80. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having lung cancer,

The treatment comprises at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the anti-TIGIT antagonist antibody and the PD- comprising the use of a uniaxial binding antagonist, wherein said treatment comprises the treatment of said subject without said anti-TIGIT antagonist antibody as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use, prolonging progression survival (PFS).

81. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a population of subjects with lung cancer,

The treatment comprises at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the anti-TIGIT antagonist antibody and the PD- An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising the use of a uniaxial binding antagonist, wherein said treatment results in a median PFS in a population of subjects from about 8.2 months to about 9.2 months.

82. The method of embodiment 80 or embodiment 81,

wherein said treatment prolongs overall survival (OS) of said subject or population of subjects compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody; Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

83. The method according to any one of embodiments 80 to 82,

wherein the treatment prolongs the PFS of the subject or population of subjects by at least about 2.4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

84. The method of embodiment 83,

wherein said treatment reduces the PFS of said subject or population of subjects by at least about 3 months to about 4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use extending by months.

85. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having lung cancer,

The treatment comprises at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the anti-TIGIT antagonist antibody and the PD- comprising the use of a uniaxial binding antagonist, wherein said treatment comprises the OS of said subject compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without said anti-TIGIT antagonist antibody. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

86. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a population of subjects with lung cancer,

The treatment comprises an effective amount of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment results in a median OS in a population of subjects from about 15.3 months to about 17.6 months.

87. The method according to any one of embodiments 82 to 86,

wherein the treatment prolongs the OS of the subject or population of subjects by at least about 3.3 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

88. The method according to any one of embodiments 82 to 86,

wherein said treatment reduces the OS of said subject or population of subjects by at least about 3 months to about 5.3 as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use extending by months.

89. The method according to any one of embodiments 80 to 88,

wherein the anti TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered in each of 4 initial dosing cycles. binding antagonists.

90. The method according to any one of embodiments 80 to 89,

wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are further administered in one or more additional cycles after the fourth initial dosing cycle.

91. The method of embodiment 90,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of one or more additional dosing cycles.

92. The method according to any one of embodiments 80 to 91,

wherein said platinum-based chemotherapeutic agent is carboplatin and said topoisomerase II inhibitor is etoposide.

93. The method according to any one of embodiments 80 to 92,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is small cell lung cancer (SCLC).

94. The method of embodiment 93,

wherein said SCLC is an expanded stage SCLC (ES-SCLC).

95. The method of embodiment 94,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects is naive to treat ES-SCLC.

96. The method according to any one of embodiments 80 to 95,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject or subjects has no presence or history of brain metastases.

97. The method according to any one of embodiments 80 to 96,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said lung cancer is not selected for PD-L1 expression.

98. The method according to any one of embodiments 80 to 96,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is selected for PD-L1 expression.

99. The method of embodiment 98,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is selected for PD-L1 expression by a detectable expression level of PD-L1.

100. The method according to any one of embodiments 80 to 99,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is metastatic.

101. The method of embodiment 100,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer has metastasized to the brain, liver, lymph node, and/or adrenal gland.

102. The method of embodiment 100 or embodiment 101,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer does not metastasize to the brain.

103. The method of any one of embodiments 100-102,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment elicits a complete response (CR) or a partial response (PR).

104. The method according to any one of embodiments 80 to 103,

wherein said anti TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 2 weeks, every 3 weeks, or every 4 weeks.

105. The method of any one of embodiments 80-104,

wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 2000 mg every 2 weeks, every 3 weeks, or every 4 weeks, an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use .

106. The method of any one of embodiments 80 to 105,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist, said anti-TIGIT antagonist antibody, said platinum-based chemotherapeutic agent, and said photoisomerase II inhibitor are administered sequentially.

107. The method of embodiment 106,

The PD-1 axis binding antagonist is administered before the anti-TIGIT antagonist antibody, the anti-TIGIT antagonist antibody is administered before the platinum-based chemotherapeutic agent, and the platinum agent is administered before the topoisomerase II inhibitor. , anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

108. The method according to any one of embodiments 80 to 107,

wherein said anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered intravenously.

109. The method according to any one of embodiments 80 to 108,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein at least one of said anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor is administered intravenously.

110. An anti TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with SCLC, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle, atezoli at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle. Zumab, carboplatin in a dose sufficient to achieve AUC=5 mg/ml/min on Day 1 of each dosing cycle, and 100 mg/day on each of Days 1, 2, and 3 of each dosing cycle comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more 21-day dosing cycles of an m2 dose of etoposide, wherein said treatment is atezolizumab, carbople without said anti-TIGIT antagonist antibody. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use, prolonging PFS and/or OS in said subject compared to treatment with Latin, and etoposide.

111. An anti TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with SCLC,

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 800 mg on Day 1 of each dosing cycle, atezoli at a dose of about 900 mg to about 1500 mg on Day 1 of each dosing cycle. Zumab, carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each dosing cycle, and 100 mg/day on each of Days 1, 2, and 3 of each dosing cycle comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in at least one 21-day dosing cycle of an m2 dose of etoposide, wherein said treatment is atezolizumab, carbople without said anti-TIGIT antagonist antibody. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use, prolonging PFS and/or OS in said subject compared to treatment with Latin, and etoposide.

112. The method of embodiment 110 or embodiment 111,

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and a dose of about 80 mg to about 1600 mg on Day 1 of each additional dosing cycle. Anti-TIGIT antagonist antibody and PD-1 axis binding for use further comprising one or more additional 21-day dosing cycles of atezolizumab, wherein carboplatin and etoposide are omitted from each of said one or more additional dosing cycles. antagonist.

113. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with ES-SCLC,

wherein said treatment comprises the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in 4 initial dosing cycles followed by one or more additional dosing cycles:

(a) said four initial dosing cycles comprise administration of a tiragolumab formulated for administration of a dose of about 600 mg on Day 1 of each initial dosing cycle, administration of a dose of about 1200 mg on Day 1 of each initial dosing cycle. Atezolizumab formulated for this purpose, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of each initial dosing cycle, and Days 1, 2, and 2 of each initial dosing cycle, and with etoposide at a dose of 100 mg/m2 on each of 3 days; and

(b) said one or more additional dosing cycles comprise a tiragolumab formulated for administration of a dose of about 600 mg on Day 1 of each additional dosing cycle and a dose of about 1200 mg on Day 1 of each additional dosing cycle. Atezolizumab formulated for administration of

wherein said four initial dosing cycles and said one or more additional dosing cycles are each 21 day dosing cycle, wherein said treatment is compared to treatment with atezolizumab, carboplatin, and etoposide without said tiragolumab tiragolumab and atezolizumab for use, thereby prolonging PFS and/or OS of said subject or population of subjects.

114. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having lung cancer,

wherein the treatment comprises at least one dosing cycle of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent, and a second chemotherapeutic agent that is a non-platinum-based chemotherapeutic agent. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the use of a TIGIT antagonist antibody and said PD-1 axis binding antagonist.

115. The method of embodiment 114,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said lung cancer is not evaluated for PD-L1 expression.

116. The method of embodiment 114 or embodiment 115,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject or subjects has not been determined to have a PD-L1 positive tumor cell fraction greater than or equal to 50%.

117. The method of embodiment 116,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects is determined to have a fraction of PD-L1 positive tumor cells of less than 50%.

118. The method of embodiment 116 or embodiment 117,

said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein said anti-PD-L1 antibody is SP263 or 22C3, anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use .

119. The method according to any one of embodiments 114 to 118,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormality.

120. The method according to any one of embodiments 114 to 119,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects has not received prior systemic therapy for said lung cancer.

121. The method of any one of embodiments 114 to 120,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is locally advanced lung cancer.

122. The method according to any one of embodiments 114 to 121,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is NSCLC, in particular locally advanced unresectable or metastatic nonsquamous NSCLC.

123. The method of embodiment 122,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said nonsquamous NSCLC is stage IV nonsquamous NSCLC.

124. The method according to any one of embodiments 114 to 123,

wherein the dosing regimen includes an induction phase comprising 4 dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent include each dosing cycle of the induction phase. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, administered on day 1 of

125. The method of embodiment 124,

wherein the dosing regimen comprises a maintenance phase after the induction phase, wherein the maintenance phase includes one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the non-platinum-based chemotherapeutic agent are the maintenance phases. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, administered on Day 1 of each dosing cycle of the phase.

126. The method of embodiment 125,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said one or more dosing cycles of said maintenance phase do not comprise administration of said platinum-based chemotherapeutic agent.

127. The method according to any one of embodiments 114 to 126,

wherein said platinum-based chemotherapeutic agent is carboplatin or cisplatin and said non-platinum-based chemotherapeutic agent is pemetrexed.

128. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with advanced nonsquamous NSCLC, comprising:

wherein the treatment comprises the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising four 21-day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed; , wherein said tiragolumab is formulated for administration of a dose of about 600 mg every 3 weeks, said atezolizumab is formulated for administration of a dose of about 1200 mg every 3 weeks, and said carboplatin is formulated for administration of a dose of about every 3 weeks. Administered at a dose sufficient to achieve AUC=5 mg/ml/min, or the cisplatin is formulated for administration of a 75 mg/m2 dose every 3 weeks, and the pemetrexed is administered in each of 4 21 day dosing cycles. tiragolumab and atezolizumab, formulated for administration at a dose of about 500 mg/m2 every 3 weeks on day 1 of

129. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with advanced nonsquamous NSCLC,

The treatment is:

(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 4 cycles of induction dosing for pemetrexed at a dose of about 500 mg/m2 per week; and

(ii) at one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m 2 every 3 weeks use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one 21-day dosing cycle of said maintenance phase does not comprise administration of said carboplatin;

wherein the subject or population of subjects has not received prior systemic therapy for advanced nonsquamous NSCLC.

130. Tiragolumab and atezolizumab for use in a method of treating a subject with advanced nonsquamous NSCLC,

The treatment is:

(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 4 cycles of induction dosing for pemetrexed at a dose of about 500 mg/m2 per week; and

(ii) at one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m 2 every 3 weeks use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one 21-day dosing cycle of said maintenance phase does not comprise administration of said carboplatin;

wherein the subject has never received prior systemic therapy for advanced nonsquamous NSCLC.

131. Tiragolumab and atezolizumab for use in a method of treating a subject with advanced nonsquamous NSCLC,

wherein the treatment comprises the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising four 21-day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed; , wherein the tiragolumab is formulated for administration at a dose of about 600 mg every 3 weeks, the atezolizumab is formulated for administration at a dose of about 1200 mg every 3 weeks, and the cisplatin is at a dose of 75 mg/m2 tiragolumab and atezolizumab, wherein the pemetrexed is formulated for administration of a dose of about 500 mg/m2 on day 1 of each of four 21 day dosing cycles.

132. The method according to any one of embodiments 114 to 131,

wherein said treatment prolongs PFS of said subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. The method according to any one of embodiments 114 to 132,

wherein said treatment results in a median PFS in a population of subjects from about 12.5 months to about 14.7 months.

134. The method according to any one of embodiments 114 to 133,

wherein said treatment prolongs the OS of said subject or population of subjects by at least about 5.5 months or about 8.0 months.

135. The method according to any one of embodiments 114 to 134,

wherein said treatment results in a median OS of a population of subjects from about 27.5 months to about 32.0 months.

136. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with resectable lung cancer, comprising:

The treatment comprises one or more administrations of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist on a cycle.

137. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with resectable lung cancer, comprising:

The treatment includes an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 800 mg every 3 weeks, and one or more doses of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist on a cycle.

138. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with lung cancer, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist, wherein at least one of said dosing cycles is 3 Neoadjuvant an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg per week, and a PD-1 axis binding antagonist formulated for administration of a dose of about 80 mg to about 1600 mg every 3 weeks. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use, including as therapy.

139. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with lung cancer, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist, wherein at least one of said dosing cycles is 3 Neoadjuvant an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 800 mg per week, and a PD-1 axis binding antagonist formulated for administration of a dose of about 900 mg to about 1500 mg every 3 weeks. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use, including as therapy.

140. The method of embodiment 138 or embodiment 139,

At least one of said dosing cycles is an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and an anti-TIGIT antagonist antibody formulated for administration of a dose of about 80 mg to about 1600 mg every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the PD-1 axis binding antagonist as neoadjuvant therapy.

141. The method of embodiment 140,

At least one of said dosing cycles is an anti-TIGIT antagonist antibody formulated for administration at a dose of about 500 mg to about 700 mg every 3 weeks, and an anti-TIGIT antagonist antibody formulated for administration of a dose of about 900 mg to about 1500 mg every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the PD-1 axis binding antagonist as neoadjuvant therapy.

142. The method according to any one of embodiments 138 to 141,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is resectable lung cancer.

143. The method according to any one of embodiments 136 to 142,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is early lung cancer.

144. The method according to any one of embodiments 136 to 143,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is stage II, IIIA, or IIIB lung cancer.

145. The method according to any one of embodiments 136 to 144,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormality.

146. The method according to any one of embodiments 136 to 145,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject is eligible for R0 resection for therapeutic purposes.

147. The method according to any one of embodiments 136 to 146,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject has never received prior therapy for lung cancer.

148. The method of embodiment 147,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said prior therapy is immunotherapy, chemotherapy, or radiotherapy.

149. The method according to any one of embodiments 136 to 148,

wherein said subject is eligible for platinum-based chemotherapy. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

150. The method of any one of embodiments 136 to 149,

wherein said first dosing cycle is initiated prior to surgery.

151. The method of embodiment 150,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein at least 1, 2, 3, or 4 dosing cycles are completed prior to said surgery.

152. The method of embodiment 150 or embodiment 151,

Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, wherein 4 dosing cycles are completed prior to said surgery.

153. The method according to any one of embodiments 136 to 152,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein at least one dosing cycle is initiated after surgery.

154. The method of embodiment 153,

Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, wherein 16 dosing cycles are completed after said surgery.

155. The method of any one of embodiments 150 to 154,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the operation is lobectomy, lobectomy, bilobectomy, or pneumonectomy.

156. The method according to any one of embodiments 136 to 155,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the method further comprises radiation therapy.

157. The method of embodiment 156,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the radiation therapy is postoperative radiation therapy.

158. The method according to any one of embodiments 136 to 157,

wherein said treatment further comprises the use of one or more chemotherapeutic agents.

159. The method of embodiment 158,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said one or more chemotherapeutic agents are administered post-surgery.

160. The method of embodiment 159,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said at least one chemotherapeutic agent is administered in 4 dosing cycles after said surgery.

161. The method according to any one of embodiments 158 to 160,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

162. The method of embodiment 161,

(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;

(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is gemcitabine;

(c) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel;

(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or

(e) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said platinum-based chemotherapeutic agent is cisplatin and said non-platinum-based chemotherapeutic agent is gemcitabine.

163. The method according to any one of embodiments 136 to 162,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment results in an increase in the major pathological response rate (MPR) compared to a baseline MPR rate.

164. The method of embodiment 163,

The reference MPR ratio is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, which is the MPR ratio of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

165. The method of any one of embodiments 136 to 164,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment results in a pathological complete response (pCR) and/or an increase in the pCR ratio compared to a reference pCR ratio.

166. The method of embodiment 165,

The reference pCR ratio is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, which is the pCR ratio of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

167. The method according to any one of embodiments 136 to 166,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment results in an increase in event-free survival (EFS) compared to baseline EFS time.

168. The method of embodiment 167,

The reference EFS time is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, which is the EFS time of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

169. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with resectable lung cancer, comprising:

The treatment includes one or more administrations of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 600 mg every 3 weeks, and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist on a cycle.

170. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with lung cancer, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist, wherein at least one of said dosing cycles is 3 Neoadjuvant an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 600 mg per week, and a PD-1 axis binding antagonist formulated for administration of a dose of about 80 mg to about 1600 mg every 3 weeks. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use, including as therapy.

171. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with resectable lung cancer, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent. and the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist with at least one dosing cycle of a non-platinum based chemotherapeutic agent.

172. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with lung cancer, comprising:

The treatment comprises the use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent. wherein at least one dosing cycle is an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, for administration of a dose of about 80 mg to about 1600 mg every 3 weeks An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising a formulated PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent as neoadjuvant therapy.

173. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with resectable lung cancer, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and: (a) (i) a platinum-based chemotherapeutic agent at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m2 every 3 weeks; and (b) (i) an antimetabolite at a dose of about 500 mg/m2 every 3 weeks or about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle; or (ii) one or more dosing cycles of the taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every 3 weeks, using said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

174. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with lung cancer,

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist with one or more dosing cycles of anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and non-platinum-based chemotherapeutic agent wherein at least one of said dosing cycles comprises: (a) an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 600 mg every 3 weeks; (b) a PD-1 axis binding antagonist formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks; (c) at (i) a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m2 every 3 weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) about 500 mg/m2 every 3 weeks or about 1000 mg/m2 on days 1 and 8 of each dosing cycle or an antimetabolite at a dose of about 1250 mg/m2; or (ii) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every 3 weeks; An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment is neoadjuvant therapy.

175. Tiragolumab and atezolizumab for use in a method of treating a subject with resectable lung cancer, comprising:

The treatment includes tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and:

(a)

(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or

(ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks; and

(b)

(i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks or gemcitabine at a dose of about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle; or

(ii) one or more dosing cycles of paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks, said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist. Lumab and Atezolizumab

176. Tiragolumab and atezolizumab for use in a method of treating a subject having lung cancer,

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist with one or more dosing cycles of tiragolumab, atezolizumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein said At least one dosing cycle includes: (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks; (b) atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks; (c) a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent is: (i) a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks of carboplatin; or (ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks or about 1000 on days 1 and 8 of each dosing cycle gemcitabine at a dose of mg/m2 or about 1250 mg/m2; or (ii) paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; Tiragolumab and atezolizumab for use, wherein said treatment is neoadjuvant treatment.

177. Tiragolumab and atezolizumab for use in a method of treating a subject with nonsquamous NSCLC,

wherein said treatment comprises use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab, wherein: (a) at least one dosing cycle is every 3 weeks tiragolumab formulated for administration of a dose of about 600 mg and atezolizumab formulated for administration of a dose of 1200 mg every 3 weeks as neoadjuvant treatment; (b) at least one dosing cycle comprising tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks and atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks as adjuvant treatment tiragolumab and atezolizumab for use.

178. A tiragolumab antibody and atezolizumab for use in a method of treating a subject with nonsquamous NSCLC, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one dosing cycle is neoadjuvant treatment and: (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks; (b) atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a targeted dose to achieve an AUC of 5 mg/mL/min every 3 weeks and pemetrexed at a dose of about 500 mg/m2 every 3 weeks; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and pemetrex at a dose of about 500 mg/m2 every 3 weeks; (II) tiragolumab formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and for administration of a dose of about 80 mg to about 1600 mg every 3 weeks, at least once in said dosing cycle Tiragolumab and atezolizumab for use comprising atezolizumab formulated as adjuvant treatment.

179. Tiragolumab and atezolizumab for use in a method of treating a subject with lung cancer,

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one dosing cycle is neoadjuvant treatment and: (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks; (b) atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles is formulated for administration of a dose of about 30 mg to about 1200 mg every 3 weeks and a dose of about 80 mg to about 1600 mg every 3 weeks. tiragolumab and atezolizumab for use comprising as adjuvant treatment atezolizumab.

180. Tiragolumab and atezolizumab for use in a method of treating a subject with lung cancer,

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist with one or more dosing cycles of tiragolumab and atezolizumab, wherein:

(I) at least one dosing cycle is neoadjuvant treatment:

(a) tiragolumab formulated for administration at a dose of about 1200 mg every 3 weeks;

(b) atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and

(c)

(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle;

(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or

(iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks or gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; and

(II) at least one of said dosing cycles is formulated for administration of a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg every 3 weeks. tiragolumab and atezolizumab for use comprising as adjuvant treatment atezolizumab.

181. Tiragolumab and atezolizumab for use in a method of treating a subject with lung cancer,

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one dosing cycle is neoadjuvant treatment and: (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks; (b) atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles as adjuvant treatment with tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks and atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks. tiragolumab and atezolizumab for use.

182. Tiragolumab and atezolizumab for use in a method of treating a subject with resectable squamous NSCLC,

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one dosing cycle is neoadjuvant treatment and: (a) tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks; (b) atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles as adjuvant treatment with tiragolumab formulated for administration at a dose of about 600 mg every 3 weeks and atezolizumab formulated for administration at a dose of about 1200 mg every 3 weeks. tiragolumab and atezolizumab for use.

183. The method according to any one of embodiments 136 to 182,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable protein expression level of PD-L1 is determined by IHC analysis comprising staining with the anti-PD-L1 antibody SP263.

184. The method of embodiment 183,

wherein the detectable protein expression level of PD-L1 is at least 50% of a fraction of PD-L1 positive tumor cells.

185. The method of any one of embodiments 73, 114 to 121, and embodiments 136 to 184,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the lung cancer is NSCLC.

186. The method of embodiment 185,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said NSCLC is squamous NSCLC.

187. The method of embodiment 185,

wherein said NSCLC is non-squamous NSCLC.

188. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is cervical cancer.

189. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1,

The treatment comprises one or more administrations of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist on a cycle.

190. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1,

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg to about 800 mg every 3 weeks. wherein said anti-PD-1 axis binding antagonist is in a dose of about 900 mg to about 1500 mg every 3 weeks.

191. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of selecting a therapy for a subject with cervical cancer, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) an anti-TIGIT antagonist formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 An anti TIGIT antagonist antibody for use, comprising selecting a regimen comprising one or more dosing cycles of the antibody and one or more dosing cycles of the PD-1 axis binding antagonist formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks. and PD-1 axis binding antagonists.

192. The method of any one of embodiments 189 to 191,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cervical cancer is squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma.

193. The method according to any one of embodiments 189 to 191,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cervical cancer is stage 4B, metastatic, recurrent, or persistent.

194. The method according to any one of embodiments 189 to 193,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cervical cancer is metastatic and/or recurrent PD-L1-positive cervical cancer.

195. The method of any one of embodiments 189 to 194,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects have received at least one line of prior therapy.

196. The method according to any one of embodiments 189 to 195,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject or subjects have received two lines of prior therapy.

197. The method according to any one of embodiments 189 to 196,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects have received more than two lines of prior therapy.

198. The method according to any one of embodiments 189 to 194,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects have not received prior therapy.

199. The method according to any one of embodiments 195 to 198,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said prior therapy is chemotherapy, surgery, and/or radiotherapy.

200. The method according to any one of embodiments 189 and 192 to 199,

wherein the treatment elicits a clinical response, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

201. The method of embodiment 200,

wherein the clinical response is an increase in the objective response rate (ORR) of the subject population as compared to a baseline ORR.

202. The method of embodiment 201,

wherein said reference ORR is the median ORR of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody and an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

203. The method of embodiment 200,

wherein said reference ORR is at least about 14.6% to about 26%.

204. The method of embodiment 200,

wherein the clinical response is CR or PR.

205. The method of any one of embodiments 200 to 204,

The clinical response is an increase in progression-free survival (PFS) of the subject compared to a baseline PFS time, an increase in the duration of response (DOR) in the subject compared to a baseline DOR time, or an increase in the subject's progression-free survival (DOR) compared to a baseline OS time. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, which is an increase in overall survival (OS).

206. The method of embodiment 205,

(a) said baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline DOR time is the median DOR time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said baseline OS time is the median OS time of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody.

207. An anti TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject having cervical cancer having a detectable expression level of PD-L1,

The treatment includes an anti TIGIT antagonist antibody formulated for administration at a dose of 600 mg every 3 weeks, and at least one dosing cycle of atezolizumab at a dose of 1200 mg every 3 weeks, the anti TIGIT antagonist antibody and the PD-1 axis binding Anti-TIGIT antagonist antibodies and atezolizumab for use, including the use of antagonists.

208. An anti TIGIT antagonist antibody and atezolizumab for use in a method of identifying a subject with cervical cancer likely to benefit from a therapy comprising at least one dosing cycle of the anti TIGIT antagonist antibody and atezolizumab,

The method is:

(a) providing a tumor sample from the subject;

(a) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(c) an anti-TIGIT antagonist antibody formulated for administration of a 600 mg dose every 3 weeks and atezolizumab formulated for administration of a 1200 mg dose every 3 weeks based on PD-L1 expression on detected tumor cells. An anti TIGIT antagonist antibody and atezolizumab for use, comprising identifying said subject as likely to benefit from a therapy comprising one or more dosing cycles.

209. An anti TIGIT antagonist antibody and atezolizumab for use in a method of selecting a therapy for a subject with cervical cancer, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) an anti TIGIT antagonist antibody formulated for administration at a dose of 600 mg every 3 weeks and 1200 every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 An anti TIGIT antagonist antibody and atezolizumab for use comprising selecting a regimen comprising one or more dosing cycles of atezolizumab formulated for administration of a mg dose.

210. Tiragolumab and atezolizumab for use in a method of treating a subject having cervical cancer having a detectable expression level of PD-L1,

wherein said treatment comprises the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; Tiragolumab and atezolizumab for use.

211. Tiragolumab and atezolizumab for use in a method of treating a subject having cervical cancer,

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) 1 of tiragolumab formulated for administration of a 600 mg dose every 3 weeks and atezolizumab formulated for administration of a 1200 mg dose every 3 weeks based on PD-L1 expression on detected tumor cells Tiragolumab and atezolizumab for use, comprising identifying said subject as likely to benefit from a therapy comprising more than one dosing cycle.

(d) administering the therapy to the identified subject.

212. Tiragolumab and atezolizumab for use in a method of selecting a therapy for a subject with cervical cancer,

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) tiragolumab formulated for administration at a dose of 600 mg every 3 weeks and 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 Tiragolumab and atezolizumab for use, comprising selecting a regimen comprising one or more dosing cycles of atezolizumab formulated for administration of a dose.

213. Tiragolumab and atezolizumab for use in a method of treating a subject having metastatic and/or recurrent cervical cancer,

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) 1 of tiragolumab formulated for administration of a 600 mg dose every 3 weeks and atezolizumab formulated for administration of a 1200 mg dose every 3 weeks based on PD-L1 expression on detected tumor cells identifying the subject as likely to benefit from a therapy comprising more than one dosing cycle; and

(d) tiragolumab and atezolizumab for use, comprising administering said therapy to the identified subject.

214. Tiragolumab and atezolizumab for use in a method of selecting a therapy for a subject with metastatic and/or recurrent cervical cancer,

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) tiragolumab formulated for administration at a dose of 600 mg every 3 weeks and 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 Tiragolumab and atezolizumab for use, comprising selecting a regimen comprising one or more dosing cycles of atezolizumab formulated for administration of a dose.

215. The method of any one of embodiments 189 to 214,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject is identified as likely to benefit from treatment based on PD-L1 expression on the detected tumor cells.

216. The method according to any one of embodiments 189 to 215,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-L1 expression level is detected using an anti-PD-L1 antibody SP263.

217. The method according to any one of embodiments 189 to 216,

wherein the detectable expression level of PD-L1 is at least 5% of tumor associated immune cells (TIC) in a sample from said subject.

218. The method of any one of embodiments 189 to 215,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-L1 expression level is detected using anti-PD-L1 antibody 22C3.

219. The method of any one of embodiments 189 to 216,

wherein said detectable expression level of PD-L1 has a composite positive score (CPS) of 1 or greater in a sample from said subject.

220. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is breast cancer.

221. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having breast cancer,

The treatment includes one or more doses of tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and nap-paclitaxel at a dose of about 100 mg/m2 of 3 weeks on/1 week off. Tiragolumab and atezolizumab for use comprising the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising a dosing cycle.

222. The method of embodiment 220 or embodiment 221,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the breast cancer is triple negative breast cancer (TNBC).

223. The method of embodiment 222,

wherein said TNBC is resectable locally advanced or metastatic TNBC.

224. The method of any one of embodiments 220 to 223,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject has not received prior systemic therapy for metastatic breast cancer.

225. The method of any one of embodiments 220-224,

wherein said treatment elicits an ORR in at least about 53% to about 67.5% of the subject population.

226. The method of any one of embodiments 222 to 225,

wherein said treatment elicits a median OS of a population of subjects of about 25.0 months of age.

227. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with early triple negative breast cancer (eTNBC), comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one dosing cycle, wherein said anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every two weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use formulated for administration, wherein said PD-1 axis binding antagonist is in a dose of about 20 mg to about 1600 mg every two weeks.

228. The method of embodiment 227,

wherein said treatment further comprises the use of one or more chemotherapeutic agents.

229. The method of embodiment 228,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The method of embodiment 227,

The method comprises (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, further comprising one or more dosing cycles of

231. The method of embodiment 229 or embodiment 230,

wherein said alkylating agent is cyclophosphamide.

232. The method of embodiment 231,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cyclophosphamide is formulated for administration at a dose of about 600 mg/m2.

233. The embodiment of any of embodiments 227-229, embodiment 231, and embodiment 232,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment further comprises the use of G-CSF or GM-CSF.

234. The method of embodiment 230 or embodiment 233,

wherein said G-CSF is pegfilgrastim or filgrastim, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

235. The method of embodiment 234,

wherein the G-CSF is pegfilgrastim, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

236. The method of embodiment 235,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said pegfilgrastim is formulated for administration in a dose of about 6 mg.

237. The embodiment of any one of embodiments 228, 229, and embodiments 231 to 236,

wherein said treatment further comprises use of said one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF.

238. The embodiment of any one of embodiments 228, 229, and embodiments 231 to 237,

wherein said one or more chemotherapeutic agents and/or G-CSF or GM-CSF are administered once weekly, once every two weeks, or once every three weeks, respectively. binding antagonists.

239. The method of any one of embodiments 229 to 238,

The platinum-based chemotherapeutic agent is administered every 3 weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every 2 weeks, the alkylating agent is administered every 2 weeks, and the G-CSF or GM- Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, CSF administered every two weeks.

240. The method of any one of embodiments 229 to 239,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said taxane or said taxane and said platinum-based chemotherapeutic agent are administered during the first 12 weeks of said dosing regimen.

241. The method of any one of embodiments 229-240,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said topoisomerase II inhibitor, said alkylating agent, and said G-CSF or GM-CSF are administered for 13 to 19 weeks of a dosing regimen.

242. The method according to any one of embodiments 227 to 241,

Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, the total duration of the dosing regimen is 19 weeks.

243. The method of any one of embodiments 227 to 242,

wherein the method is neoadjuvant therapy, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

244. The method according to any one of embodiments 227 to 243,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein surgery is performed after said dosing regimen.

245. The method of embodiment 244,

wherein said surgery is performed between 2 and 6 weeks after the last dose of said dosing regimen.

246. The method of embodiment 244 or embodiment 245,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the surgery comprises a mastectomy.

247. The method according to any one of embodiments 244 to 246,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said surgery comprises axillary lymph node surgery.

248. The method of any one of embodiments 229 to 247,

wherein the topoisomerase II inhibitor is doxorubicin, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

249. The method according to any one of embodiments 229 to 247,

wherein said taxane is nap-paclitaxel, said platinum-based chemotherapeutic agent is carboplatin, and said topoisomerase II inhibitor is doxorubicin.

250. The method of embodiment 248 or embodiment 249,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said doxorubicin is formulated for administration at a dose of about 60 mg/m2.

251. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with eTNBC, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every 2 weeks, a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every 2 weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or comprising the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising GM-CSF,

wherein said method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

252. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with eTNBC, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every 2 weeks, a PD-L1 binding antagonist at a dose of about 600 mg to about 1200 mg every 2 weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or comprising the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising GM-CSF,

wherein said method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

253. An anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody for use in a method of treating a subject with eTNBC, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every two weeks, an anti-PD-L1 antagonist antibody formulated for administration of a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or comprising the use of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a dosing regimen comprising GM-CSF,

wherein said method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

254. A tiragolumab and an anti-PD-L1 antagonist antibody for use in a method of treating a subject with eTNBC, comprising:

The treatment comprises tiragolumab at a dose of about 300 mg to about 600 mg every two weeks, an anti-PD-L1 antagonist antibody formulated for administration of a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or comprising the use of an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody in a dosing regimen comprising GM-CSF,

wherein said method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

255. An anti TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with eTNBC,

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 600 mg every 2 weeks, atezolizumab at a dose of about 600 mg to about 1200 mg every 2 weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or comprising the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising GM-CSF,

wherein said method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

256. Tiragolumab and atezolizumab for use in a method of treating a subject with eTNBC,

The treatment includes tiragolumab at a dose of about 300 mg to about 600 mg every 2 weeks, atezolizumab at a dose of about 600 mg to about 1200 mg every 2 weeks, and:

(a)

(i) nap-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen CSF; or

(b)

(i) nap-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen comprising the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising CSF,

tiragolumab and atezolizumab for use, wherein said method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

257. Tiragolumab and atezolizumab for use in a method of treating a subject with eTNBC,

The treatment includes tiragolumab at a dose of about 420 mg every 2 weeks, atezolizumab at a dose of about 840 mg every 2 weeks, and:

(a)

(i) nap-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen CSF; or

(b)

(i) nap-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen comprising the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising CSF,

tiragolumab and atezolizumab for use, wherein said method further comprises surgery between 2 and 6 weeks after the last dose of said dosing regimen.

258. The method of any one of embodiments 220 to 257,

Anti-TIGIT antagonist antibody and PD-1 axis for use, wherein detectable protein expression level of PD-L1 is determined in a tumor sample from said subject determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142 binding antagonists.

259. The method of embodiment 258,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC) in the tumor sample is at least 1%.

260. The method according to any one of embodiments 227 to 259,

wherein said eTNBC is represented as T2-4d TNBC, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

261. The method according to any one of embodiments 227 to 260,

wherein said eTNBC is presented as cT2-cT4, cN0-cN3, and cM0 TNBC.

262. The method of any one of embodiments 227 to 261,

wherein the subject has not previously been treated for eTNBC, an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

263. The method according to any one of embodiments 227 to 262,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment elicits a pathological complete response (pCR).

264. The method of any one of embodiments 227 to 263,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment results in an increase in overall survival (OS) or event-free survival (EFS).

265. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is head and neck cancer.

266. The method of embodiment 265,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said head and neck cancer is squamous cell carcinoma (SCCHN) of said head and neck.

267. Use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1,

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein said anti-PD-1 axis binding antagonist is in a dose of about 80 mg to about 1600 mg every 3 weeks.

268. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1,

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg to about 800 mg every 3 weeks. wherein said anti-PD-1 axis binding antagonist is in a dose of about 900 mg to about 1500 mg every 3 weeks.

269. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of selecting a therapy for a subject or population of subjects with SCCHN,

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and 3 weeks based on PD-L1 expression detected for said subject or population of subjects having a detectable expression level of PD-L1 Anti-TIGIT antagonist antibody for use and PD-1 axis binding, comprising selecting a regimen comprising one or more dosing cycles of the anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg per time. antagonist.

270. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1, the method comprising:

The treatment comprises the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is formulated for administration at a dose of about 600 mg every 3 weeks and atezolizumab is 1200 mg every 3 weeks. tiragolumab and atezolizumab for use.

271. The method according to any one of embodiments 267 to 270,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein said subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

272. The method of any one of embodiments 266 to 271,

wherein said SSCHN is human papillomavirus (HPV) positive.

273. The method according to any one of embodiments 266 to 272,

wherein the SSCHN is HPV negative, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

274. The method of embodiment 272 or embodiment 273,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein HPV status is determined by p16 IHC, in situ hybridization, or PCR.

275. The method according to any one of embodiments 266 to 274,

wherein said SCCHN is recurrent and/or metastatic SCCHN.

276. The method according to any one of embodiments 265 to 275,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects have not received prior therapy.

277. The method of embodiment 276,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said prior therapy is prior systemic therapy for recurrent and/or metastatic disease.

278. The embodiment of any one of embodiments 265-268 and embodiments 270-277,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment results in CR or PR.

279. The method according to any one of embodiments 265 to 268 and 270 to 277,

wherein said treatment results in an increase in objective response rate (ORR) in said subject population compared to a baseline ORR.

280. The method of embodiment 279,

wherein said reference ORR is the median ORR of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody and an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

281. The method of embodiment 279 or embodiment 280,

wherein said reference ORR is at least about 19% to about 36%.

282. The method of any one of embodiments 265-268 and 270-281,

wherein the treatment is associated with an increase in progression-free survival (PFS) of the subject or subject population as compared to a baseline PFS time, an increase in the duration of response (DOR) of the subject or subject population compared to a baseline DOR time, or a baseline OS time and An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, as compared to cause an increase in overall survival (OS) of said subject or population of subjects.

283. The method of embodiment 282,

(a) said baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline DOR time is the median DOR time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said baseline OS time is the median OS time of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody.

284. The method of embodiment 282,

wherein said reference DOR time is at least about 6.7 months to about 23.4 months.

285. The method of embodiment 282,

wherein said baseline OS time is at least about 11.6 months to about 14.9 months.

286. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with SCCHN having a detectable expression level of PD-L1, comprising:

wherein said treatment comprises the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist with one or more dosing cycles of said PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, said anti TIGIT An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks.

287. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with SCCHN having a detectable expression level of PD-L1, comprising:

wherein said treatment comprises the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks, wherein said anti TIGIT antagonist antibody is 3 An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use formulated for administration of a dose of about 600 mg per week.

288. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with SCCHN having a detectable expression level of PD-L1,

wherein said treatment comprises the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles of a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, wherein said anti TIGIT antagonist An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks.

289. Tiragolumab and atezolizumab for use in a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

The treatment includes an anti-TIGIT antagonist antibody and the PD-1 axis in one or more dosing cycles of atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks. Tiragolumab and atezolizumab for use, including the use of binding antagonists.

290. Tiragolumab and atezolizumab for use in a method of treating a subject having SCCHN having a detectable expression level of PD-L1,

wherein said treatment comprises the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; Tiragolumab and atezolizumab for use.

291. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) administering to the subject a dose of about 80 mg to about 1600 mg of the PD-1 axis binding antagonist every 3 weeks and a dose of about 30 mg to about 1200 mg of an anti TIGIT antagonist antibody formulated for administration every 3 weeks. identifying as a person likely to benefit from a therapy comprising more than one dosing cycle; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

292. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) administering the subject to a regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks. confirming as; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

293. Tiragolumab and atezolizumab for use in a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) subjecting the subject to one or more dosing cycles of atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks. identifying as a potential person; and

(d) tiragolumab and atezolizumab for use, comprising administering said therapy to an identified subject having a detectable expression level of PD-L1.

294. Tiragolumab and atezolizumab for use in a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks. ; and

(d) tiragolumab and atezolizumab for use, comprising administering said therapy to an identified subject having a detectable expression level of PD-L1.

295. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of selecting a therapy for a subject with SCCHN, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and about 30 every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising selecting a regimen comprising one or more dosing cycles of the anti-TIGIT antagonist antibody formulated for administration of a dose of mg to about 1200 mg.

296. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of selecting a therapy for a subject with SCCHN, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) administering a dose of about 1200 mg of a PD-1 axis binding antagonist every 3 weeks and a dose of about 600 mg every 3 weeks based on detected PD-L1 expression for said subject having a detectable expression level of PD-L1 An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising selecting a regimen comprising one or more dosing cycles of the anti-TIGIT antagonist antibody formulated for use.

297. Tiragolumab and atezolizumab for use in a method of selecting a therapy for a subject with SCCHN,

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and about 30 mg to about every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 Tiragolumab and atezolizumab for use, comprising selecting a regimen comprising one or more dosing cycles of tiragolumab at a dose of 1200 mg.

298. Tiragolumab and atezolizumab for use in a method of selecting a therapy for a subject with SCCHN,

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 Tiragolumab and atezolizumab for use, comprising selecting a regimen comprising one or more dosing cycles.

299. The method according to any one of embodiments 267 to 298,

wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1 determined by immunohistochemical (IHC) analysis comprising the step of staining with anti-PD-L1 antibody SP263, an anti-TIGIT antagonist for use Antibodies and PD-1 axis binding antagonists.

300. The method of embodiment 299,

The detectable protein expression level of PD-L1 is in the tumor sample:

(a) at least 5%;

(b) at least 5% and less than 20%; or

(c) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein at least 20% tumor-associated immune cells (TIC).

301. One or more dosing cycles of the PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of identifying a subject having SCCHN as a person likely to benefit from a therapy comprising:

The method comprises detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the protein of PD-L1 has a TIC of at least 5%. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the expression level identifies the subject as likely to benefit from the therapy.

302. One or more dosing cycles of the PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of identifying a subject having SCCHN as a person likely to benefit from a therapy comprising:

The method comprises detecting the protein expression level of PD-L1 in a tumor sample from the subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the PD-L1 TIC is greater than or equal to 5% and less than 20%. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the protein expression level of L1 identifies the subject as likely to benefit from the therapy.

303. One or more dosing cycles of the PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of identifying a subject having SCCHN as a person likely to benefit from a therapy comprising:

The method comprises detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the protein of PD-L1 has a TIC of at least 20%. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the expression level identifies the subject as likely to benefit from the therapy.

304. The method of any one of embodiments 301 to 303,

wherein said subject is identified as likely to benefit from said therapy and said method further comprises administering said therapy to said subject.

305. The method of any one of embodiments 301 to 304,

wherein said TIC is determined using a Ventana SP263 IHC assay.

306. The method of any one of embodiments 267 to 305,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or population of subjects is identified as likely to benefit from a treatment based on PD-L1 expression on a detected tumor cell.

307. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is liver cancer.

308. The method of embodiment 307,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the liver cancer is hepatocellular carcinoma (HCC).

309. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having hepatocellular carcinoma (HCC), comprising:

wherein said treatment comprises use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti TIGIT antagonist antibody is formulated for administration and is said PD-1 axis binding antagonist, wherein An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or population of subjects has not received prior systemic therapy for HCC.

310. The method of embodiment 309,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the treatment further comprises the use of a VEGF antagonist.

311. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having HCC, comprising:

wherein said treatment comprises the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist with one or more dosing cycles of anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, and VEGF antagonist, anti TIGIT antagonist antibody for use and PD-1 axis binding antagonists.

312. The method of embodiment 310 and embodiment 311,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the VEGF antagonist is formulated for administration at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks.

313. The method of any one of embodiments 309 to 312,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks.

314. The method of embodiment 313,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 800 mg every 3 weeks.

315. The method of any one of embodiments 309 to 314,

wherein said anti TIGIT antagonist antibody is formulated for administration at a dose of about 600 mg every 3 weeks.

316. The method of any one of embodiments 309 to 315,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks.

317. The method of any one of embodiments 309 to 316,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 900 mg to about 1500 mg every 3 weeks.

318. The method of embodiment 310 or embodiment 311,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the VEGF antagonist is formulated for administration at a dose of about 1 mg/kg to about 20 mg/kg every two weeks.

319. The method of embodiment 318,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the VEGF antagonist is formulated for administration at a dose of about 5 mg/kg to about 10 mg/kg every two weeks.

320. The method of embodiment 319,

wherein the VEGF antagonist is formulated for administration at a dose of about 5 mg/kg, about 7.5 mg/kg, or about 10 mg/kg every two weeks.

321. The embodiment of any one of embodiments 309 to 311 and embodiments 318 to 320,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti TIGIT antagonist antibody is formulated for administration at a dose of about 10 mg to about 1000 mg every two weeks.

322. The embodiment of any one of embodiments 309 to 311 and embodiments 318 to 321,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 20 mg to about 1600 mg every two weeks.

323. according to embodiment 309 to embodiment 311,

wherein said anti TIGIT antagonist antibody is formulated for administration at a dose of about 200 mg to about 2000 mg every 4 weeks.

324. The method according to any one of embodiments 309 to 311 and 323,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 2000 mg every 4 weeks.

325. The embodiment of any one of embodiments 309 to 311, 323, and 324,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 1400 mg to about 2000 mg every 4 weeks.

326. The method of any one of embodiments 309 to 325,

wherein said HCC is locally advanced or metastatic HCC.

327. The method of any one of embodiments 309 to 326,

wherein said HCC is unresectable HCC.

328. The method of any one of embodiments 309 to 327,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects is determined to have adequate liver function.

329. The method of embodiment 328,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said appropriate liver function is characterized as Child-Pugh class A.

330. The method of any one of embodiments 309 to 329,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject or HCC tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

331. The method of any one of embodiments 309 to 330,

wherein the method comprises administering to the subject or population of subjects at least 4 dosing cycles.

332. The method of embodiment 331,

wherein the method comprises administering to the subject or population of subjects at least 16 dosing cycles.

333. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having HCC,

The treatment includes one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and bevacizumab at a dose of about 15 mg/kg every 3 weeks with one or more dosing cycles of the anti-TIGIT antagonist. Tiragolumab and atezolizumab for use, comprising the use of antibodies and PD-1 axis binding antagonists.

334. The method of any one of embodiments 311 to 333,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects has not received prior systemic treatment for HCC.

335. The method of any one of embodiments 309 to 334,

wherein said treatment results in a median PFS in the subject population of at least about 5.6 months to at least about 6.83 months.

336. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is bladder cancer.

337. The method of embodiment 336,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said bladder cancer is muscle invasive bladder cancer (MIBC).

338. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC,

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, wherein the subject is ineligible for treatment with a platinum-based chemotherapeutic agent. TIGIT antagonist antibodies and PD-1 axis binding antagonists.

339. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC,

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg to about 800 mg every 3 weeks. wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 900 mg to about 1500 mg every 3 weeks, wherein the subject is ineligible for treatment with a platinum-based chemotherapeutic agent. TIGIT antagonist antibodies and PD-1 axis binding antagonists.

340. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, wherein said treatment is perioperative treatment. Axial bond antagonists.

341. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg to about 800 mg every 3 weeks. wherein said PD-1 axis binding antagonist is in a dose of about 900 mg to about 1500 mg every 3 weeks, wherein said treatment is perioperative treatment.

342. The method of any one of embodiments 338 to 341,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects has a creatinine clearance of less than 60 mL/min.

343. The method of any one of embodiments 338 to 342,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects has a hearing loss of grade 2 or greater.

344. The method of any one of embodiments 338 to 343,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject or subjects has neuropathy of grade 2 or greater.

345. The method of any one of embodiments 338 to 344,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects have refused treatment with a platinum-based chemotherapeutic agent.

346. The method according to any one of embodiments 338 or 342 to 345,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the platinum-based chemotherapeutic agent is cisplatin.

347. The method of any one of embodiments 338 to 346,

The MIBC is an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, capable of surgery.

348. The method of embodiment 347,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the method further comprises surgery.

349. The method of embodiment 348,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein at least one dosing cycle is initiated prior to said surgery.

350. The method of embodiment 348 or embodiment 349,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein at least one, two, or three dosing cycles are completed prior to said surgery.

351. The method of any one of embodiments 348 to 350,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein at least one dosing cycle is initiated between 4 and 6 weeks post-surgery.

352. The method of embodiment 351,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein 1 to 17 dosing cycles are completed after said surgery.

353. The method of any one of embodiments 348 to 352,

wherein the surgery is cystectomy and/or lymphadenectomy.

354. The method of any one of embodiments 338 to 353,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment elicits a pathological complete response (pCR).

355. The method of any one of embodiments 338 to 354,

wherein the treatment is an increase in relapse-free survival (RFS) of the subject or subjects as compared to a baseline RFS time, an increase in the event-free survival (EFS) of the subject or subjects compared to a baseline EFS time, or an increase in the event-free survival (EFS) of the subject or subjects as compared to a baseline OS time. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, which cause an increase in OS in the subject or subjects.

356. The method of embodiment 355,

(a) said baseline RFS time is the median RFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline EFS time is the median EFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said baseline OS time is the median OS time of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody.

357. The method of any one of embodiments 338 to 356,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment results in pathological downstaging.

358. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC,

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, wherein the subject is cisplatin ineligible, an anti TIGIT antagonist antibody for use and the PD-1 axis binding antagonists.

359. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein said PD-1 axis binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, wherein said treatment is perioperative treatment. Axial bond antagonists.

360. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein the PD-L1 binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, wherein the subject is cisplatin ineligible, an anti TIGIT antagonist antibody for use and a PD-1 axis binding antagonist.

361. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with MIBC, comprising:

wherein said treatment comprises the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in one or more dosing cycles, wherein said anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. wherein said PD-L1 binding antagonist is formulated for administration at a dose of about 80 mg to about 1600 mg every 3 weeks, wherein said treatment is perioperative treatment. binding antagonists.

362. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with MIBC,

The treatment comprises the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is formulated for administration in a dose of about 30 mg to about 1200 mg every 3 weeks, and atezolizumab is administered in 3 Tiragolumab and atezolizumab for use, wherein the subject is cisplatin ineligible, formulated for administration of a dose of about 80 mg to about 1600 mg per week.

363. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having MIBC,

The treatment comprises the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is formulated for administration in a dose of about 30 mg to about 1200 mg every 3 weeks, and atezolizumab is administered in 3 Tiragolumab and atezolizumab for use, wherein the treatment is perioperative treatment, wherein the treatment is formulated for administration of a dose of about 80 mg to about 1600 mg per week.

364. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with MIBC,

The treatment comprises the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is formulated for administration of a dose of about 600 mg every 3 weeks and atezolizumab is about 1200 every 3 weeks. Tiragolumab and atezolizumab for use, formulated for administration of a mg dose, wherein the subject or subjects are cisplatin ineligible.

365. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having MIBC,

The treatment comprises the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is formulated for administration of a dose of about 600 mg every 3 weeks and atezolizumab is about 1200 every 3 weeks. Tiragolumab and atezolizumab for use, wherein the treatment is perioperative treatment.

366. The method of any one of embodiments 338-365,

wherein said treatment elicits an ORR in at least about 13.4% to about 15% of a subject population.

367. The method of any one of embodiments 338 to 366,

wherein said treatment results in a median OS in the subject population of at least about 7.9 months to about 8.6 months.

368. The method of any one of embodiments 338 to 367,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable protein expression level of PD-L1 is determined by IHC analysis comprising staining with the anti-PD-L1 antibody SP142.

369. The method of embodiment 368,

The detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction in which the proportion of tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC) is 5% or more, anti-TIGIT antagonist antibody and PD for use -1 axis binding antagonists.

370. The method of embodiment 336,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the bladder cancer is urothelial cell carcinoma (UC).

371. The method of embodiment 370,

wherein said UC is metastatic urothelial cell carcinoma (mUC).

372. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with mUC, comprising:

The treatment comprises one or more administrations of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising a cycle.

373. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with mUC, comprising:

The treatment includes an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 800 mg every 3 weeks, and one or more doses of a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising a cycle.

374. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with mUC, comprising:

The treatment comprises one or more administrations of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks. an anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist for use, comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising a cycle, wherein said subject has not received prior cancer immunotherapy binding antagonists.

375. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with mUC, comprising:

The treatment comprises one or more administrations of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist every 3 weeks. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising a cycle, wherein said treatment is a second line treatment.

376. The method of any one of embodiments 372, 372, and 375,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects has not received prior cancer immunotherapy.

377. The method according to any one of embodiments 372 to 374,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said treatment is second-line treatment.

378. The method of any one of embodiments 372 to 377,

wherein said mUC is during or after platinum containing therapy.

379. The method according to any one of embodiments 372 to 378,

The method further comprises administering to the subject or subjects a second dosing regimen after the subject or population of subjects has experienced disease progression or unacceptable toxicity. uniaxial binding antagonists.

380. The method of embodiment 379,

wherein said second dosing regimen comprises at least one dosing cycle of said PD-1 axis binding antagonist and an antibody-drug conjugate (ADC).

381. The method of embodiment 380,

wherein said ADC is (a) enfortumab vedotin or (b) sacituzumab gobitecan.

382. The method of embodiment 381,

(a) enfortumab vedotin is formulated for administration at a weekly dose of 1.25 mg/kg with a 2-week dosing/1 week off, or (b) sacituzumab gobitecan is administered at a 2-week dosing/1 week off An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use formulated for administration at a dose of 10 mg/kg weekly.

383. The method of embodiment 381 or embodiment 382,

(a) enfortumab vedotin is formulated for administration at a dose of 1.25 mg/kg on days 1 and 8 of each 21-day cycle, or (b) sacituzumab gobitecan is administered on days 1 and 8 of each 21-day cycle. Formulated for administration of a dose of 10 mg/kg on days 1 and 8. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

384. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with mUC, comprising:

The treatment comprises one or more dosing cycles of an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks, and a dose of about 80 mg to about 1600 mg of PD-L1 binding antagonist every 3 weeks. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising

385. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with mUC, comprising:

The treatment includes an anti-TIGIT antagonist antibody and Tiragolumab and atezolizumab for use, comprising the use of a PD-1 axis binding antagonist.

386. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with mUC, comprising:

The treatment comprises the use of tiragolumab and atezolizumab in one or more dosing cycles, wherein tiragolumab is formulated for administration at a dose of about 600 mg every 3 weeks and atezolizumab is 1200 mg every 3 weeks. tiragolumab and atezolizumab for use.

387. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with mUC, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a first dosing regimen followed by a second dosing regimen, wherein:

(a) said first dosing regimen is an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks and a dose of about 80 mg to about 1600 mg every 3 weeks. comprising one or more dosing cycles of a PD-1 axis binding antagonist; and

(b) said second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist formulated for administration of a dose of about 80 mg to about 1600 mg every 3 weeks, and (i) Enfortumab Be Dotin is formulated for administration at a weekly dose of 1.25 mg/kg on a 2-week dosing/1 week off, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg on a 2-week dos/week off. formulated for administration, wherein said second dosing regimen is administered to said subject or subject population after said subject or subject population experiences disease progression or unacceptable toxicity during said first dosing regimen. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists.

388. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects with mUC, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a first dosing regimen followed by a second dosing regimen, wherein:

(a) said first dosing regimen comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks and a dose of about 80 mg to about 1600 mg of a PD-L1 binding antagonist every 3 weeks. comprising one or more dosing cycles; and

(b) said second dosing regimen comprises one or more dosing cycles of the PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, (i) Enfortumab vedotin is administered for 2 weeks / is formulated for administration of a weekly dose of 1.25 mg/kg of a week off, or (ii) sacituzumab gobitecan is formulated for administration of a weekly dose of 10 mg/kg of a dose of two weeks of dosing/week off; wherein said second dosing regimen is administered to said subject after said subject experiences disease progression or unacceptable toxicity during said first dosing regimen.

389. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects with mUC, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a first dosing regimen followed by a second dosing regimen, wherein:

(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; and

(b) said second dosing regimen comprises at least one dosing cycle of atezolizumab at a dose of about 1200 mg every 3 weeks, and (i) enfortumab vedotin is administered at 1.25 weekly doses of 2 weeks on/1 week off. is formulated for administration of a mg/kg dose, or (ii) sacituzumab gobitecan is formulated for administration of a weekly 10 mg/kg dose of 2 weeks dosing/1 week off, wherein the second dosing regimen is administered to said subject after said subject experiences disease progression or unacceptable toxicity during said first dosing regimen.

390. The method of any one of embodiments 372 to 389,

wherein said treatment elicits an ORR in at least about 13.4% to at least about 31% of the subject population.

391. The method of any one of embodiments 372 to 390,

wherein said treatment elicits a median OS of a population of subjects from about 7.9 months to about 16.3 months.

392. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is pancreatic cancer.

393. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having pancreatic cancer,

The treatment comprises tiragolumab at a dose of about 420 mg on days 1 and 15 of each 28-day dosing cycle, atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle, each Gemcitabine at a dose of about 1000 mg/m2 on days 1, 8, and 15 of a 28-day dosing cycle, and about 125 mg/m on Days 1, 8, and 15 of each 28-day dosing cycle. Tiragolumab and atezolizumab for use comprising the use of said anti TGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one 28-day dosing cycle of m2 dose of nap-paclitaxel.

394. The method of embodiment 392 or embodiment 393,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

395. The method of embodiment 394,

wherein said PDAC is a metastatic PDAC.

396. The method of any one of embodiments 392 to 395,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects have not received prior systemic therapy for metastatic PDAC.

397. The method of any one of embodiments 392 to 396,

wherein said treatment results in an ORR in at least about 41.7% to about 46.7% of the subject population.

398. The method of any one of embodiments 392 to 397,

wherein said treatment results in an increase in ORR of at least about 20% as compared to treatment comprising gemcitabine and nap-paclitaxel in the absence of anti-TIGIT antagonist antibody and PD-1 axis binding antagonist and anti-TIGIT antagonist antibody and PD- uniaxial binding antagonists.

399. The method of any one of embodiments 392 to 398,

wherein said treatment results in a median PFS in a population of subjects of at least about 5.5 months to about 7 months.

400. The method of any one of embodiments 392 to 399,

wherein said treatment results in a median OS in the subject population of at least about 8.5 months to about 10.6 months.

401. The method of embodiment 72,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the cancer is esophageal cancer.

402. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration of a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 80 mg to about 1600 mg of PD- on Day 1 of each dosing cycle. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one 21 day dosing cycle of said uniaxial binding antagonist .

403. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration of a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of PD- on Day 1 of each dosing cycle. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising the use of said anti TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one 21 day dosing cycle of said uniaxial binding antagonist .

404. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having esophageal cancer,

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration of a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 80 mg to about 1600 mg of PD- on Day 1 of each dosing cycle. comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one 21 day dosing cycle of a uniaxial binding antagonist, wherein said subject is a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapy agent. Zero previously treated, anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

405. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having esophageal cancer,

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300 mg to about 800 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of PD- on Day 1 of each dosing cycle. comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one 21 day dosing cycle of a uniaxial binding antagonist, wherein said subject is a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapy agent. Zero previously treated, anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

406. The method of embodiment 402 or embodiment 403,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject or subjects has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. The method of any one of embodiments 404 to 406,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects experienced disease progression or unacceptable toxicity during said prior treatment.

408. The method of embodiment 402 or embodiment 403,

wherein said 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

409. The method of embodiment 408,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses.

410. The method of any one of embodiments 404 to 409,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the platinum-based chemotherapeutic agent is cisplatin.

411. The method of embodiment 410,

An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, wherein cisplatin is formulated for administration at a dose of about 80 mg/m2 on Day 1 of each dosing cycle.

412. The method of any one of embodiments 404 to 411,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the non-platinum-based chemotherapeutic agent is an antimetabolites.

413. The method of embodiment 412,

wherein said antimetabolite is 5-fluorouracil. Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

414. The method of embodiment 413,

An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, wherein 5-fluorouracil is formulated for administration at a dose of 800 mg/m 2 /24 hour on days 1 to 5 of each 21 day cycle.

415. The method of any one of embodiments 404 to 414,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the esophageal cancer is advanced or metastatic esophageal cancer.

416. The embodiment of any one of embodiments 402, 403, 408, and 409,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or subjects has not received prior treatment for metastatic esophageal cancer.

417. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer,

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle, PD- at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle. A uniaxial binding antagonist, a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on Day 1 of each dosing cycle, and a non-vaccine at a dose of about 800 mg/m2/24 hours on Days 1-5 of each 21-day cycle. and the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising at least one 21 day dosing cycle of a gold-based chemotherapeutic agent, wherein said platinum-based chemotherapeutic agent is administered after 6 doses Anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, omitted from therapy.

418. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer,

The treatment comprises an anti-TIGIT antagonist antibody formulated for administration at a dose of about 600 mg on Day 1 of each dosing cycle, a dose of about 1200 mg of PD-1 axis binding antagonist on Day 1 of each dosing cycle, each dosing cycle. one or more 21-day dosing cycles of cisplatin at a dose of about 80 mg/m2 on Day 1 of an anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist for use comprising the use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a dosing regimen comprising: wherein cisplatin is omitted from said dosing regimen after 6 doses. binding antagonists.

419. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer,

The treatment is tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle, and about 80 mg/m2 on day 1 of each dosing cycle. The anti-TIGIT antagonist antibody in a dosing regimen comprising a dose of cisplatin and one or more 21-day dosing cycles of 5-fluorouracil at a dose of about 800 mg/m2/24 hours on days 1-5 of each 21-day cycle. and use of said PD-1 axis binding antagonist, wherein cisplatin is omitted from said dosing regimen after 6 doses.

420. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer,

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a first dosing regimen and a second dosing regimen, wherein:

(a) said first dosing regimen comprises at least one 21-day dosing cycle of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses; ; and

(b) said second dosing regimen comprises an anti-TIGIT antagonist antibody formulated for administration of a dose of from about 30 mg to about 1200 mg on Day 1 of each dosing cycle and from about 80 mg to about Day 1 of each dosing cycle. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising at least one 21 day dosing cycle of the PD-1 axis binding antagonist at a dose of 1600 mg.

421. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a first dosing regimen and a second dosing regimen, wherein:

(a) said first dosing regimen comprises a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on Day 1 of each dosing cycle and 800 mg/m2/24 hour dose on Days 1-5 of each 21-day cycle. at least one 21-day dosing cycle of a non-platinum-based chemotherapeutic agent, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses; and

(b) said second dosing regimen comprises an anti-TIGIT antagonist antibody formulated for administration of a dose of from about 30 mg to about 1200 mg on Day 1 of each dosing cycle and from about 80 mg to about Day 1 of each dosing cycle. An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising at least one 21 day dosing cycle of the PD-1 axis binding antagonist at a dose of 1600 mg.

422. Tiragolumab and atezolizumab for use in a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer,

wherein said treatment comprises use of said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist in a first dosing regimen and a second dosing regimen, wherein:

(a) said first dosing regimen is cisplatin at a dose of about 80 mg/m2 on day 1 of each dosing cycle and 5-fluoro at a dose of 800 mg/m2/24 hours on days 1-5 of each 21 day cycle one or more 21-day dosing cycles of lauracil, wherein cisplatin is omitted from said dosing regimen after 6 doses; and

(b) said second dosing regimen is one or more 21 day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle tiragolumab and atezolizumab for use, comprising:

423. The method of any one of embodiments 402 to 422,

wherein said treatment elicits an ORR in at least about 14% of the subject population.

424. The method according to any one of embodiments 47 to 423,

The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):

HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);

HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

425. The method of embodiment 424,

The anti-TIGIT antagonist antibody has the following light chain variable region framework regions (FR):

FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);

FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);

FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, further comprising FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

426. The method of embodiment 424,

The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs:

(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;

FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);

FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, further comprising FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

427. The method of embodiment 426,

X1 is E, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

428. The method of embodiment 426,

X1 is Q; an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

429. The method of any one of embodiments 424 to 428,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or

(c) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising a VH domain as in case (a) and a VL domain as in case (b).

430. The method of any one of embodiments 424 to 429,

The anti-TIGIT antagonist antibody is:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and

(b) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19.

431. The embodiment of any one of embodiments 424 to 427, 429, and 430,

The anti-TIGIT antagonist antibody is:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and

(b) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19.

432. The method of any one of embodiments 424 to 427 and embodiments 429 to 431,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and

(b) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use comprising a light chain comprising the amino acid sequence of SEQ ID NO:34.

433. The method of any one of embodiments 424 to 432,

The anti-TIGIT antagonist antibody is a monoclonal antibody, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

434. The method of any one of embodiments 424 to 433,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody is a human antibody.

435. The method of any one of embodiments 424 to 434,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody is a full-length antibody.

436. The method of any one of embodiments 424 to 427 and embodiments 429 to 436,

wherein said anti-TIGIT antagonist antibody is tyragolumab; an anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

437. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, embodiment 421, and embodiment any one of embodiments 424 to 436,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody is tiragolumab, bivostoliumab, etigilumab, EOS084448, SGN-TGT or TJ-T6.

438. The method of embodiment 437,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody has a prototypical Fc-mediated effector function.

439. according to embodiment 437 or embodiment 438,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody has enhanced Fc-mediated effector function.

440. The method of any one of embodiments 437 to 439,

wherein said anti-TIGIT antagonist antibody is SGN-TGT.

441. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, and embodiment 421 according to any one of embodiments,

wherein said anti-TIGIT antagonist antibody is dombanalimab, BMS-986207, ASP8374 or COM902, anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

442. The method of any one of embodiments 424 to 431 and 441,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody has no Fc-mediated effector function.

443. The method according to any one of embodiments 47 to 442,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

444. The method of embodiment 443,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said IgG class antibody is an IgG1 subclass antibody.

445. of embodiment 444,

wherein said anti-TIGIT antagonist antibody is tiragolumab, bivostolimab, etigilimab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, dombanalimab, or BMS-986207. Antibodies and PD-1 axis binding antagonists.

446. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, and embodiment 421 according to any one of embodiments,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said IgG class antibody is an IgG4 subclass antibody.

447. The method of embodiment 446,

wherein said anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. The method of any one of embodiments 424 to 434,

wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, bis-Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab')2 fragment, Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

449. The method of any one of embodiments 424 to 448,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody is a monospecific antibody.

450. The method of any one of embodiments 424 to 448,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-TIGIT antagonist antibody is a multispecific antibody.

451. The method of embodiment 450,

wherein said multispecific antibody is a bispecific antibody, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

452. The method of any one of embodiments 424 to 451

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

453. The method of embodiment 452,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is a PD-L1 binding antagonist.

454. The method of embodiment 453,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-L1 binding antagonist inhibits binding of PD-L1 to one or more of its ligand binding partners.

455. The method of embodiment 454,

wherein said PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1, anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use .

456. The method according to any one of embodiments 453-455,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The method of embodiment 456,

The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

458. The method of embodiment 457,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-PD-L1 antagonist antibody is atezolizumab.

459. The method of embodiment 456,

The anti-PD-L1 antagonist antibody has the following HVRs:

HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);

HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);

HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22);

HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);

HVR-L2 comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising HVR-L3 comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25).

460. The method of embodiment 459,

The anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or

(c) an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising a VH domain as in case (a) and a VL domain as in case (b).

461. The method of embodiment 460,

The anti-PD-L1 antagonist antibody comprises:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and

(b) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:27.

462. The method of embodiment 461,

The anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 28; and

(b) An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, comprising a light chain comprising the amino acid sequence of SEQ ID NO:29.

463. The method according to any one of embodiments 459 to 462,

wherein said anti-PD-L1 antagonist antibody is a monoclonal antibody, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

464. The method of any one of embodiments 459 to 463,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-PD-L1 antagonist antibody is a humanized antibody.

465. The method of embodiment 463 or embodiment 464,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-PD-L1 antagonist antibody is a full-length antibody.

466. The method according to any one of embodiments 459 to 464,

wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab')2 fragments. Antibodies and PD-1 axis binding antagonists.

467. The method according to any one of embodiments 459 to 465,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said anti-PD-L1 antagonist antibody is an IgG class antibody.

468. The method of embodiment 467,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said IgG class antibody is an IgG1 subclass antibody.

469. The method of embodiment 452,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. The method of embodiment 469,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 binding antagonist inhibits binding of PD-1 to one or more of its ligand binding partners.

471. The method of embodiment 470,

wherein said PD-1 binding antagonist inhibits PD-L1 from binding to PD-L1, PD-L2, or both PD-L1 and PD-L2. .

472. The method according to any one of embodiments 469 to 471,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The method of embodiment 472,

Said anti-PD-L1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, progolimab, camrelizumab, scintilimab, tislelizumab, torifaliz Mab, dostalimab, retipanrimab, sasanrimab, fenpulimab, CS1003, HLX10, SCT-I10A, gimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, For use which is HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21 Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists.

474. The method according to any one of embodiments 469 to 471,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the PD-1 binding antagonist is an Fc fusion protein.

475. The method of embodiment 474,

The Fc fusion protein is AMP-224, anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

476. The method of any one of embodiments 80-112, 114-127 and 309-312,

The method comprises administering to the subject or population of subjects an anti TIGIT antagonist antibody and PD-1 formulated for administration at a dose of about 30 mg to about 1200 mg every 3 weeks. Axial binding antagonists.

477. Embodiment 51, Embodiment 54, Embodiment 60, Embodiment 62, Embodiment 63, Embodiment 65-67, Embodiment 80-112, Embodiment 114-127, Embodiment 136- Embodiment 140, embodiment 169-174, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301, embodiment 302, embodiment 303, embodiment 313, embodiment 315, embodiment 338, embodiment 340, embodiment 358 to embodiment 361, embodiment 372, embodiment 384, embodiment 387, embodiment 388, embodiment 402 to According to any one of embodiments 404, 417, 420, 421, and 476,

wherein said method comprises administering to said subject an anti TIGIT antagonist antibody formulated for administration at a dose of about 600 mg every three weeks.

478. Embodiment 51, Embodiment 54, Embodiment 60, Embodiment 62, Embodiment 63, Embodiment 65-67, Embodiment 80-112, Embodiment 114-127, Embodiment 136- Embodiment 140, embodiment 169-174, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301, embodiment 302, Embodiment 303, Embodiment 309, Embodiment 313, Embodiment 315, Embodiment 338, Embodiment 340, Embodiment 358 to Embodiment 361, Embodiment 372, Embodiment 384, Embodiment 387, Embodiment 388, The embodiment of any one of Embodiments 402 to 404, Embodiment 417, Embodiment 420, Embodiment 421, and Embodiment 476,

The method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects in stepwise doses based on the body weight of said subject, wherein said subject has a body weight of:

(a) weighing no more than 15 kg, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300 mg every 3 weeks;

(b) greater than 15 kg and less than or equal to 40 kg, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 400 mg every 3 weeks; or

(c) greater than 40 kg, wherein said anti TIGIT antagonist antibody is formulated for administration at a dose of about 600 mg every 3 weeks. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

479. The embodiment of any one of embodiments 47, 48, 77, 78, 82, and 83,

The method comprises administering to the subject or population of subjects an anti TIGIT antagonist antibody and PD-1 formulated for administration at a dose of about 700 mg to about 1000 mg every 4 weeks. Axial binding antagonists.

480. The embodiment of any one of embodiments 47, 48, 59, 67, 323, and 479,

wherein said method comprises administering to said subject an anti TIGIT antagonist antibody formulated for administration at a dose of about 840 mg every 4 weeks.

481. The embodiment of any one of embodiments 49, 50, and 104,

The method comprises administering to the subject or population of subjects an anti TIGIT antagonist antibody and PD-1 formulated for administration at a dose of about 300 mg to about 600 mg every two weeks. Axial binding antagonists.

482. The embodiment of any one of embodiments 49, 50, 227, 251 to 253, 255, and 481,

wherein said method comprises administering to said subject an anti TIGIT antagonist antibody formulated for administration at a dose of about 420 mg every two weeks.

483. The method according to any one of embodiments 47 to 482,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the dose of said anti-TIGIT antagonist antibody is a fixed dose.

484. The embodiment of any one of embodiments 54, 62, 63, 65-67, 80-109, and 27-2698,

The method comprises administering to the subject or population of subjects a Pd-1 axis binding antagonist formulated for administration at a dose of about 900 mg to about 1500 mg every 3 weeks. -1 axis binding antagonists.

485. embodiment 54, embodiment 60, embodiment 62, embodiment 63, embodiment 65-67, embodiment 80-112, embodiment 114-127, embodiment 136-140, Embodiment 169 to embodiment 172, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301 to embodiment 303, embodiment 309, embodiment 311, embodiment 313, embodiment 315, embodiment 338, embodiment 340, embodiment 358 to embodiment 361, embodiment 372 to embodiment 375, embodiment 384, embodiment 387, embodiment 388, The embodiment of any one of Embodiments 402 to 405, Embodiment 417, Embodiment 420, Embodiment 421, and Embodiment 484,

wherein said method comprises administering to said subject a PD-1 axis binding antagonist formulated for administration at a dose of about 1200 mg every 3 weeks.

486. The embodiment of any one of embodiments 47, 50, 80-109, and embodiment 324,

The method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody and PD formulated for administration at a dose of about 1400 mg to about 2000 mg every 4 weeks to the subject or population of subjects. -1 axis binding antagonists.

487. The embodiment of any one of embodiments 47, 50, 59, 67, 324, and 479,

wherein said method comprises administering to said subject an anti-PD-1 axis binding antagonist formulated for administration at a dose of about 1680 mg every 4 weeks.

488. The method of any one of embodiments 48, 49, 80-109, and embodiment 481,

The method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody and PD formulated for administration of a dose of about 600 mg to about 1200 mg every two weeks to the subject or population of subjects. -1 axis binding antagonists.

489. The embodiment of any one of embodiments 48, 49, 80 to 109, 227, 251 to 253, and 481,

wherein said method comprises administering to said subject an anti-PD-1 axis binding antagonist formulated for administration at a dose of about 840 mg every two weeks.

490. The method according to any one of embodiments 47 to 489,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the dose of the PD-1 axis binding antagonist is a fixed dose.

491. The method of embodiment 60 or embodiment 61,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, the method comprising administering to the subject pembrolizumab at a fixed dose of about 200 mg every 3 weeks or 400 mg every 6 weeks.

492. The embodiment of any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191,

wherein each of said one or more dosing cycles is 21 days in length.

493. The embodiment of any one of embodiments 47, 59, 67, 80 to 109, and embodiments 309 to 311,

wherein each of said one or more dosing cycles is 28 days in length.

494. The embodiment of any one of embodiments 49, 80 to 109, and embodiments 309 to 311,

wherein each of said one or more dosing cycles is 14 days in length.

495. The method according to any one of embodiments 47 to 494,

wherein said method comprises administering said anti TIGIT antagonist antibody to said subject or population of subjects on about day 1 of each of said one or more dosing cycles.

496. The method according to any one of embodiments 47 to 495,

wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects on about day 1 of each of said one or more dosing cycles and said anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

497. according to embodiment 321 or embodiment 493,

wherein said method comprises administering said anti TIGIT antagonist antibody to said subject on about 15 days of each of said one or more dosing cycles.

498. The method of embodiment 321 or embodiment 493,

wherein said method comprises administering said PD-1 axis binding antagonist to said subject on about 15 days of each of said one or more dosing cycles.

499. The method according to any one of embodiments 47 to 498,

wherein said method comprises administering to said subject or population of subjects said anti-TIGIT antagonist antibody prior to said anti-TIGIT antagonist antibody or said anti-TIGIT antagonist antibody prior to said PD-1 axis binding antagonist or said PD-1 axis binding antagonist. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

500. The method of embodiment 499,

wherein said method comprises a first observation period following administration of said PD-1 axis binding antagonist or said anti TIGIT antagonist antibody.

501. The method of embodiment 500,

wherein said first observation period is between about 30 minutes and about 60 minutes in length.

502. The method of embodiment 500 or embodiment 501,

wherein said method comprises a second observation period following administration of said anti-TIGIT antagonist antibody or said PD-1 axis binding antagonist.

503. The method of embodiment 502,

wherein said second observation period is between about 30 minutes and about 60 minutes in length.

504. The method of any one of embodiments 47 to 503,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects concurrently with said anti TIGIT antagonist antibody.

505. The method of any one of embodiments 47 to 504,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said method comprises intravenously administering said anti TIGIT antagonist antibody and PD-1 axis binding antagonist to said subject or population of subjects.

506. The method of embodiment 505,

wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes over an anti TIGIT antagonist antibody and PD -1 axis binding antagonists.

507. The method of embodiment 505 or embodiment 506,

wherein said method comprises administering said anti TIGIT antagonist antibody to said subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes over an anti TIGIT antagonist antibody and PD-1 Axial binding antagonists.

508. The method of any one of embodiments 47-114 and 116-507,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the level of PD-L1 expression in said subject or a tumor sample obtained from said subjects is determined.

509. The method of embodiment 508,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

510. The method of embodiment 509,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1.

511. The method of embodiment 510,

The detectable protein expression level of PD-L1 is determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody suitable for staining, anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonists.

512. The method of embodiment 511,

wherein said anti-PD-L1 antibody suitable for staining is said anti-PD-L1 antibody SP263, SP142, 22C3 or 28-8, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

513. The method of embodiment 511 or embodiment 512,

The detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a PalmDx 28-8 IHC assay. Anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for

514. The embodiment of any of embodiments 47 to 109, 188, 220 to 265, and embodiments 307 to 423,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable protein expression level of PD-L1 is determined by IHC analysis comprising staining with the anti-PD-L1 antibody SP263.

515. The embodiment of any one of embodiments 47 to 220, 265 to 338, and embodiments 370 to 423,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable protein expression level of PD-L1 is determined by IHC analysis comprising staining with the anti-PD-L1 antibody SP142.

516. The embodiment of any of embodiments 47 to 113, 136 to 187, and any of embodiments 220 to 423,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 22C3 is determined.

517. The method of any one of embodiments 47 to 114 and embodiments 116 to 423,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 28-8 is determined.

518. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% of tumor associated immune cells (TICs) in the tumor sample.

519. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of greater than or equal to 5% and less than 20% in the tumor sample.

520. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 10% in the tumor sample.

521. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 20% in the tumor sample.

522. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of greater than or equal to 10% and less than 50% in the tumor sample.

523. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 50% in the tumor sample.

524. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is at least 1% of a fraction of PD-L1 positive tumor cells.

525. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is at least 30% of a fraction of PD-L1 positive tumor cells.

526. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 1% and less than 50% of a fraction of PD-L1 positive tumor cells.

527. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is at least 50% of a fraction of PD-L1 positive tumor cells.

528. The method of embodiment 515,

wherein the PD-L1-positive tumor cell fraction is a proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC).

529. The method of embodiment 515,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is at least 1%.

530. The method of embodiment 515,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is at least 5%.

531. The method of embodiment 516,

wherein the detectable protein expression level of PD-L1 has a composite positive score (CPS) of 1 or greater.

532. The method of embodiment 516,

The detectable protein expression level of PD-L1 is a CPS of 10 or more, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

533. The method of embodiment 516,

The detectable protein expression level of PD-L1 is a CPS of 20 or more, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

534. The method of any one of embodiments 528 to 530,

wherein the IHC assay is a Ventana SP142 IHC assay.

535. The method of embodiment 509,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1.

536. The method of embodiment 535,

The detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. Antibodies and PD-1 axis binding antagonists.

537. The method according to any one of embodiments 47 to 423,

wherein said treatment results in an increase in overall survival (OS) of said subject compared to baseline OS time and/or an increase in progression free survival (PFS) in said subject compared to baseline PFS time. uniaxial binding antagonists.

538. The method of embodiment 537,

(a) said baseline OS time is the median OS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without an anti-PD-1 axis binding antagonist; and/or

(b) the baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without an anti-PD-1 axis binding antagonist. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

539. The embodiment of any one of embodiments 52, 158, and 228,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents.

540. The method of embodiment 539,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. The method of embodiment 69, embodiment 92, embodiment 127, embodiment 131, embodiment 249, and embodiment 540,

wherein the carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min or AUC=6 mg/ml/min.

542. The method of embodiment 69, embodiment 127, embodiment 162, embodiment 164, embodiment 166, embodiment 168, and embodiment 540,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said cisplatin is formulated for administration at a dose of about 75 mg/m2 or 80 mg/m2.

543. The method of any one of embodiments 539 to 542,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said at least one non-platinum-based chemotherapeutic agent is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

544. The embodiment of any one of embodiments 62, 173, 174, and 543,

wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. The embodiment of any one of embodiments 69, 127, 162, and 544,

An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, wherein said pemetrexed is formulated for administration at a dose of about 500 mg/m2.

546. The embodiment of any one of embodiments 63, 64, 162, 398, and 544,

An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use, wherein said gemcitabine is formulated for administration at a dose of about 1000 mg/m2 or about 1250 mg/m2.

547. The method of embodiment 544,

wherein the antimetabolite is capecitabine, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

548. The method of embodiment 544 or embodiment 547,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said capecitabine is formulated for administration at a dose of about 1250 mg/m2.

549. The embodiment of any one of embodiments 173, 174, 229, 230, 239, 240, and 543 to 548,

wherein said taxane is paclitaxel or nap-paclitaxel.

550. The method of any one of embodiments 69, 162, and 549,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said paclitaxel is formulated for administration at a dose of about 175 mg/m2 or about 200 mg/m2.

551. The embodiment of any one of embodiments 63, 64, 249, 398, and 549,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said nap-paclitaxel is formulated for administration at a dose of about 100 mg/m2.

552. The embodiment of any one of embodiments 80-91, 229, 230, 239, 241, 251, 255, and 543-551. ,

wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331. Antagonist Antibodies and PD-1 Axis Binding Antagonists.

553. The embodiment of any one of embodiments 69, 92, and 552,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said etoposide is formulated for administration at a dose of about 100 mg/m2.

554. The method of any one of embodiments 543 to 553,

The one or more chemotherapeutic agents are each administered once every week, once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, twice every 4 weeks, or 3 times every 4 weeks. , anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists for use.

555. The method of any one of embodiments 543 to 554,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said at least one chemotherapeutic agent is administered on Day 1 of at least one dosing cycle.

556. The method of any one of embodiments 544 to 555,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the gemcitabine is administered 3 times every 4 weeks.

557. The method of any one of embodiments 544 to 556,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said gemcitabine is administered on days 1, 8, and/or 15 of one or more dosing cycles.

558. The method of any one of embodiments 544 to 557,

wherein said capecitabine is administered daily for 2 weeks. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

559. The method according to any one of embodiments 544 to 558,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said capecitabine is administered on days 1 to 14 of one or more dosing cycles.

560. The method of any one of embodiments 549 to 559,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said nap-paclitaxel is administered three times every four weeks.

561. The method of any one of embodiments 549 to 560,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said nap-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles.

562. The method of any one of embodiments 552 to 561,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said etoposide is administered on days 1 to 3 every 3 weeks.

563. The method of any one of embodiments 552 to 562,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said etoposide is administered on days 1-3 of one or more dosing cycles.

564. The method of any one of embodiments 543 to 563,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said at least one chemotherapeutic agent is administered prior to said PD-1 axis binding antagonist and/or said anti TIGIT antagonist antibody.

565. The method of any one of embodiments 543 to 564,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said one or more chemotherapeutic agents are administered after said PD-1 axis binding antagonist and/or said anti TIGIT antagonist antibody.

566. The method of any one of embodiments 543 to 565,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said at least one chemotherapeutic agent is administered intravenously or orally.

567. The embodiment of any one of embodiments 65, 310, and 311,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the VEGF antagonist is formulated for administration at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks.

568. The method of embodiment 312 or embodiment 567,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the VEGF antagonist is formulated for administration at a dose of about 10 mg/kg to about 20 mg/kg every 3 weeks.

569. The method of embodiment 318 or embodiment 568,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the VEGF antagonist is formulated for administration at a dose of about 15 mg/kg every 3 weeks.

570. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 569,

The VEGF antagonist is an anti-VEGF antibody, anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

571. The method of embodiment 570,

The anti-VEGF antibody comprises a VH domain and a VL domain of bevacizumab, an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use.

572. The method of embodiment 570 or embodiment 571,

The anti-VEGF antibody is bevacizumab, anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use.

573. The embodiment of any one of embodiments 65, 310 to 312, and embodiments 318 to 320,

The anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the VEGF antagonist is bevacizumab.

574. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 573,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said method comprises administering said VEGF antagonist to said subject on Day 1 of one or more dosing cycles.

575. The method of any one of embodiments 318 to 320,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein said method comprises administering said VEGF antagonist to said subject on day 15 of one or more dosing cycles.

576. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 575,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the VEGF antagonist is administered intravenously.

577. The method of embodiment 576,

wherein said VEGF antagonist is administered to said subject by intravenous infusion over 90±15 minutes.

578. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 577,

wherein said method comprises administering said PD-1 axis binding antagonist prior to said VEGF antagonist, and said VEGF antagonist prior to said anti TIGIT antagonist antibody to said subject, anti TIGIT antagonist antibody and PD-1 axis for use binding antagonists.

579. The method of embodiment 578,

The method comprises a first observation period after administration of the PD-1 axis binding antagonist, a second observation period after administration of the VEGF antagonist, and a third observation period after administration of the anti-TIGIT antagonist antibody. and PD-1 axis binding antagonists.

580. The method of embodiment 579,

wherein said first observation period, said second observation period, and said third observation period are each about 30 minutes to about 120 minutes in length.

581. Embodiment 113, Embodiment 128, Embodiment 129 to Embodiment 131, Embodiment 175 to Embodiment 182, Embodiment 210 to Embodiment 214, Embodiment 221, Embodiment 256, Embodiment 257, Embodiment 270, Embodiment 289, Embodiment 290, Embodiment 293, Embodiment 294, Embodiment 297, Embodiment 298, Embodiment 333, Embodiment 362 to Embodiment 365, Embodiment 385, Embodiment 386, Embodiment 389, Embodiment 393, embodiment 419, and embodiment 422 according to any one of embodiments,

An anti TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein tiragolumab and atezolizumab are bound to an IV bag prior to administration.

582. The method according to any one of embodiments 47 to 581,

An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use, wherein the subject is a human.

583. The method according to any one of embodiments 47 to 582,

wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in separate formulations.

584. The method according to any one of embodiments 47 to 582,

wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are provided in a single dosage form.

Implementation Set C:

1. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dose of about 500 mg to about 700 mg of an anti-TIGIT antagonist antibody every 3 weeks, a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and 3 A use comprising administering to the subject a dosing regimen comprising at least one dosing cycle of a non-platinum-based chemotherapeutic agent per week.

2. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks, and at least one dosing cycle of a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks. Use comprising administering to a subject.

3. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks, and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks. use comprising administering to the subject.

4. according to embodiment 2 or embodiment 3,

The method further comprises administering to the subject one or more chemotherapeutic agents.

5. The method according to any one of embodiments 1 to 4,

wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.

6. The method according to any one of embodiments 1 to 5,

The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):

(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);

(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

(d) an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

(e) an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

(f) use comprising HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

7. The method according to any one of embodiments 1 to 6,

The anti-TIGIT antagonist antibody has the following light chain variable region framework regions (FR):

(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);

(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);

(c) FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and

(d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and

The following heavy chain variable region FRs:

(a) FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;

(b) FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);

(c) FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and

(d) use, further comprising FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

8. The method according to any one of embodiments 1 to 7,

The anti-TIGIT antagonist antibody comprises:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or

(c) a use comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The method according to any one of embodiments 1 to 8,

wherein the anti-TIGIT antagonist antibody is tyragolumab.

10. The method according to any one of embodiments 1 to 9,

wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

11. The method according to any one of embodiments 1 to 10,

The use wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The method according to any one of embodiments 1 to 11,

The use of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The method of embodiment 12,

The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636, used.

14. The method according to any one of embodiments 1 to 13,

wherein the PD-1 axis binding antagonist is atezolizumab.

15. The method according to any one of embodiments 1 to 11,

The use of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The method of embodiment 15,

Said anti-PD-L1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, progolimab, camrelizumab, scintilimab, tislelizumab, torifaliz Mab, dostalimab, retipanrimab, sasanrimab, fenfulimab, CS1003, HLX10, SCT-I10A, zimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21, for use.

17. The method according to any one of embodiments 2 to 16,

The method comprises administering to the subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. according to embodiment 1 or embodiment 17,

The non-platinum-based chemotherapeutic agent is a topoisomerase II inhibitor.

19. The method of embodiment 18,

wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331, in particular etoposide; use.

20. The method of embodiment 18 or embodiment 19,

wherein the topoisomerase II inhibitor is administered at a dose of 100 mg/m2.

21. The method according to any one of embodiments 17 to 20,

wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin.

22. The method according to any one of embodiments 17 to 21,

wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration.

23. The method according to any one of embodiments 1-22,

The method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. The method of embodiment 23,

wherein the induction phase comprises 4 initial dosing cycles and the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent are administered in each of the four initial dosing cycles.

25. according to embodiment 23 or embodiment 24,

wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent and/or the non-platinum-based chemotherapeutic agent.

26. The method according to any one of embodiments 1 to 25,

wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody.

27. The method according to any one of embodiments 1-26,

wherein said treatment prolongs the overall survival of said subject as compared to treatment without said anti-TIGIT antagonist antibody.

28. The method according to any one of embodiments 1 to 27,

wherein the cancer is lung cancer.

29. The method of embodiment 28,

wherein the lung cancer is small cell lung cancer (SCLC), in particular expanded stage SCLC (ES-SCLC).

30. The method of embodiment 28,

wherein the lung cancer is small cell lung cancer (SCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. The method of embodiment 28,

wherein the lung cancer is locally advanced unresectable or metastatic nonsquamous NSCLC.

32. The method of embodiment 28,

wherein the lung cancer is resectable lung cancer.

33. The method according to any one of embodiments 1 to 27,

wherein the cancer is cervical cancer.

34. The method according to any one of embodiments 1 to 27,

wherein the cancer is early triple negative breast cancer (eTNBC).

35. The method according to any one of embodiments 1 to 27,

wherein the cancer is head and neck cancer.

36. The method of any one of embodiments 1 to 27,

wherein the cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. The method according to any one of embodiments 1 to 27,

wherein the cancer is bladder cancer.

38. The method of embodiment 37,

wherein the cancer is urothelial cell carcinoma (UC), in particular metastatic urothelial cell carcinoma (mUC).

39. The method according to any one of embodiments 1 to 27,

wherein the cancer is pancreatic cancer, in particular pancreatic ductal cell carcinoma (PDAC).

40. The method according to any one of embodiments 1 to 27,

wherein said cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer.

41. Use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having cancer, comprising:

The method comprises a dose of about 500 mg to about 700 mg of an anti-TIGIT antagonist antibody every 3 weeks, a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and 3 A use comprising administering to the subject a dosing regimen comprising at least one dosing cycle of a non-platinum-based chemotherapeutic agent per week.

42. Use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having cancer, comprising:

The method comprises administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks, and at least one dosing cycle of a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks. Use comprising administering to a subject.

43. Use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks, and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks. use comprising administering to the subject.

44. Use of a PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject having cancer, comprising:

(a) the method comprises a dose of about 500 mg to about 700 mg of an anti-TIGIT antagonist antibody every 3 weeks, a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks and administering to the subject a dosing regimen comprising at least one dosing cycle of a non-platinum-based chemotherapeutic agent every three weeks; (b) the method comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks. or administering to the subject; or (c) the method comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks. use comprising administering a dosing regimen to the subject.

45. The method of embodiment 44,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

46. The method of embodiment 44,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single dosage form.

47. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks, and a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks. use comprising administering to the subject.

48. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks, and a PD-1 axis binding antagonist at a dose of about 20 mg to about 1600 mg every 2 weeks. use comprising administering to the subject.

49. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every two weeks, and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 20 mg to about 1600 mg every two weeks. use comprising administering to the subject.

50. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every two weeks, and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks. use comprising administering to the subject.

51. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, and a PD-1 axis binding antagonist at a dose of about 100 mg to about 1000 mg every 6 weeks. use comprising administering to the subject.

52. The method according to any one of embodiments 47 to 51,

The method further comprises administering to the subject one or more chemotherapeutic agents.

53. The method of embodiment 52,

wherein said method comprises administering to said subject a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

54. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and 3 A use comprising administering to the subject a dosing regimen comprising at least one dosing cycle of a non-platinum-based chemotherapeutic agent per week.

55. according to embodiment 53 or embodiment 54,

wherein the method comprises an induction phase and a maintenance phase.

56. The method of embodiment 55,

wherein the induction phase and maintenance phase each comprise one or more dosing cycles.

57. according to embodiment 55 or embodiment 56,

wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent.

58. The method according to any one of embodiments 55 to 57,

wherein the maintenance phase does not include administration of the non-platinum-based chemotherapeutic agent.

59. The method of embodiment 58,

wherein said maintenance phase comprises one or more dosing cycles of anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks.

60. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks. administering to the subject, wherein the anti-PD-1 antagonist antibody is pembrolizumab.

61. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab and pembrolizumab, wherein the pembrolizumab is administered at a dose of about 100 mg to about 1000 mg every 6 weeks. administered, use.

62. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises a dose of about 30 mg to about 1200 mg of anti-TIGIT antagonist antibody every 3 weeks, a dose of about 80 mg to about 1600 mg of PD-1 axis binding antagonist every 3 weeks, and 3 weeks of 2 weeks dosing/ 1 week washout. Use, comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an antimetabolite at a dose of about 10 mg/m2 to about 10000 mg/m2 orally twice daily every time.

63. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises one or more doses of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, gemcitabine, and nap-paclitaxel. Use comprising administering to the subject a dosing regimen comprising a dosing cycle.

64. The method of embodiment 52,

wherein said at least one chemotherapeutic agent is gemcitabine and nap-paclitaxel.

65. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and about 1 mg/kg to about every 3 weeks. Use comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a VEGF antagonist at a dose of 35 mg/kg.

66. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) the induction phase is an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks , and at least one dosing cycle of a non-platinum-based chemotherapeutic agent every 3 weeks; and

(b) said maintenance phase comprises at least one additional dosing cycle of said anti-TIGIT antagonist antibody every 3 weeks, said PD-1 axis binding antagonist every 3 weeks, and said non-platinum-based chemotherapeutic agent every 3 weeks, wherein said maintenance wherein the phase does not include administration of said platinum-based chemotherapeutic agent.

67. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having cancer, comprising:

The method comprises administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) the induction phase is an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks , and at least one dosing cycle of a non-platinum-based chemotherapeutic agent every 3 weeks; and

(b) the maintenance phase comprises one or more additional dosing cycles of the anti-TIGIT antagonist antibody at a dose of about 200 mg to about 2000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 2000 mg every 4 weeks and wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent.

68. The method of any one of embodiments 56-59, 66 and 67,

wherein the induction phase comprises 4 to 6 dosing cycles.

69. The method of any one of embodiments 53-59 and 66-68,

(a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;

(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel; or

(c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is etoposide.

70. The method according to any one of embodiments 47 to 69,

wherein the cancer is a solid tumor.

71. The method according to any one of embodiments 47 to 70,

wherein the cancer is locally advanced or metastatic.

72. The method according to any one of embodiments 47 to 71,

wherein said cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, kidney cancer, melanoma, or ovarian cancer.

73. The method of embodiment 72,

wherein the cancer is lung cancer.

74. The method of embodiment 73,

wherein the lung cancer is NSCLC, in particular locally advanced unresectable NSCLC.

75. The method of embodiment 74,

wherein said NSCLC is stage IIIB NSCLC.

76. The method according to any one of embodiments 73 to 75,

wherein the lung cancer is relapsed or metastatic NSCLC.

77. The method of embodiment 76,

wherein said NSCLC is stage IV NSCLC.

78. The method of embodiment 77,

The subject has not previously been treated for stage IV NSCLC.

79. The method of embodiment 73,

wherein the lung cancer is small cell lung cancer (SCLC).

80. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having lung cancer,

The method comprises administering to the subject or population of subjects a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. wherein said treatment improves progression-free survival (PFS) of said subject as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. prolonged use.

81. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a population of subjects having lung cancer, comprising:

The method comprises administering to said subject population a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. and wherein the treatment results in a median PFS of the subject population of about 8.2 months to about 9.2 months.

82. The method of embodiment 80 or embodiment 81,

wherein said treatment prolongs overall survival (OS) of said subject or population of subjects compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody; use.

83. The method according to any one of embodiments 80 to 82,

wherein the treatment prolongs the PFS of the subject or population of subjects by at least about 2.4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , use.

84. The method of embodiment 83,

wherein said treatment reduces the PFS of said subject or population of subjects by at least about 3 months to about 4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. Extending by months, use.

85. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having lung cancer,

The method comprises administering to the subject or population of subjects a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. wherein the treatment prolongs the OS of the subject as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

86. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a population of subjects having lung cancer, comprising:

The method comprises administering to said subject population a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor. and wherein the treatment results in a median OS in the subject population of about 15.3 months to about 17.6 months.

87. The method according to any one of embodiments 82 to 86,

wherein the treatment prolongs the OS of the subject or population of subjects by at least about 3.3 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , use.

88. The method according to any one of embodiments 82 to 86,

wherein said treatment reduces the OS of said subject or population of subjects by at least about 3 months to about 5.3 as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. Extending by months, use.

89. The method according to any one of embodiments 80 to 88,

wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered in each of four initial dosing cycles.

90. The method according to any one of embodiments 80 to 89,

wherein said anti-TIGIT antagonist antibody and said PD-1 axis binding antagonist are further administered in one or more additional cycles after the fourth initial dosing cycle.

91. The method of embodiment 90,

wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of one or more additional dosing cycles.

92. The method according to any one of embodiments 80 to 91,

wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide.

93. The method according to any one of embodiments 80 to 92,

wherein the lung cancer is small cell lung cancer (SCLC).

94. The method of embodiment 93,

wherein the SCLC is an extended-stage SCLC (ES-SCLC).

95. The method of embodiment 94,

wherein the subject or subjects is naive to treat ES-SCLC.

96. The method according to any one of embodiments 80 to 95,

wherein the subject or subjects do not have the presence or history of brain metastases.

97. The method according to any one of embodiments 80 to 96,

wherein the lung cancer is not selected for PD-L1 expression.

98. The method according to any one of embodiments 80 to 96,

wherein the lung cancer is selected for PD-L1 expression.

99. The method of embodiment 98,

wherein the lung cancer is selected for PD-L1 expression by a detectable expression level of PD-L1.

100. The method according to any one of embodiments 80 to 99,

wherein the lung cancer is metastatic.

101. The method of embodiment 100,

wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal glands.

102. The method of embodiment 100 or embodiment 101,

The lung cancer does not metastasize to the brain.

103. The method of any one of embodiments 100-102,

wherein the treatment elicits a complete response (CR) or a partial response (PR).

104. The method according to any one of embodiments 80 to 103,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 2 weeks, every 3 weeks, or every 4 weeks.

105. The method of any one of embodiments 80-104,

wherein the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 2 weeks, every 3 weeks, or every 4 weeks.

106. The method of any one of embodiments 80 to 105,

wherein the PD-1 axis binding antagonist, the anti-TIGIT antagonist antibody, the platinum-based chemotherapeutic agent, and the photoisomerase II inhibitor are sequentially administered.

107. The method of embodiment 106,

The PD-1 axis binding antagonist is administered before the anti-TIGIT antagonist antibody, the anti-TIGIT antagonist antibody is administered before the platinum-based chemotherapeutic agent, and the platinum agent is administered before the topoisomerase II inhibitor. , use.

108. The method according to any one of embodiments 80 to 107,

wherein said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, said platinum-based chemotherapeutic agent, and said topoisomerase II inhibitor are administered intravenously.

109. The method according to any one of embodiments 80 to 108,

wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered subcutaneously.

110. The use of an anti TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of treating a subject with SCLC,

The method comprises a dose of about 30 mg to about 1200 mg of an anti-TIGIT antagonist antibody on Day 1 of each dosing cycle, a dose of about 80 mg to about 1600 mg of atezolizumab on Day 1 of each dosing cycle, Carboplatin at a dose sufficient to achieve AUC=5 mg/ml/min on Day 1, and etoposide at a dose of 100 mg/m2 on each of Days 1, 2, and 3 of each dosing cycle. administering to the subject at least one 21 day dosing cycle of Use to extend PFS and/or OS.

111. The use of an anti TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of treating a subject with SCLC, comprising:

Anti TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg on day 1 of each dosing cycle, atezolizumab at a dose of about 900 mg to about 1500 mg on Day 1 of each dosing cycle, Day 1 of each dosing cycle Carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min, and one dose of etoposide at 100 mg/m2 on each of Days 1, 2, and 3 of each dosing cycle. administering to said subject at least a 21-day dosing cycle, wherein said treatment comprises the subject's PFS and/or compared to treatment with atezolizumab, carboplatin, and etoposide in the absence of said anti-TIGIT antagonist antibody. or extending the OS.

112. The method of embodiment 110 or embodiment 111,

One or more additional 21 doses of anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each additional dosing cycle and atezolizumab at a dose of about 80 mg to about 1600 mg on Day 1 of each additional dosing cycle administering to said subject one dosing cycle, wherein carboplatin and etoposide are omitted from each of said one or more additional dosing cycles.

113. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with ES-SCLC,

The method comprises administering to the subject or population of subjects four initial dosing cycles followed by one or more additional dosing cycles, wherein:

(a) said four initial dosing cycles are tiragolumab at a dose of about 600 mg on day 1 of each initial dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each initial dosing cycle, each initial dosing cycle Carboplatin at a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of administering poside; and

(b) said one or more additional dosing cycles administering about 600 mg of tiragolumab on day 1 of each additional dosing cycle and about 1200 mg of atezolizumab on day 1 of each additional dosing cycle comprising the steps of

wherein said four initial dosing cycles and said one or more additional dosing cycles are each 21 day dosing cycle, wherein said treatment is compared to treatment with atezolizumab, carboplatin, and etoposide without said tiragolumab to prolong the PFS and/or OS of the subject or population of subjects.

114. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having lung cancer,

The method comprises administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent, and a second chemotherapeutic agent that is a non-platinum-based chemotherapeutic agent. or administering to a population of subjects.

115. The method of embodiment 114,

wherein the lung cancer is not evaluated for PD-L1 expression.

116. The method of embodiment 114 or embodiment 115,

wherein the subject or subjects has not been determined to have a fraction of PD-L1 positive tumor cells greater than or equal to 50%.

117. The method of embodiment 116,

wherein the subject or subjects is not determined to have a fraction of PD-L1 positive tumor cells of less than 50%.

118. The method of embodiment 116 or embodiment 117,

wherein said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein said anti-PD-L1 antibody is SP263 or 22C3.

119. The method according to any one of embodiments 114 to 118,

wherein said subject or subjects do not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormality.

120. The method according to any one of embodiments 114 to 119,

wherein said subject or subjects have not received prior systemic therapy for said lung cancer.

121. The method of any one of embodiments 114 to 120,

wherein the lung cancer is locally advanced lung cancer.

122. The method according to any one of embodiments 114 to 121,

wherein the lung cancer is NSCLC, in particular locally advanced unresectable or metastatic non-squamous NSCLC.

123. The method of embodiment 122,

wherein said nonsquamous NSCLC is stage IV nonsquamous NSCLC.

124. The method according to any one of embodiments 114 to 123,

wherein the dosing regimen includes an induction phase comprising 4 dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent include each dosing cycle of the induction phase. Administered on the first day of the use.

125. The method of embodiment 124,

wherein the dosing regimen comprises a maintenance phase after the induction phase, wherein the maintenance phase includes one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the non-platinum chemotherapeutic agent are the maintenance phases. Use, administered on Day 1 of each dosing cycle of the phase.

126. The method of embodiment 125,

wherein one or more dosing cycles of the maintenance phase do not include administration of the platinum-based chemotherapeutic agent.

127. The method according to any one of embodiments 114 to 126,

wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed.

128. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with advanced nonsquamous NSCLC, comprising:

The method comprises administering to the subject or population of subjects a dosing regimen comprising four 21 day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein the tyra Golumab is administered at a dose of about 600 mg every 3 weeks, the atezolizumab is administered at a dose of about 1200 mg every 3 weeks, and the carboplatin is administered at a dose of about 1200 mg every 3 weeks to achieve AUC=5 mg/ml/min every 3 weeks. or the cisplatin is administered at a dose of 75 mg/m2 every 3 weeks, and the pemetrexed at a dose of about 500 mg/m2 every 3 weeks on day 1 of each of four 21-day dosing cycles Administered as, use.

129. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with advanced nonsquamous NSCLC, comprising:

The method comprises administering to the subject or population of subjects:

(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 4 cycles of induction dosing for pemetrexed at a dose of about 500 mg/m2 per week; and

(ii) one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m2 every 3 weeks. administering, wherein at least one 21-day dosing cycle of said maintenance phase does not comprise administration of said carboplatin;

wherein the subject or population of subjects has not received prior systemic therapy for advanced nonsquamous NSCLC.

130. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with advanced nonsquamous NSCLC, comprising:

The method comprises administering to the subject or population of subjects:

(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 4 cycles of induction dosing for pemetrexed at a dose of about 500 mg/m2 per week; and

(ii) one or more maintenance phase dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m2 every 3 weeks. administering, wherein at least one 21-day dosing cycle of said maintenance phase does not comprise administration of said carboplatin;

wherein the subject has not received prior systemic therapy for advanced nonsquamous NSCLC.

131. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with advanced nonsquamous NSCLC, comprising:

The method comprises administering to the subject a dosing regimen comprising four 21 day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein the tiragolumab is Administered at a dose of about 600 mg every 3 weeks, the atezolizumab is administered at a dose of about 1200 mg every 3 weeks, the cisplatin is administered at a dose of 75 mg/m 2 , and the pemetrexed is administered 4 times on 21 days Use, administered at a dose of about 500 mg/m2 every 3 weeks on each day 1 of the cycle.

132. The method according to any one of embodiments 114 to 131,

wherein the treatment prolongs the PFS of the subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. The method according to any one of embodiments 114 to 132,

wherein said treatment results in a median PFS of a population of subjects from about 12.5 months to about 14.7 months.

134. The method according to any one of embodiments 114 to 133,

wherein the treatment prolongs the OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months.

135. The method according to any one of embodiments 114 to 134,

wherein said treatment results in a median OS in the subject population of about 27.5 months to about 32.0 months.

136. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with resectable lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks. Use, including steps.

137. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with resectable lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks. Use, including steps.

138. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of the dosing cycles is from about 30 mg to about 1200 mg every 3 weeks. Use comprising administering as neoadjuvant treatment a dose of anti-TIGIT antagonist antibody and a dose of about 80 mg to about 1600 mg of PD-1 axis binding antagonist every 3 weeks.

139. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of the dosing cycles is from about 300 mg to about 800 mg every 3 weeks. Use comprising administering as neoadjuvant treatment a dose of anti-TIGIT antagonist antibody and a dose of about 900 mg to about 1500 mg of PD-1 axis binding antagonist every 3 weeks.

140. The method of embodiment 138 or embodiment 139,

At least one of said dosing cycles is administered to said subject as adjuvant treatment with an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 every 3 weeks Use, comprising the step of:

141. The method of embodiment 140,

At least once in said dosing cycle administering to said subject as adjuvant treatment a dose of about 500 mg to about 700 mg of an anti-TIGIT antagonist antibody every 3 weeks and a dose of about 900 mg to about 1500 of a PD-1 axis binding antagonist every 3 weeks Use, comprising the step of:

142. The method according to any one of embodiments 138 to 141,

wherein the lung cancer is resectable lung cancer.

143. The method according to any one of embodiments 136 to 142,

wherein the lung cancer is early lung cancer.

144. The method according to any one of embodiments 136 to 143,

wherein the lung cancer is stage II, IIIA, or IIIB lung cancer.

145. The method according to any one of embodiments 136 to 144,

wherein the lung cancer does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor abnormality.

146. The method according to any one of embodiments 136 to 145,

wherein said subject is eligible for R0 resection for therapeutic purposes.

147. The method according to any one of embodiments 136 to 146,

wherein the subject has never received prior therapy for lung cancer.

148. The method of embodiment 147,

wherein said prior therapy is immunotherapy, chemotherapy, or radiotherapy.

149. The method according to any one of embodiments 136 to 148,

wherein the subject is eligible for platinum-based chemotherapy.

150. The method of any one of embodiments 136 to 149,

wherein the first dosing cycle is initiated prior to surgery.

151. The method of embodiment 150,

wherein at least 1, 2, 3, or 4 dosing cycles are completed prior to said surgery.

152. The method of embodiment 150 or embodiment 151,

4 dosing cycles are completed prior to the surgery.

153. The method according to any one of embodiments 136 to 152,

wherein at least one dosing cycle is initiated after surgery.

154. The method of embodiment 153,

16 dosing cycles completed after said surgery.

155. The method of any one of embodiments 150 to 154,

wherein the operation is lobectomy, lobectomy, bilobectomy, or pneumonectomy.

156. The method according to any one of embodiments 136 to 155,

The method further comprises radiation therapy.

157. The method of embodiment 156,

wherein the radiation therapy is post-operative radiation therapy.

158. The method according to any one of embodiments 136 to 157,

The method further comprises administering one or more chemotherapeutic agents.

159. The method of embodiment 158,

wherein said one or more chemotherapeutic agents are administered after surgery.

160. The method of embodiment 159,

wherein said one or more chemotherapeutic agents are administered in 4 dosing cycles after said surgery.

161. The method according to any one of embodiments 158 to 160,

wherein said at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

162. The method of embodiment 161:

(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;

(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is gemcitabine;

(c) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel;

(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or

(e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine.

163. The method according to any one of embodiments 136 to 162,

wherein the treatment results in an increase in the major pathological response rate (MPR) compared to the baseline MPR rate.

164. The method of embodiment 163,

The reference MPR ratio is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) use, which is the MPR rate of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

165. The method of any one of embodiments 136 to 164,

wherein said treatment results in a pathological complete response (pCR) and/or an increase in the pCR ratio compared to a baseline pCR ratio.

166. The method of embodiment 165,

The reference pCR ratio is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) the pCR ratio of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

167. The method according to any one of embodiments 136 to 166,

wherein said treatment results in an increase in event-free survival (EFS) compared to baseline EFS time.

168. The method of embodiment 167,

The reference EFS time is:

(a) a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; and/or

(b) use, which is the EFS time of a population of subjects receiving treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab.

169. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with resectable lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 600 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks. Use, including steps.

170. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of the dosing cycles is from about 30 mg to about 600 mg every 3 weeks. Use comprising administering as neoadjuvant treatment a dose of anti-TIGIT antagonist antibody and a dose of about 80 mg to about 1600 mg of PD-1 axis binding antagonist every 3 weeks.

171. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with resectable lung cancer, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapy. use comprising administering to the subject one or more dosing cycles of the agent.

172. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one of the dosing cycles comprises: anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent Use, comprising administering as an adjuvant treatment.

173. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with resectable lung cancer, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and: (a) (i) every 3 weeks a platinum-based chemotherapeutic agent at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m2 every 3 weeks; and (b) (i) an antimetabolite at a dose of about 500 mg/m2 every 3 weeks or about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle; or (ii) administering to the subject one or more dosing cycles of the taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every 3 weeks.

174. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one of the dosing cycles One dose is administered to the subject: (a) an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 600 mg every 3 weeks; (b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks; (c) at (i) a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or (ii) a platinum-based chemotherapeutic agent at a dose of about 75 mg/m2 every 3 weeks; and (d) administering a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) about 500 mg/m2 every 3 weeks or on days 1 and 8 of each dosing cycle. an antimetabolite at a dose of 1000 mg/m2 or about 1250 mg/m2; or (ii) a taxane at a dose of about 100 mg/m2, about 175 mg/m2, or about 200 mg/m2 every 3 weeks; wherein the treatment is neoadjuvant treatment.

175. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with resectable lung cancer, comprising:

The method comprises tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and:

(a)

(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or

(ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks; and

(b)

(i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks or gemcitabine at a dose of about 1000 mg/m2 or about 1250 mg/m2 on days 1 and 8 of each dosing cycle; or

(ii) administering to the subject one or more dosing cycles of paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks.

176. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having lung cancer,

The method comprises administering to the subject one or more dosing cycles of tiragolumab, atezolizumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one dosing cycle comprises said To the subject: (a) tyragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks; (c) administering a non-platinum-based chemotherapeutic agent, wherein the platinum-based chemotherapeutic agent: (i) achieves an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks a dose of carboplatin targeted to or (ii) cisplatin at a dose of about 75 mg/m2 every 3 weeks; and (d) a non-platinum-based chemotherapeutic agent, wherein the non-platinum-based chemotherapeutic agent is: (i) pemetrexed at a dose of about 500 mg/m2 every 3 weeks or about 1000 on days 1 and 8 of each dosing cycle gemcitabine at a dose of mg/m2 or about 1250 mg/m2; or (ii) paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; wherein the treatment is neoadjuvant treatment.

177. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with nonsquamous NSCLC, comprising:

The method comprises administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (a) at least one of the dosing cycles is about a 600 mg dose of tiragolumab every 3 weeks and administering to the subject as neoadjuvant treatment atezolizumab at a dose of 1200 mg every 3 weeks; (b) use of at least one dosing cycle comprising administering to the subject as adjuvant treatment a dose of about 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of atezolizumab every 3 weeks.

178. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with nonsquamous NSCLC, comprising:

The method comprises administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment, and to the subject: ( a) tyragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a targeted dose to achieve an AUC of 5 mg/mL/min every 3 weeks and pemetrexed at a dose of about 500 mg/m2 every 3 weeks; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and pemetrex at a dose of about 500 mg/m2 every 3 weeks; (II) at least one of said dosing cycles is adjuvant treatment with an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks Use comprising administering.

179. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment, and to the subject: ( a) tyragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles comprises administering as adjuvant treatment a dose of about 30 mg to about 1200 mg of tiragolumab every 3 weeks and a dose of about 80 mg to about 1600 mg of atezolizumab every 3 weeks Including, use.

180. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein:

(I) at least one of said dosing cycles is neoadjuvant treatment, to said subject:

(a) tyragolumab at a dose of about 1200 mg every 3 weeks;

(b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and

(c)

(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle;

(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or

(iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks or gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; and

(II) administering to the subject as adjuvant treatment at least one of said dosing cycles is tiragolumab at a dose of about 300 mg to about 800 mg every 3 weeks and atezolizumab at a dose of about 900 mg to about 1500 mg every 3 weeks Use, comprising the step of:

181. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having lung cancer, comprising:

The method comprises administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment, and to the subject: ( a) tyragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) use of at least one of said dosing cycles comprising administering as adjuvant treatment a dose of about 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of atezolizumab every 3 weeks.

182. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with resectable squamous NSCLC, comprising:

The method comprises administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein: (I) at least one of the dosing cycles is neoadjuvant treatment, and to the subject: ( a) tyragolumab at a dose of about 600 mg every 3 weeks; (b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m2 on days 1 and 8 of each dosing cycle; (ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m2 or about 200 mg/m2 every 3 weeks; or (iii) administering cisplatin at a dose of about 75 mg/m2 every 3 weeks and gemcitabine at a dose of about 1250 mg/m2 on days 1 and 8 of each dosing cycle; (II) at least one of said dosing cycles comprises administering as adjuvant treatment a dose of about 600 mg of tiragolumab every 3 weeks and a dose of about 1200 mg of atezolizumab every 3 weeks

183. The method according to any one of embodiments 136 to 182,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP263 is determined.

184. The method of embodiment 183,

The detectable protein expression level of PD-L1 is 50% or more in the fraction of PD-L1 positive tumor cells.

185. The method of any one of embodiments 73, 114 to 121, and embodiments 136 to 184,

wherein the lung cancer is NSCLC.

186. according to embodiment 185,

wherein said NSCLC is squamous NSCLC.

187. The method of embodiment 185,

wherein said NSCLC is non-squamous NSCLC.

188. The method of embodiment 72,

wherein the cancer is cervical cancer.

189. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1,

The method comprises administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or population of subjects. Use, comprising the step of administering to.

190. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1,

The method comprises administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks to the subject or population of subjects. Use, comprising the step of administering to.

191. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting a therapy for a subject with cervical cancer, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) an anti-TIGIT antagonist antibody administered at a dose of about 30 mg to about 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 and 3 use comprising selecting a regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist administered at a dose of about 80 mg to about 1600 mg per week

192. The method of any one of embodiments 189 to 191,

wherein the cervical cancer is squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma.

193. The method according to any one of embodiments 189 to 191,

wherein the cervical cancer is stage 4B, metastatic, recurrent, or persistent.

194. The method according to any one of embodiments 189 to 193,

wherein the cervical cancer is metastatic and/or recurrent PD-L1 positive cervical cancer.

195. The method of any one of embodiments 189 to 194,

The subject or subjects have received at least one line of prior therapy.

196. The method according to any one of embodiments 189 to 195,

wherein the subject or subjects have received two lines of prior therapy.

197. The method according to any one of embodiments 189 to 196,

The subject or subjects received more than 2 lines of prior therapy.

198. The method according to any one of embodiments 189 to 194,

wherein said subject or subjects have not received prior therapy.

199. The method according to any one of embodiments 195 to 198,

wherein said prior therapy is chemotherapy, surgery, and/or radiation therapy.

200. The method according to any one of embodiments 189 and 192 to 199,

wherein said treatment elicits a clinical response.

201. The method of embodiment 200,

wherein the clinical response is an increase in the objective response rate (ORR) of the subject population as compared to a baseline ORR.

202. The method of embodiment 201,

wherein the reference ORR is the median ORR of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody.

203. The method of embodiment 200,

wherein the reference ORR is at least about 14.6% to about 26%.

204. The method of embodiment 200,

wherein the clinical response is CR or PR.

205. The method of any one of embodiments 200 to 204,

The clinical response is an increase in progression-free survival (PFS) of the subject compared to a baseline PFS time, an increase in the duration of response (DOR) in the subject compared to a baseline DOR time, or an increase in the subject's progression-free survival (DOR) compared to a baseline OS time. Use, which is an increase in overall survival (OS).

206. The method of embodiment 205:

(a) said baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline DOR time is the median DOR time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) the baseline OS time is the median OS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

207. The use of an anti TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of treating a subject having cervical cancer having a detectable expression level of PD-L1,

Use comprising administering to the subject one or more dosing cycles of a 600 mg dose of anti-TIGIT antagonist antibody every 3 weeks and atezolizumab at a 1200 mg dose every 3 weeks.

208. Anti TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of identifying a subject with cervical cancer likely to benefit from a therapy comprising one or more dosing cycles of anti TIGIT antagonist antibody and atezolizumab As the use of

The method is:

(a) providing a tumor sample from the subject;

(a) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(c) one or more dosing cycles of anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks, based on PD-L1 expression on detected tumor cells. Use comprising identifying the subject as likely to benefit from a therapy comprising

209. The use of an anti TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of selecting a therapy for a subject with cervical cancer,

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) an anti-TIGIT antagonist antibody administered at a dose of 600 mg every 3 weeks and 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 Use comprising selecting a regimen comprising one or more dosing cycles of atezolizumab administered as a dose.

210. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having cervical cancer having a detectable expression level of PD-L1,

wherein the method comprises administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

211. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having cervical cancer, comprising:

The method is:

(a) obtaining a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) one or more dosing cycles of tyrazolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on PD-L1 expression on detected tumor cells. identifying the subject as likely to benefit from therapy; and

(d) administering said therapy to the identified subject.

212. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting a therapy for a subject having cervical cancer, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) tiragolumab administered at a dose of 600 mg every 3 weeks and a dose of 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 Selecting a regimen comprising one or more dosing cycles of atezolizumab administered as

213. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having metastatic and/or recurrent cervical cancer, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) one or more dosing cycles of tyrazolumab administered at a dose of 600 mg every 3 weeks and atezolizumab administered at a dose of 1200 mg every 3 weeks based on PD-L1 expression on detected tumor cells. identifying the subject as likely to benefit from therapy; and

(d) administering said therapy to the identified subject.

214. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting a therapy for a subject with metastatic and/or recurrent cervical cancer, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) tiragolumab administered at a dose of 600 mg every 3 weeks and a dose of 1200 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1 Selecting a regimen comprising one or more dosing cycles of atezolizumab administered as

215. The method of any one of embodiments 189 to 214,

wherein the subject is identified as likely to benefit from treatment based on PD-L1 expression on the detected tumor cells.

216. The method according to any one of embodiments 189 to 215,

Using, the PD-L1 expression level is detected using the anti-PD-L1 antibody SP263.

217. The method according to any one of embodiments 189 to 216,

wherein the detectable expression level of PD-L1 is greater than or equal to 5% of tumor associated immune cells (TICs) in the sample from the subject.

218. The method of any one of embodiments 189 to 215,

Using, PD-L1 expression levels are detected using anti-PD-L1 antibody 22C3.

219. The method of any one of embodiments 189 to 216,

wherein the detectable expression level of PD-L1 has a composite positive score (CPS) of 1 or greater in a sample from the subject.

220. The use of embodiment 72, wherein the cancer is breast cancer.

221. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects having breast cancer,

The method comprises one or more doses of tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and nap-paclitaxel at a dose of about 100 mg/m2 of 3 weeks dosing/1 week holiday. A use comprising administering to the subject or population of subjects a dosing regimen comprising a dosing cycle.

222. The method of embodiment 220 or embodiment 221,

wherein the breast cancer is triple negative breast cancer (TNBC).

223. The method of embodiment 222,

wherein said TNBC is resectable locally advanced or metastatic TNBC.

224. The method of any one of embodiments 220 to 223,

wherein the subject has not received prior systemic therapy for metastatic breast cancer.

225. The method of any one of embodiments 220-224,

wherein said treatment results in an ORR in at least about 53% to about 67.5% of the subject population.

226. The method of any one of embodiments 222 to 225,

wherein said treatment results in a median OS of a subject population of about 25.0 months.

227. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with early stage triple negative breast cancer (eTNBC), comprising:

The method comprises a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 10 mg to about 1000 mg every two weeks, and one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 20 mg to about 1600 mg every two weeks. use comprising administering to the subject.

228. The method of embodiment 227,

The method further comprises administering to the subject one or more chemotherapeutic agents.

229. The method of embodiment 228,

wherein said at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The method of embodiment 227,

The method comprises (a) one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, topoisomerase II inhibitor, alkylating agent, and granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) use, further comprising administering one or more dosing cycles of

231. The method of embodiment 229 or embodiment 230,

wherein the alkylating agent is cyclophosphamide.

232. The method of embodiment 231,

wherein the cyclophosphamide is administered at a dose of about 600 mg/m2.

233. The embodiment of any one of embodiments 227 to 229, embodiments 231 and 232,

Use, comprising further administering to the subject G-CSF or GM-CSF.

234. The method of embodiment 230 or embodiment 233,

The G-CSF is pegfilgrastim or filgrastim, use.

235. The method of embodiment 234,

The G-CSF is pegfilgrastim, use.

236. The method of embodiment 235,

wherein the pegfilgrastim is administered in a dose of about 6 mg.

237. The embodiment of any one of embodiments 228, 229, and embodiments 231 to 236,

wherein said method further comprises administering to said subject said one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF.

238. The embodiment of any one of embodiments 228, 229, and embodiments 231 to 237,

wherein said one or more chemotherapeutic agents and/or G-CSF or GM-CSF are administered once every week, once every 2 weeks, or once every 3 weeks, respectively.

239. The method of any one of embodiments 229 to 238,

The platinum-based chemotherapeutic agent is administered every 3 weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every 2 weeks, the alkylating agent is administered every 2 weeks, and the G-CSF or GM- CSF used, administered every two weeks.

240. The method of any one of embodiments 229 to 239,

wherein said taxane or said taxane and said platinum-based chemotherapeutic agent are administered during the first 12 weeks of said dosing regimen.

241. The method of any one of embodiments 229-240,

wherein said topoisomerase II inhibitor, said alkylating agent, and said G-CSF or GM-CSF are administered for 13 to 19 weeks of a dosing regimen.

242. The method according to any one of embodiments 227 to 241,

The total duration of the dosing regimen was 19 weeks, use.

243. The method of any one of embodiments 227 to 242,

The method is neoadjuvant treatment.

244. The method according to any one of embodiments 227 to 243,

wherein surgery is performed after said dosing regimen.

245. The method of embodiment 244,

wherein said surgery is performed between 2 and 6 weeks after the last dose of said dosing regimen.

246. The method of embodiment 244 or embodiment 245,

wherein said surgery comprises a mastectomy.

247. The method according to any one of embodiments 244 to 246,

wherein said surgery comprises axillary lymph node surgery.

248. The method of any one of embodiments 229 to 247,

wherein the topoisomerase II inhibitor is doxorubicin.

249. The method according to any one of embodiments 229 to 247,

wherein the taxane is nap-paclitaxel, the platinum-based chemotherapeutic agent is carboplatin, and the topoisomerase II inhibitor is doxorubicin.

250. The method of embodiment 248 or embodiment 249,

Doxorubicin is administered at a dose of about 60 mg/m2.

251. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks, a PD-1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

252. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks, a PD-L1 axis binding antagonist at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

253. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks, an anti-PD-L1 antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

254. Use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with eTNBC, comprising:

The method comprises tyragolumab at a dose of about 300 mg to about 600 mg every two weeks, an anti-PD-L1 antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

255. The use of an anti TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for a method of treating a subject with eTNBC, comprising:

The method comprises an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks, atezolizumab at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) a dose of about 125 mg/m2 of taxane every week for the first 12 weeks of the dosing regimen and a dose of platinum agent targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or

(b)

(i) a taxane at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) a topoisomerase II inhibitor at a dose of about 60 mg/m2 every 2 weeks, an alkylating agent at a dose of about 600 mg/m2 every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

256. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with eTNBC, comprising:

The method comprises tiragolumab at a dose of about 300 mg to about 600 mg every two weeks, atezolizumab at a dose of about 600 mg to about 1200 mg every two weeks, and:

(a)

(i) nap-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen CSF; or

(b)

(i) nap-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen administering to the subject a dosing regimen comprising CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

257. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with eTNBC, comprising:

The method comprises tiragolumab at a dose of about 420 mg every 2 weeks, atezolizumab at a dose of about 840 mg every 2 weeks, and:

(a)

(i) nap-paclitaxel at a dose of about 125 mg/m2 every week for the first 12 weeks of the dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen CSF; or

(b)

(i) nap-paclitaxel at a dose of about 125 mg/m2 weekly for the first 12 weeks of said dosing regimen; and

(ii) doxorubicin at a dose of about 60 mg/m2 every 2 weeks, cyclophosphamide at a dose of about 600 mg/m2 every 2 weeks, and G-CSF or GM- every 2 weeks for weeks 13 to 19 of the dosing regimen administering to the subject a dosing regimen comprising CSF;

wherein the method further comprises surgery between 2 and 6 weeks after the last dose of the dosing regimen.

258. The method of any one of embodiments 220 to 257,

wherein the detectable protein expression level of PD-L1 is determined in a tumor sample from said subject determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142.

259. The method of embodiment 258,

In the tumor sample, the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC) is 1% or more.

260. The method of any one of embodiments 227 to 259,

wherein said eTNBC is referred to as T2-4d TNBC.

261. The method according to any one of embodiments 227 to 260,

wherein the eTNBC is presented as cT2-cT4, cN0-cN3, and cM0 TNBC.

262. The method of any one of embodiments 227 to 261,

wherein the subject has not been previously treated for eTNBC.

263. The method according to any one of embodiments 227 to 262,

wherein said treatment results in a pathological complete response (pCR).

264. The method of any one of embodiments 227 to 263,

wherein the treatment results in an increase in overall survival (OS) or event-free survival (EFS).

265. The method of embodiment 72,

wherein the cancer is head and neck cancer.

266. The method of embodiment 265,

wherein the head and neck cancer is squamous cell carcinoma (SCCHN) of the head and neck.

267. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1, the use of

The method comprises administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or population of subjects. Use, comprising the step of administering to.

268. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1,

The method comprises administering one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks to the subject or population of subjects. Use, comprising the step of administering to.

269. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting a therapy for a subject or population of subjects with SCCHN,

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and 3 weeks based on PD-L1 expression detected for said subject or population of subjects having a detectable expression level of PD-L1 selecting a regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg per time.

270. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1, the use of

wherein the method comprises administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

271. The method according to any one of embodiments 267 to 270,

wherein said subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

272. The method of any one of embodiments 266 to 271,

wherein the SSCHN is human papillomavirus (HPV) positive.

273. The method according to any one of embodiments 266 to 272,

wherein the SSCHN is HPV negative.

274. The method of embodiment 272 or embodiment 273,

HPV status is determined by p16 IHC, in situ hybridization, or PCR.

275. The method according to any one of embodiments 266 to 274,

wherein said SCCHN is recurrent and/or metastatic SCCHN.

276. The method according to any one of embodiments 265 to 275,

wherein said subject or subjects have not received prior therapy.

277. The method of embodiment 276,

wherein said prior therapy is prior systemic therapy for recurrent and/or metastatic disease.

278. The embodiment of any one of embodiments 265-268 and embodiments 270-277,

wherein said treatment causes CR or PR.

279. The method according to any one of embodiments 265 to 268 and 270 to 277,

wherein said treatment results in an increase in objective response rate (ORR) in said subject population compared to a baseline ORR.

280. The method of embodiment 279,

wherein the reference ORR is the median ORR of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody.

281. The method of embodiment 279 or embodiment 280,

wherein the reference ORR is at least about 19% to about 36%.

282. The method of any one of embodiments 265-268 and 270-281,

wherein the treatment is associated with an increase in progression-free survival (PFS) of the subject or subject population as compared to a baseline PFS time, an increase in the duration of response (DOR) of the subject or subject population compared to a baseline DOR time, or a baseline OS time and as compared to cause an increase in overall survival (OS) of the subject or population of subjects.

283. The method of embodiment 282:

(a) said baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline DOR time is the median DOR time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) the baseline OS time is the median OS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

284. The method of embodiment 282,

wherein the baseline DOR time is at least about 6.7 months to about 23.4 months.

285. The method of embodiment 282,

wherein the baseline OS time is at least about 11.6 months to about 14.9 months.

286. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

The method comprises administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti-TGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks. Use, including steps.

287. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

wherein the method comprises administering to the subject one or more dosing cycles of an anti-TGIT antagonist antibody at a dose of about 1200 mg every 3 weeks and an anti-TGIT antagonist antibody at a dose of about 600 mg every 3 weeks.

288. The use of an anti-TIGIT antagonist antibody and a PD-L1 binding antagonist in the manufacture of a medicament for a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

The method comprises administering to the subject one or more dosing cycles of a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti-TGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks. including, use.

289. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

Use comprising administering to the subject one or more dosing cycles of atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks.

290. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject having SCCHN having a detectable expression level of PD-L1, comprising:

wherein the method comprises administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

291. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) administering the subject to one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks. identifying as a person likely to benefit from; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

292. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) administering the subject to a regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks and an anti-TIGIT antagonist antibody at a dose of about 600 mg every 3 weeks. confirming as; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

293. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) subjecting the subject to one or more dosing cycles of atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks. identifying as a potential person; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

294. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject with SCCHN, comprising:

The method is:

(a) providing a tumor sample from the subject;

(b) detecting the protein expression level of PD-L1 in said tumor sample by IHC analysis using an anti-PD-L1 antibody suitable for staining;

(c) identifying the subject as likely to benefit from a therapy comprising one or more dosing cycles of atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks. ; and

(d) administering said therapy to an identified subject having a detectable expression level of PD-L1.

295. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting a therapy for a subject with SCCHN, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and about 30 every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 selecting a regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of mg to about 1200 mg.

296. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of selecting a therapy for a subject with SCCHN, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) a dose of about 1200 mg of a PD-1 axis binding antagonist every 3 weeks and a dose of about 600 mg of anti every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 A use comprising selecting a regimen comprising one or more dosing cycles of the TIGIT antagonist antibody.

297. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting a therapy for a subject with SCCHN, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks and about 30 mg to about every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 and selecting a regimen comprising one or more dosing cycles of tiragoluumab at a dose of 1200 mg.

298. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of selecting a therapy for a subject with SCCHN, comprising:

The method is:

(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and

(b) atezolizumab at a dose of about 1200 mg every 3 weeks and tiragolumab at a dose of about 600 mg every 3 weeks based on PD-L1 expression detected for said subject having a detectable expression level of PD-L1 Use, comprising selecting a regimen comprising one or more dosing cycles.

299. The method according to any one of embodiments 267 to 298,

wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1 determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody SP263.

300. The method of embodiment 299,

The detectable protein expression level of PD-L1 is in the tumor sample:

(a) at least 5%;

(b) at least 5% and less than 20%; or

(c) at least 20% tumor-associated immune cells (TICs).

301. would benefit from a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of identifying a subject with SCCHN as a probable one, comprising:

The method comprises detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the protein of PD-L1 has a TIC of at least 5%. The expression level identifies the subject as likely to benefit from the therapy.

302. would benefit from a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of identifying a subject with SCCHN as a probable one, comprising:

The method comprises detecting the protein expression level of PD-L1 in a tumor sample from the subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the PD-L1 TIC is greater than or equal to 5% and less than 20%. wherein the protein expression level of L1 identifies the subject as likely to benefit from the therapy.

303. would benefit from a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks and an anti TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of identifying a subject with SCCHN as a probable one, comprising:

The method comprises detecting the protein expression level of PD-L1 in a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining, wherein the protein of PD-L1 has a TIC of at least 20%. The expression level identifies the subject as likely to benefit from the therapy.

304. The method of any one of embodiments 301 to 303,

wherein said subject is identified as likely to benefit from said therapy and said method further comprises administering said therapy to said subject.

305. The method of any one of embodiments 301 to 304,

The TIC used, determined using the Ventana SP263 IHC assay.

306. The method of any one of embodiments 267 to 305,

wherein the subject or population of subjects is identified as likely to benefit from treatment based on PD-L1 expression on the detected tumor cells.

307. The method of embodiment 72,

wherein the cancer is liver cancer.

308. The method of embodiment 307,

wherein the liver cancer is hepatocellular carcinoma (HCC).

309. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having hepatocellular carcinoma (HCC), comprising:

The method comprises administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject or population of subjects has not received prior systemic therapy for HCC. no, use.

310. The method of embodiment 309,

The method further comprises administering to the subject or population of subjects a VEGF antagonist.

311. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having HCC, comprising:

wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist.

312. The method of embodiment 310 and embodiment 311,

wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks.

313. The method of any one of embodiments 309 to 312,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 3 weeks.

314. The method of embodiment 313,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 800 mg every 3 weeks.

315. The method of any one of embodiments 309 to 314,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks.

316. The method of any one of embodiments 309 to 315,

wherein the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 1600 mg every 3 weeks.

317. The method of any one of embodiments 309 to 316,

wherein the PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every 3 weeks.

318. The method of embodiment 310 or embodiment 311,

wherein the VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks.

319. The method of embodiment 318,

wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 10 mg/kg every two weeks.

320. The method of embodiment 319,

wherein the VEGF antagonist is administered at a dose of about 5 mg/kg, about 7.5 mg/kg, or about 10 mg/kg every two weeks.

321. The embodiment of any one of embodiments 309 to 311 and embodiments 318 to 320,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10 mg to about 1000 mg every two weeks.

322. The embodiment of any one of embodiments 309 to 311 and embodiments 318 to 321,

wherein the PD-1 axis binding antagonist is administered at a dose of about 20 mg to about 1600 mg every two weeks.

323. according to embodiment 309 to embodiment 311,

wherein the anti-TIGIT antagonist antibody is administered at a dose of about 200 mg to about 2000 mg every 4 weeks.

324. The method according to any one of embodiments 309 to 311 and 323,

wherein the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 4 weeks.

325. The embodiment of any one of embodiments 309 to 311, 323, and 324,

wherein the PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every 4 weeks.

326. The method of any one of embodiments 309 to 325,

wherein the HCC is locally advanced or metastatic HCC.

327. The method of any one of embodiments 309 to 326,

wherein the HCC is unresectable HCC.

328. The method of any one of embodiments 309 to 327,

wherein the subject or subjects is determined to have adequate liver function.

329. The method of embodiment 328,

wherein said adequate liver function is characterized by Child-Pugh class A.

330. The method of any one of embodiments 309 to 329,

wherein the subject or HCC tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

331. The method of any one of embodiments 309 to 330,

wherein the method comprises administering to the subject or population of subjects at least 4 dosing cycles.

332. The method of embodiment 331,

wherein the method comprises administering to the subject or population of subjects at least 16 dosing cycles.

333. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects having HCC,

administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and bevacizumab at a dose of about 15 mg/kg every 3 weeks. Use, including steps.

334. The method of any one of embodiments 311 to 333,

The subject or subjects have not received prior systemic treatment for HCC.

335. The method of any one of embodiments 309 to 334,

wherein said treatment results in a median PFS in the subject population of at least about 5.6 months to at least about 6.83 months.

336. The method of embodiment 72,

wherein the cancer is bladder cancer.

337. The method of embodiment 336,

wherein the bladder cancer is muscle invasive bladder cancer (MIBC).

338. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the subject is ineligible for treatment with a platinum-based chemotherapeutic agent.

339. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks wherein the subject is ineligible for treatment with a platinum-based chemotherapeutic agent.

340. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC,

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the treatment is perioperative treatment.

341. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks wherein the treatment is perioperative treatment.

342. The method of any one of embodiments 338 to 341,

wherein the subject or subjects have a creatinine clearance of less than 60 mL/min.

343. The method of any one of embodiments 338 to 342,

wherein the subject or subjects have a hearing loss of grade 2 or greater.

344. The method of any one of embodiments 338 to 343,

wherein said subject or subjects have grade 2 or greater neuropathy.

345. The method of any one of embodiments 338 to 344,

The subject or subjects refused treatment with a platinum-based chemotherapeutic agent.

346. The method according to any one of embodiments 338 or 342 to 345,

The platinum-based chemotherapeutic agent is cisplatin.

347. The method of any one of embodiments 338 to 346,

The MIBC can be used, surgically.

348. The method of embodiment 347,

The method further comprises surgery.

349. The method of embodiment 348,

at least one dosing cycle is initiated prior to the surgery.

350. The method of embodiment 348 or embodiment 349,

wherein at least 1, 2, or 3 dosing cycles are completed prior to the surgery.

351. The method of any one of embodiments 348 to 350,

wherein at least one dosing cycle is initiated between 4 and 6 weeks after said surgery.

352. The method of embodiment 351,

1 to 17 dosing cycles are completed after said surgery.

353. The method of any one of embodiments 348 to 352,

wherein the operation is cystectomy and/or lymphadenectomy.

354. The method of any one of embodiments 338 to 353,

wherein said treatment results in a pathological complete response (pCR).

355. The method of any one of embodiments 338 to 354,

wherein the treatment is an increase in relapse-free survival (RFS) of the subject or subjects as compared to a baseline RFS time, an increase in the event-free survival (EFS) of the subject or subjects compared to a baseline EFS time, or an increase in the event-free survival (EFS) of the subject or subjects as compared to a baseline OS time. causing an increase in OS of the subject or subjects.

356. The method of embodiment 355:

(a) said baseline RFS time is the median RFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;

(b) said baseline EFS time is the median EFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or

(c) the baseline OS time is the median OS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

357. The method of any one of embodiments 338 to 356,

wherein said treatment results in pathological downstaging.

358. Use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC,

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the subject is cisplatin ineligible.

359. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the treatment is perioperative treatment.

360. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the subject is cisplatin ineligible.

361. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks wherein the treatment is perioperative treatment.

362. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks and atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks; , wherein the subject is cisplatin ineligible.

363. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks and atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks; , wherein said treatment is perioperative treatment.

364. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks, wherein the subject or subjects have cisplatin ineligible for use.

365. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with MIBC, comprising:

administering to said subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks, wherein said treatment comprises perioperative treatment In, use.

366. The method of any one of embodiments 338-365,

wherein said treatment results in an ORR in at least about 13.4% to about 15% of the subject population.

367. The method of any one of embodiments 338 to 366,

wherein said treatment results in a median OS in the subject population of at least about 7.9 months to about 8.6 months.

368. The method of any one of embodiments 338 to 367,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142 is determined.

369. The method of embodiment 368,

wherein the detectable protein expression level of PD-L1 is a fraction of PD-L1-positive tumor cells in which the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC) is 5% or more.

370. The method of embodiment 336,

wherein the bladder cancer is urothelial cell carcinoma (UC).

371. The method of embodiment 370,

wherein the UC is metastatic urothelial cell carcinoma (mUC).

372. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or subject. Use comprising administering to a population.

373. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks to the subject or subject. Use comprising administering to a population.

374. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or subject. administering to a population, wherein the subject has not received prior cancer immunotherapy.

375. Use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks to the subject or subject. administering to a population, wherein said treatment is a second line treatment.

376. The method of any one of embodiments 372, 372, and 375,

wherein said subject or subjects have not received prior cancer immunotherapy.

377. The method according to any one of embodiments 372 to 374,

wherein the treatment is a second line treatment.

378. The method of any one of embodiments 372 to 377,

wherein said mUC proceeds during or after platinum containing therapy.

379. The method according to any one of embodiments 372 to 378,

The method further comprises administering a second dosing regimen to the subject or subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity.

380. The method of embodiment 379,

wherein the second dosing regimen comprises one or more dosing cycles of the PD-1 axis binding antagonist and the antibody-drug conjugate (ADC).

381. The method of embodiment 380,

wherein said ADC is (a) enfortumab vedotin or (b) sacituzumab gobitecan.

382. The method of embodiment 381,

(a) enfortumab vedotin is administered at a weekly dose of 1.25 mg/kg on a 2-week dosing/week break, or (b) sacituzumab gobitecan is administered at 10 mg/week on a 2-week dos/week break Administered in kg dose, use.

383. The method of embodiment 381 or embodiment 382,

(a) enfortumab vedotin is administered at a dose of 1.25 mg/kg on days 1 and 8 of each 21-day cycle, or (b) sacituzumab gobitecan is administered on day 1 of each 21-day cycle and use, administered at a dose of 10 mg/kg on day 8.

384. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks; Use, comprising the step of administering to.

385. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of tyragolumab at a dose of about 30 mg to about 1200 mg every 3 weeks and atezolizumab at a dose of about 80 mg to about 1600 mg every 3 weeks Use, including steps.

386. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

Use comprising administering to said subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks.

387. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

The method comprises administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein:

(a) said first dosing regimen comprises at least one dosing cycle of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks comprising; and

(b) said second dosing regimen comprises one or more dosing cycles of the PD-1 axis binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, and (i) Enfortumab vedotin is administered for 2 weeks. administered at a weekly dose of 1.25 mg/kg with a weekly break of one week, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg with a two-week dosing/1 week off, wherein the second dosing regimen is wherein said subject or population of subjects experiences disease progression or unacceptable toxicity during said first dosing regimen.

388. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

The method comprises administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein:

(a) said first dosing regimen comprises one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks and a PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks including; and

(b) said second dosing regimen comprises one or more dosing cycles of the PD-L1 binding antagonist at a dose of about 80 mg to about 1600 mg every 3 weeks, (i) Enfortumab vedotin is administered for 2 weeks / administered at a weekly dose of 1.25 mg/kg with a one-week break, or (ii) sacituzumab gobitecan is administered at a weekly dose of 10 mg/kg with a two-week dosing/week break, wherein the second dosing regimen is administered to the subject after the subject experiences disease progression or unacceptable toxicity during said first dosing regimen.

389. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects with mUC, comprising:

The method comprises administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein:

(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; and

(b) said second dosing regimen comprises at least one dosing cycle of atezolizumab at a dose of about 1200 mg every 3 weeks, and (i) enfortumab vedotin is administered at 1.25 weekly doses of 2 weeks on/1 week off. is administered in a mg/kg dose, or (ii) sacituzumab gobitecan is administered at a weekly 10 mg/kg dose of 2 weeks dosing/1 week off, wherein the second dosing regimen is such that the subject administers the first dose The use of which is administered to a subject after experiencing disease progression or unacceptable toxicity during therapy.

390. The method of any one of embodiments 372 to 389,

wherein said treatment results in an ORR in at least about 13.4% to at least about 31% of the subject population.

391. The method of any one of embodiments 372 to 390,

wherein said treatment results in a median OS in the subject population of about 7.9 months to about 16.3 months.

392. The method of embodiment 72,

wherein the cancer is pancreatic cancer.

393. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects having pancreatic cancer,

Tiragolumab at a dose of about 420 mg on days 1 and 15 of each 28-day dosing cycle, atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle, each 28 days. Gemcitabine at a dose of about 1000 mg/m2 on days 1, 8, and 15 of the dosing cycle, and at a dose of about 125 mg/m2 on days 1, 8, and 15 of each 28-day dosing cycle. A use comprising administering to the subject or population of subjects a dosing regimen comprising at least one 28-day dosing cycle of nap-paclitaxel.

394. The method of embodiment 392 or embodiment 393,

wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

395. The method of embodiment 394,

wherein the PDAC is a metastatic PDAC.

396. The method of any one of embodiments 392 to 395,

The subject or subjects have not received prior systemic therapy for metastatic PDAC.

397. The method of any one of embodiments 392 to 396,

wherein said treatment results in an ORR in at least about 41.7% to about 46.7% of the subject population.

398. The method of any one of embodiments 392 to 397,

wherein said treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nap-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

399. The method of any one of embodiments 392 to 398,

wherein said treatment results in a median PFS in the subject population of at least about 5.5 months to about 7 months.

400. The method of any one of embodiments 392 to 399,

wherein said treatment results in a median OS in the subject population of at least about 8.5 months to about 10.6 months.

401. The method of embodiment 72,

wherein the cancer is esophageal cancer.

402. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

One or more times 21 of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. A use comprising administering to the subject or population of subjects a dosing regimen comprising a dosing cycle.

403. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

One or more 21 doses of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle 21 A use comprising administering to the subject or population of subjects a dosing regimen comprising a dosing cycle.

404. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having esophageal cancer,

The method comprises one dose of an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and a dose of about 80 mg to about 1600 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. administering to the subject or population of subjects a dosing regimen comprising at least 21 dosing cycles, wherein the subject has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

405. Use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having esophageal cancer,

The method comprises one dose of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 800 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. administering to the subject or population of subjects a dosing regimen comprising at least 21 dosing cycles, wherein the subject has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

406. The method of embodiment 402 or embodiment 403,

wherein the subject or subjects has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. The method of embodiment 404 or embodiment 406,

wherein said subject or subjects experienced disease progression or unacceptable toxicity during said prior treatment.

408. The method of embodiment 402 or embodiment 403,

The 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

409. The method of embodiment 408,

wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses.

410. The method of any one of embodiments 404 to 409,

The platinum-based chemotherapeutic agent is cisplatin.

411. The method of embodiment 410,

Cisplatin is administered at a dose of about 80 mg/m2 on Day 1 of each dosing cycle.

412. The method of any one of embodiments 404 to 411,

The non-platinum-based chemotherapeutic agent is an antimetabolites.

413. The method of embodiment 412,

wherein the antimetabolite is 5-fluorouracil.

414. The method of embodiment 413,

5-fluorouracil is administered at a dose of about 800 mg/m2/24 hours on days 1-5 of each 21-day cycle.

415. The method of any one of embodiments 404 to 414,

wherein the esophageal cancer is advanced or metastatic esophageal cancer.

416. The embodiment of any one of embodiments 402, 403, 408, and 409,

wherein said subject or subjects have not received prior treatment for metastatic esophageal cancer.

417. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

Anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle, a dose of about 80 mg to about 1600 mg of PD-1 axis binding antagonist on Day 1 of each dosing cycle, One or more 21 doses of a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on Day 1, and a non-platinum-based chemotherapeutic agent at a dose of about 800 mg/m2/24 hours on days 1-5 of each 21-day cycle. administering to the subject or population of subjects a dosing regimen comprising one dosing cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses.

418. The use of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer,

Anti-TIGIT antagonist antibody at a dose of about 600 mg on day 1 of each dosing cycle, a dose of about 1200 mg of PD-1 axis binding antagonist on day 1 of each dosing cycle, about 80 mg/day on day 1 of each dosing cycle a dosing regimen comprising one or more 21-day dosing cycles of cisplatin at an m2 dose, and 5-fluorouracil at a dose of about 800 mg/m2/24 hour on days 1-5 of each 21-day cycle to the subject or subject administering to a population, wherein splatin is omitted from said dosing regimen after 6 doses.

419. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

Tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle, cisplatin at a dose of about 80 mg/m2 on day 1 of each dosing cycle and administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of 5-fluorouracil at a dose of about 800 mg/m2/24 hours on days 1-5 of each 21-day cycle. wherein cisplatin is omitted from said dosing regimen after 6 doses.

420. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

The method comprises administering a first dosage regimen and a second dosage regimen to the subject or population of subjects, wherein:

(a) said first dosing regimen comprises at least one 21-day dosing cycle of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses; ; and

(b) said second dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and PD- at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle. Use comprising one or more 21 day dosing cycles of a uniaxial binding antagonist.

421. The use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, comprising:

The method comprises administering a first dosage regimen and a second dosage regimen to the subject or population of subjects, wherein:

(a) said first dosing regimen comprises a platinum-based chemotherapeutic agent at a dose of about 80 mg/m2 on Day 1 of each dosing cycle and 800 mg/m2/24 hour dose on Days 1-5 of each 21-day cycle. at least one 21-day dosing cycle of a non-platinum-based chemotherapeutic agent, wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses; and

(b) said second dosing regimen comprises an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg on Day 1 of each dosing cycle and PD- at a dose of about 80 mg to about 1600 mg on Day 1 of each dosing cycle. Use comprising one or more 21 day dosing cycles of a uniaxial binding antagonist.

422. The use of tiragolumab and atezolizumab in the manufacture of a medicament for a method of treating a subject or population of subjects having advanced or metastatic esophageal cancer,

The method comprises administering a first dosage regimen and a second dosage regimen to the subject or population of subjects, wherein:

(a) said first dosing regimen is cisplatin at a dose of about 80 mg/m2 on day 1 of each dosing cycle and 5-fluoro at a dose of 800 mg/m2/24 hours on days 1-5 of each 21 day cycle one or more 21-day dosing cycles of lauracil, wherein cisplatin is omitted from said dosing regimen after 6 doses; and

(b) said second dosing regimen is one or more 21 day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle including, use.

423. The method of any one of embodiments 402 to 422,

wherein said treatment results in an ORR in at least about 14% of the subject population.

424. The method according to any one of embodiments 47 to 423,

The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):

HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);

HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

A use comprising an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

425. The method of embodiment 424,

The anti-TIGIT antagonist antibody has the following light chain variable region framework regions (FR):

FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);

FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);

FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and

The use, further comprising FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

426. The method of embodiment 424,

The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs:

FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X1 is E or Q;

FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);

FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and

The use, further comprising FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

427. The method of embodiment 426,

X1 is E, use.

428. The method of embodiment 426,

X1 is Q, use.

429. The method of any one of embodiments 424 to 428,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or

(c) a use comprising a VH domain as in case (a) and a VL domain as in case (b).

430. The method of any one of embodiments 424 to 429,

The anti-TIGIT antagonist antibody is:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and

(b) A use comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19.

431. The embodiment of any one of embodiments 424 to 427, 429, and 430,

The anti-TIGIT antagonist antibody is:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and

(b) A use comprising a VL domain comprising the amino acid sequence of SEQ ID NO:19.

432. The method of any one of embodiments 424 to 427 and embodiments 429 to 431,

The anti-TIGIT antagonist antibody is:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and

(b) use comprising a light chain comprising the amino acid sequence of SEQ ID NO:34.

433. The method of any one of embodiments 424 to 432,

wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

434. The method of any one of embodiments 424 to 433,

wherein the anti-TIGIT antagonist antibody is a human antibody.

435. The method of any one of embodiments 424 to 434,

wherein the anti-TIGIT antagonist antibody is a full-length antibody.

436. The method of any one of embodiments 424 to 427 and embodiments 429 to 436,

wherein the anti-TIGIT antagonist antibody is tyragolumab.

437. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, embodiment 421, and embodiment any one of embodiments 424 to 436,

wherein said anti-TIGIT antagonist antibody is tiragolumab, bivostoliumab, ethigiliumab, EOS084448, SGN-TGT or TJ-T6.

438. The method of embodiment 437,

wherein said anti-TIGIT antagonist antibody has prototypical Fc-mediated effector function.

439. according to embodiment 437 or embodiment 438,

wherein said anti-TIGIT antagonist antibody has enhanced Fc-mediated effector function.

440. The method of any one of embodiments 437 to 439,

wherein the anti-TIGIT antagonist antibody is SGN-TGT.

441. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, and embodiment 421 according to any one of embodiments,

wherein the anti-TIGIT antagonist antibody is dombanalimab, BMS-986207, ASP8374 or COM902.

442. The embodiment of any one of embodiments 424 to 431, and embodiment 441,

wherein said anti-TIGIT antagonist antibody has no Fc-mediated effector function.

443. The method according to any one of embodiments 47 to 442,

wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

444. The method of embodiment 443,

wherein said IgG class antibody is an IgG1 subclass antibody.

445. of embodiment 444,

wherein said anti-TIGIT antagonist antibody is tiragolumab, bivostolimab, etigilumab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, dombanalimab, or BMS-986207.

446. Embodiment 47 to embodiment 112, embodiment 114 to embodiment 127, embodiment 136 to embodiment 174, embodiment 188 to embodiment 209, embodiment 227 to embodiment 253, embodiment 255, embodiment 265 to Embodiment 269, Embodiment 286 to Embodiment 288, Embodiment 291, Embodiment 292, Embodiment 295, Embodiment 296, Embodiment 301 to Embodiment 332, Embodiment 336 to Embodiment 361, Embodiment 370 to Embodiment 384, embodiment 387, embodiment 388, embodiment 401 to embodiment 418, embodiment 420, and embodiment 421,

wherein said IgG class antibody is an IgG4 subclass antibody.

447. The method of embodiment 446,

wherein the anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. The method of any one of embodiments 424 to 434,

wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, bis-Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab')2 fragment, use.

449. The method of any one of embodiments 424 to 448,

wherein the anti-TIGIT antagonist antibody is a monospecific antibody.

450. The method of any one of embodiments 424 to 448,

wherein the anti-TIGIT antagonist antibody is a multispecific antibody.

451. The method of embodiment 450,

wherein said multispecific antibody is a bispecific antibody.

452. The method of any one of embodiments 424 to 451

wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

453. The method of embodiment 452,

wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

454. The method of embodiment 453,

wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

455. The method of embodiment 454,

wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1.

456. The method according to any one of embodiments 453-455,

wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The method of embodiment 456,

The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636, used.

458. The method of embodiment 457,

wherein the anti-PD-L1 antagonist antibody is atezolizumab.

459. The method of embodiment 456,

The anti-PD-L1 antagonist antibody has the following HVRs:

HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);

HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);

HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22);

HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);

HVR-L2 comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and

use comprising HVR-L3 comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25).

460. The method of embodiment 459,

The anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or

(c) a use comprising a VH domain as in case (a) and a VL domain as in case (b).

461. The method of embodiment 460,

The anti-PD-L1 antagonist antibody comprises:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and

(b) A use comprising a VL domain comprising the amino acid sequence of SEQ ID NO:27.

462. The method of embodiment 461,

The anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 28; and

(b) A use comprising a light chain comprising the amino acid sequence of SEQ ID NO:29.

463. The method according to any one of embodiments 459 to 462,

wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

464. The method of any one of embodiments 459 to 463,

wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

465. The method of embodiment 463 or embodiment 464,

wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

466. The method according to any one of embodiments 459 to 464,

wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab')2 fragments.

467. The method according to any one of embodiments 459 to 465,

wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

468. The method of embodiment 467,

wherein said IgG class antibody is an IgG1 subclass antibody.

469. The method of embodiment 452,

wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. The method of embodiment 469,

wherein the PD-1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

471. The method of embodiment 470,

wherein the PD-1 binding antagonist inhibits PD-L1 from binding to PD-L1, PD-L2, or both PD-L1 and PD-L2.

472. The method according to any one of embodiments 469 to 471,

wherein said PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The method of embodiment 472,

Said anti-PD-L1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, progolimab, camrelizumab, scintilimab, tislelizumab, torifaliz Mab, dostalimab, retipanrimab, sasanrimab, fenfulimab, CS1003, HLX10, SCT-I10A, zimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21, for use.

474. The method according to any one of embodiments 469 to 471,

wherein the PD-1 binding antagonist is an Fc fusion protein.

475. The method of embodiment 474,

The Fc fusion protein is AMP-224, use.

476. The embodiment of any one of embodiments 80-112, 114-127, and embodiments 309-312,

wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody at a dose of about 30 mg to about 1200 mg every 3 weeks.

477. Embodiment 51, Embodiment 54, Embodiment 60, Embodiment 62, Embodiment 63, Embodiment 65-67, Embodiment 80-112, Embodiment 114-127, Embodiment 136- Embodiment 140, embodiment 169-174, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301, embodiment 302, embodiment 303, embodiment 313, embodiment 315, embodiment 338, embodiment 340, embodiment 358 to embodiment 361, embodiment 372, embodiment 384, embodiment 387, embodiment 388, embodiment 402 to The embodiment of any one of embodiments 404, 417, 420, 421, and 476,

wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 600 mg every 3 weeks.

478. Embodiment 51, Embodiment 54, Embodiment 60, Embodiment 62, Embodiment 63, Embodiment 65-67, Embodiment 80-112, Embodiment 114-127, Embodiment 136- Embodiment 140, embodiment 169-174, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301, embodiment 302, Embodiment 303, Embodiment 309, Embodiment 313, Embodiment 315, Embodiment 338, Embodiment 340, Embodiment 358 to Embodiment 361, Embodiment 372, Embodiment 384, Embodiment 387, Embodiment 388, The embodiment of any one of Embodiments 402 to 404, Embodiment 417, Embodiment 420, Embodiment 421, and Embodiment 476,

The method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects in stepwise doses based on the body weight of said subject, wherein said subject has a body weight of:

(a) weighing 15 kg or less, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg every 3 weeks;

(b) greater than 15 kg and less than or equal to 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 400 mg every 3 weeks; or

(c) greater than 40 kg, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks.

479. The embodiment of any one of embodiments 47, 48, 77, 78, 82, and 83,

wherein said method comprises administering said anti TIGIT antagonist antibody to said subject or population of subjects at a dose of about 700 mg to about 1000 mg every 4 weeks.

480. The embodiment of any one of embodiments 47, 48, 59, 67, 323, and 479,

wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 840 mg every 4 weeks.

481. The embodiment of any one of embodiments 49, 50, and 104,

wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 300 mg to about 600 mg every two weeks.

482. The embodiment of any one of embodiments 49, 50, 227, 251 to 253, 255, and 481,

wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject at a dose of about 420 mg every two weeks.

483. The method according to any one of embodiments 47 to 482,

wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose.

484. The embodiment of any one of embodiments 54, 62, 63, 65-67, 80-109, and 27-2698,

wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects at a dose of about 900 mg to about 1500 mg every 3 weeks.

485. embodiment 54, embodiment 60, embodiment 62, embodiment 63, embodiment 65-67, embodiment 80-112, embodiment 114-127, embodiment 136-140, Embodiment 169 to embodiment 172, embodiment 189, embodiment 191, embodiment 267, embodiment 269, embodiment 286, embodiment 288, embodiment 291, embodiment 295, embodiment 301 to embodiment 303, embodiment 309, embodiment 311, embodiment 313, embodiment 315, embodiment 338, embodiment 340, embodiment 358 to embodiment 361, embodiment 372 to embodiment 375, embodiment 384, embodiment 387, embodiment 388, The embodiment of any one of Embodiments 402 to 405, Embodiment 417, Embodiment 420, Embodiment 421, and Embodiment 484,

wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 1200 mg every 3 weeks.

486. The embodiment of any one of embodiments 47, 50, 80-109, and embodiment 324,

wherein the method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist at a dose of about 1400 mg to about 2000 mg every 4 weeks.

487. The embodiment of any one of embodiments 47, 50, 59, 67, 324, and 479,

wherein said method comprises administering said PD-1 axis binding antagonist to said subject at a dose of about 1680 mg every 4 weeks.

488. according to embodiment 48, embodiment 49, embodiment 80-109, and embodiment 481,

wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of about 600 mg to about 1200 mg every two weeks.

489. The embodiment of any one of embodiments 48, 49, 80 to 109, 227, 251 to 253, and 481,

wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 840 mg every two weeks.

490. The method according to any one of embodiments 47 to 489,

wherein the dose of the PD-1 axis binding antagonist is a fixed dose.

491. The method of embodiment 60 or embodiment 61,

wherein the method comprises administering to the subject pembrolizumab in a fixed dose of about 200 mg every 3 weeks or 400 mg every 6 weeks.

492. The embodiment of any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191,

The length of each of said one or more dosing cycles is 21 days.

493. The embodiment of any one of embodiments 47, 59, 67, 80 to 109, and embodiments 309 to 311,

The length of each of said one or more dosing cycles is 28 days.

494. The embodiment of any one of embodiments 49, 80 to 109, and embodiments 309 to 311,

The length of each of said one or more dosing cycles is 14 days.

495. The method according to any one of embodiments 47 to 494,

wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject or population of subjects on about Day 1 of each of said one or more dosing cycles.

496. The method according to any one of embodiments 47 to 495,

wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects on about Day 1 of each of the one or more dosing cycles.

497. according to embodiment 321 or embodiment 493,

wherein said method comprises administering said anti-TIGIT antagonist antibody to said subject on about day 15 of each of said one or more dosing cycles.

498. The method of embodiment 321 or embodiment 493,

wherein the method comprises administering the PD-1 axis binding antagonist to the subject on about day 15 of each of the one or more dosing cycles.

499. The method according to any one of embodiments 47 to 498,

wherein the method comprises administering to the subject or population of subjects the PD-1 axis binding antagonist prior to the anti TIGIT antagonist antibody or the anti TIGIT antagonist antibody prior to the PD-1 axis binding antagonist.

500. The method of embodiment 499,

a first observation period following administration of the PD-1 axis binding antagonist or the anti-TIGIT antagonist antibody.

501. The method of embodiment 500,

wherein said first observation period is between about 30 minutes and about 60 minutes in length.

502. The method of embodiment 500 or embodiment 501,

wherein said method comprises a second observation period following administration of said anti-TIGIT antagonist antibody or said PD-1 axis binding antagonist.

503. The method of embodiment 502,

wherein the second observation period is between about 30 minutes and about 60 minutes in length.

504. The method of any one of embodiments 47 to 503,

wherein said method comprises administering said PD-1 axis binding antagonist to said subject or population of subjects concurrently with said anti-TIGIT antagonist antibody.

505. The method of any one of embodiments 47 to 504,

use, wherein said method comprises intravenously administering said anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist to said subject or population of subjects.

506. The method of embodiment 505,

wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects as an intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes.

507. The method of embodiment 505 or embodiment 506,

wherein the method comprises administering the anti TIGIT antagonist antibody to the subject or population of subjects as an intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes.

508. The method of any one of embodiments 47-114 and 116-507,

A use, wherein the level of PD-L1 expression in the subject or a tumor sample obtained from subjects is determined.

509. The method of embodiment 508,

wherein said subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1.

510. The method of embodiment 509,

wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1.

511. The method of embodiment 510,

wherein the detectable protein expression level of PD-L1 is determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody suitable for staining.

512. The method of embodiment 511,

wherein said anti-PD-L1 antibody suitable for staining is said anti-PD-L1 antibody SP263, SP142, 22C3 or 28-8.

513. The method of embodiment 511 or embodiment 512,

The detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a PalmDx 28-8 IHC assay. .

514. The embodiment of any of embodiments 47 to 109, 188, 220 to 265, and embodiments 307 to 423,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP263 is determined.

515. The embodiment of any one of embodiments 47 to 220, 265 to 338, and embodiments 370 to 423,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142 is determined.

516. The embodiment of any one of embodiments 47 to 113, 136 to 187, and 220 to 423,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 22C3 is determined.

517. The method of any one of embodiments 47 to 114 and embodiments 116 to 423,

wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 28-8 is determined.

518. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% of tumor-associated immune cells (TICs) in the tumor sample.

519. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% and less than 20% of the TIC in the tumor sample.

520. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 10% in the tumor sample.

521. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 has a TIC of at least 20% in the tumor sample.

522. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% and less than 50% of the TIC in the tumor sample.

523. The method of embodiment 514,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 50% TIC in the tumor sample.

524. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 1% of the PD-L1 positive tumor cell fraction.

525. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is 30% or more in a fraction of PD-L1 positive tumor cells.

526. The embodiment of any one of embodiments 514, 516, and 517,

wherein the detectable protein expression level of PD-L1 is greater than or equal to 1% and less than 50% of a fraction of PD-L1-positive tumor cells in the tumor sample.

527. The embodiment of any one of embodiments 514, 516, and 517,

The detectable protein expression level of PD-L1 is 50% or more in the fraction of PD-L1 positive tumor cells.

528. The method of embodiment 515,

wherein the PD-L1-positive tumor cell fraction is a proportion of the tumor area occupied by PD-L1-expressing tumor-infiltrating immune cells (IC).

529. The method of embodiment 515,

Use, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is 1% or more.

530. The method of embodiment 515,

Use, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is 5% or more.

531. The method of embodiment 516,

wherein the detectable protein expression level of PD-L1 has a composite positive score (CPS) of 1 or more.

532. The method of embodiment 516,

The detectable protein expression level of PD-L1 is a CPS of 10 or more.

533. The method of embodiment 516,

The detectable protein expression level of PD-L1 is CPS of 20 or more.

534. The method of any one of embodiments 528 to 530,

wherein the IHC assay is a Ventana SP142 IHC assay.

535. The method of embodiment 509,

wherein the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1.

536. The method of embodiment 535,

The detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH or a combination thereof.

537. The method according to any one of embodiments 47 to 423,

wherein said treatment results in an increase in overall survival (OS) of said subject compared to baseline OS time and/or an increase in progression free survival (PFS) in said subject compared to baseline PFS time.

538. The method of embodiment 537:

(a) said baseline OS time is the median OS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without an anti-PD-1 axis binding antagonist; and/or

(b) the baseline PFS time is the median PFS time of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without an anti-PD-1 axis binding antagonist.

539. The embodiment of any one of embodiments 52, 158, and 228,

wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents.

540. The method of embodiment 539,

The platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. The method of embodiment 69, embodiment 92, embodiment 127, embodiment 131, embodiment 249, and embodiment 540,

wherein the carboplatin is administered in a dose sufficient to achieve AUC=5 mg/ml/min or AUC=6 mg/ml/min.

542. The method of embodiment 69, embodiment 127, embodiment 162, embodiment 164, embodiment 166, embodiment 168, and embodiment 540,

wherein the cisplatin is administered at a dose of about 75 mg/m2 or 80 mg/m2.

543. The method of any one of embodiments 539 to 542,

wherein the at least one non-platinum-based chemotherapeutic agent is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

544. The method of embodiment 62, embodiment 173, embodiment 174, and embodiment 543,

wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. The embodiment of any one of embodiments 69, 127, 162, and 544,

wherein the pemetrexed is administered at a dose of about 500 mg/m2.

546. The embodiment of any one of embodiments 63, 64, 162, 398, and 544,

wherein the gemcitabine is administered at a dose of about 1000 mg/m2 or about 1250 mg/m2.

547. The method of embodiment 544,

The antimetabolite is capecitabine, use.

548. The method of embodiment 544 or embodiment 547,

wherein the capecitabine is administered at a dose of about 1250 mg/m2.

549. The embodiment of any one of embodiments 173, 174, 229, 230, 239, 240, and 543 to 548,

wherein the taxane is paclitaxel or nap-paclitaxel.

550. The method of any one of embodiments 69, 162, and 549,

wherein the paclitaxel is administered at a dose of about 175 mg/m2 or about 200 mg/m2.

551. The embodiment of any one of embodiments 63, 64, 249, 398, and 549,

wherein the nap-paclitaxel is administered at a dose of about 100 mg/m2.

552. The embodiment of any one of embodiments 80-91, 229, 230, 239, 241, 251, 255, and 543-551. ,

wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331.

553. The embodiment of any one of embodiments 69, 92, and 552,

wherein the etoposide is administered at a dose of about 100 mg/m2.

554. The method of any one of embodiments 543 to 553,

The one or more chemotherapeutic agents are each administered once every week, once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, twice every 4 weeks, or 3 times every 4 weeks. , use.

555. The method of any one of embodiments 543 to 554,

wherein said one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles.

556. The method of any one of embodiments 544 to 555,

wherein the gemcitabine is administered 3 times every 4 weeks.

557. The method according to any one of embodiments 544 to 556,

wherein the gemcitabine is administered on days 1, 8, and/or 15 of one or more dosing cycles.

558. The method of any one of embodiments 544 to 557,

wherein the capecitabine is administered daily for 2 weeks.

559. The method according to any one of embodiments 544 to 558,

wherein said capecitabine is administered on days 1 to 14 of one or more dosing cycles.

560. The method of any one of embodiments 549 to 559,

wherein the nap-paclitaxel is administered 3 times every 4 weeks.

561. The method of any one of embodiments 549 to 560,

wherein said nap-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles.

562. The method of any one of embodiments 552 to 561,

wherein said etoposide is administered on days 1 to 3 every 3 weeks.

563. The method of any one of embodiments 552 to 562,

wherein said etoposide is administered on days 1 to 3 of one or more dosing cycles.

564. The method of any one of embodiments 543 to 563,

wherein said one or more chemotherapeutic agents are administered prior to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

565. The method of any one of embodiments 543 to 564,

wherein said one or more chemotherapeutic agents are administered after said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody.

566. The method of any one of embodiments 543 to 565,

wherein said one or more chemotherapeutic agents are administered intravenously or orally.

567. The embodiment of any one of embodiments 65, 310, and 311,

wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks.

568. The method of embodiment 312 or embodiment 567,

wherein the VEGF antagonist is administered at a dose of about 10 mg/kg to about 20 mg/kg every 3 weeks.

569. according to embodiment 318 and embodiment 568,

wherein the VEGF antagonist is administered at a dose of about 15 mg/kg every 3 weeks.

570. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 569,

The VEGF antagonist is an anti-VEGF antibody, use.

571. The method of embodiment 570,

The use of the anti-VEGF antibody comprising the VH domain and the VL domain of bevacizumab.

572. The method of embodiment 570 or embodiment 571,

The anti-VEGF antibody is bevacizumab, use.

573. The embodiment of any one of embodiments 65, 310 to 312, and embodiments 318 to 320,

The anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the VEGF antagonist is bevacizumab.

574. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 573,

use, comprising administering said VEGF antagonist to said subject on Day 1 of one or more dosing cycles.

575. The method of any one of embodiments 318 to 320,

use, comprising administering said VEGF antagonist to said subject on day 15 of one or more dosing cycles.

576. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 575,

wherein the VEGF antagonist is administered intravenously.

577. The method of embodiment 576,

wherein said VEGF antagonist is administered to said subject by intravenous infusion over 90 ± 15 minutes.

578. The embodiment of any one of embodiments 65, 310 to 312, 318 to 320, and embodiments 567 to 577,

Use comprising administering to the subject the PD-1 axis binding antagonist prior to the VEGF antagonist, and the VEGF antagonist prior to the anti-TIGIT antagonist antibody.

579. The method of embodiment 578,

wherein the method comprises a first observation period after administration of the PD-1 axis binding antagonist, a second observation period after administration of the VEGF antagonist, and a third observation period after administration of the anti-TIGIT antagonist antibody.

580. The method of embodiment 579,

wherein the first observation period, the second observation period, and the third observation period are each about 30 minutes to about 120 minutes in length.

581. Embodiment 113, Embodiment 128, Embodiment 129 to Embodiment 131, Embodiment 175 to Embodiment 182, Embodiment 210 to Embodiment 214, Embodiment 221, Embodiment 256, Embodiment 257, Embodiment 270, Embodiment 289, Embodiment 290, Embodiment 293, Embodiment 294, Embodiment 297, Embodiment 298, Embodiment 333, Embodiment 362 to Embodiment 365, Embodiment 385, Embodiment 386, Embodiment 389, Embodiment 393, embodiment 419, and embodiment 422 according to any one of embodiments,

Use, wherein tiragolumab and atezolizumab are bound to an IV bag prior to administration.

582. The method according to any one of embodiments 47 to 581,

wherein the subject is a human.

583. The method according to any one of embodiments 47 to 582,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

584. The method according to any one of embodiments 47 to 582,

wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single dosage form.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, these descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited herein are expressly incorporated herein in their entirety.

SEQUENCE LISTING <110> Genentech, Inc. F. Hoffmann-La Roche AG Hoffmann-La Roche Inc. <120> METHODS FOR TREATMENT OF CANCER WITH AN ANTI-TIGIT ANTAGONIST ANTIBODY <130> 50474-206WO2 <150> US 63/127,109 <151> 2020-12-17 <150> US 63/124,693 <151> 2020-12- 11 <150> US 63/114,517 <151> 2020-11-16 <150> US 63/105,198 <151> 2020-10-23 <150> US 63/085,890 <151> 2020-09-30 <150> PCT /US2020/049415 <151> 2020-09-04 <150> US 63/074,827 <151> 2020-09-04 <150> US 63/074,807 <151> 2020-09-04 <150> US 63/059,960 < 151> 2020-07-31 <150> US 63/059,054 <151> 2020-07-30 <150> PCT/US2020/024526 <151> 2020-03-24 <150> US 62/994,272 <151> 2020- 03-24 <150> US 62/985,822 <151> 2020-03-05 <150> US 62/966,448 <151> 2020-01-27 <160> 34 <170> PatentIn version 3.5 <210> 1 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 1 Ser Asn Ser Ala Ala Trp Asn 1 5 <210> 2 <211> 18 <212> PRT <213> Artificial Sequence <220 > <223> Synthetic Construct <400> 2 Lys Thr Tyr Tyr Arg Phe Lys Trp Tyr Ser Asp Tyr Ala Val Ser Val 1 5 10 15 Lys Gly <210> 3 <211> 1 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 3 Glu Ser Thr Thr Tyr Asp Leu Leu Ala Gly Pro Phe Asp Tyr 1 5 10 <210> 4 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 4 Lys Ser Ser Gln Thr Val Leu Tyr Ser Ser Asn Asn Lys Lys Tyr Leu 1 5 10 15 Ala <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 5 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 6 Gln Gln Tyr Tyr Ser Thr Pro Phe Thr 1 5 <210> 7 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 7 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys 20 <210> 8 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct < 400> 8 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile Tyr 1 5 10 15 <210> 9 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 9 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys 20 25 30 <210> 10 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 10 Phe Gly Pro Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 11 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <220> <221> MISC_FEATURE <222> (1 )..(1) <223> Xaa is Gln or Glu <400> 11 Xaa Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser 20 25 30 <210> 12 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 12 Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu Trp Leu Gly 1 5 10 <210> 13 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 1 3 Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe Ser Leu Gln 1 5 10 15 Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Phe Tyr Cys Thr Arg 20 25 30 <210> 14 <211> 11 <212 > PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 14 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 15 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 15 Glu Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser 20 25 30 < 210> 16 <211> 30 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 16 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser 20 25 30 <210> 17 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 17 Glu Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Asn 20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Lys Thr Tyr Tyr Arg Phe Lys Trp Tyr Ser Asp Tyr Ala 50 55 60 Val Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Phe Tyr Cys Thr Arg Glu Ser Thr Thr Tyr Asp Leu Leu Ala Gly Pro 100 105 110 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 18 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 18 Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Lys Thr Tyr Tyr Arg Phe Lys Trp Tyr Ser Asp Tyr Ala 50 55 60 Val Ser Val Lys Gl y Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Phe Tyr Cys Thr Arg Glu Ser Thr Thr Tyr Asp Leu Leu Ala Gly Pro 100 105 110 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 19 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 19 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Thr Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Lys Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Asn Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Glu Ile 100 105 110 L ys <210> 20 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 20 Gly Phe Thr Phe Ser Asp Ser Trp Ile His 1 5 10 <210> 21 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 21 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 1 5 10 15 Lys Gly <210> 22 <211 > 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 22 Arg His Trp Pro Gly Gly Phe Asp Tyr 1 5 <210> 23 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 23 Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala 1 5 10 <210> 24 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 24 Ser Ala Ser Phe Leu Tyr Ser 1 5 <210> 25 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 25 Gln Gln Tyr Leu Tyr His Pro Ala Thr 1 5 <210> 26 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 26 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser 20 25 30 Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 27 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 27 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser GlyVal Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> 28 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 28 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser 20 25 30 Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Trp Ile Ser Pro Tyr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Ly s Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <210> 29 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 29 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 30 <211> 244 <212> PRT <213> Homo sapiens <400> 30 Met Arg Trp Cys Leu Leu Leu Ile Trp Ala Gln Gly Leu Arg Gln Ala 1 5 10 15 Pro Leu Ala Ser Gly Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn 20 25 30 Ile Ser Ala Glu Lys Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser 35 40 45 Ser Thr Thr Ala Gln Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln 50 55 60 Leu Leu Ala Ile Cy s Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser 65 70 75 80 Phe Lys Asp Arg Val Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln 85 90 95 Ser Leu Thr Val Asn Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr 100 105 110 Tyr Pro Asp Gly Thr Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu 115 120 125 Ser Ser Val Ala Glu His Gly Ala Arg Phe Gln Ile Pro Leu Leu Gly 130 135 140 Ala Met Ala Ala Thr Leu Val Val Ile Cys Thr Ala Val Ile Val Val 145 150 155 160 Val Ala Leu Thr Arg Lys Lys Lys Ala Leu Arg Ile His Ser Val Glu 165 170 175 Gly Asp Leu Arg Arg Lys Ser Ala Gly Gin Glu Glu Trp Ser Pro Ser 180 185 190 Ala Pro Ser Pro Pro Gly Ser Cys Val Gln Ala Glu Ala Ala Pro Ala 195 200 205 Gly Leu Cys Gly Glu Gln Arg Gly Glu Asp Cys Ala Glu Leu His Asp 210 215 220 Tyr Phe Asn Val Leu Ser Tyr Arg Ser Leu Gly Asn Cys Ser Phe Phe 225 230 235 240 Thr Glu Thr Gly <210> 31 <211> 223 <212> PRT <213> Homo sapiens <400> 31 Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys 1 5 10 15 Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln 20 25 30 Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys 35 40 45 Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val 50 55 60 Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn 65 70 75 80 Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr 85 90 95 Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu 100 105 110 His Gly Ala Arg Phe Gln Ile Pro Leu Leu Gly Ala Met Ala Ala Thr 115 120 125 Leu Val Val Ile Cys Thr Ala Val Ile Val Val Val Ala Leu Thr Arg 130 135 140 Lys Lys Lys Ala Leu Arg Ile His Ser Val Glu Gly Asp Leu Arg Arg 145 150 155 160 Lys Ser Ala Gly Gln Glu Glu Trp Ser Pro Ser Ala Pro Ser Pro Pro 165 170 175 Gly Ser Cys Val Gln Ala Glu Ala Ala Pro Ala Gly Leu Cys Gly Glu 180 185 190 Gln Arg Gly Glu Asp Cys Ala Glu Leu His Asp Tyr Phe Asn Val Leu 195 200 205 Ser Tyr Arg Ser Leu Gly Asn Cys Ser Phe Phe Thr Glu Thr Gly 210 215 220 <210> 32 <211 > 290 <212> PRT <213> Homo sapiens <400> 32 Met Arg Ile Phe Ala Val Phe Ile Phe Met Thr Tyr Trp His Leu Leu 1 5 10 15 Asn Ala Phe Thr Val Thr Val Pro Lys Asp Leu Tyr Val Val Glu Tyr 20 25 30 Gly Ser Asn Met Thr Ile Glu Cys Lys Phe Pro Val Glu Lys Gln Leu 35 40 45 Asp Leu Ala Ala Leu Ile Val Tyr Trp Glu Met Glu Asp Lys Asn Ile 50 55 60 Ile Gln Phe Val His Gly Glu Glu Asp Leu Lys Val Gln His Ser Ser 65 70 75 80 Tyr Arg Gln Arg Ala Arg Leu Leu Lys Asp Gln Leu Ser Leu Gly Asn 85 90 95 Ala Ala Leu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr 100 105 110 Arg Cys Met Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Val 115 120 125 Lys Val Asn Ala Pro Tyr Asn Lys Ile Asn Gln Arg Ile Leu Val Val 130 135 140 Asp Pro Val Thr Ser Glu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr 145 150 155 160 Pro Lys Ala Glu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser 165 170 175 Gly Lys Thr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn 180 185 190 Val Thr Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr 195 200 205 Cys Thr Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu 210 215 220 Val Ile Pro Glu Leu Pro Leu Ala His Pro Asn Glu Arg Thr His 225 230 235 240 Leu Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala Leu Thr 245 250 255 Phe Ile Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val Lys Lys Cys 260 265 270 Gly Ile Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp Thr His Leu Glu 275 280 285 Glu Thr 290 <210> 33 <211> 456 <212> PRT <213> Homo sapiens <400> 33 Glu Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Lys Thr Tyr Tyr Arg Phe Lys Trp Tyr Ser Asp Tyr Ala 50 55 60 Val Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Phe Tyr Cys Thr Arg Glu Ser Thr Thr Tyr Asp Leu Leu Ala Gly Pro 100 105 110 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 130 135 140 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 145 150 155 160 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 165 170 175 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 180 185 190 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 195 200 205 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 210 215 220 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Cys Pro Ala 225 230 235 240 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 275 280 285 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 305 310 315 320 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 325 330 335 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 340 345 350 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 355 360 365 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 385 390 395 400 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445 Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 34 <211> 220 <212> PRT <213> Homo sapiens <400> 34 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Ser Gln Thr Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Lys Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Asn Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gl n Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220

Claims (503)

A method of treating a subject having cancer, comprising:
anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and an evacuation every 3 weeks A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a gold-based chemotherapeutic agent. A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 1400 mg to 2000 mg every 4 weeks A method comprising steps. A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks A method comprising the step of 4. The method of claim 2 or 3,
The method further comprising administering to the subject one or more chemotherapeutic agents. 5. The method according to any one of claims 1 to 4,
wherein said anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody. 6. The method according to any one of claims 1 to 5,
The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):
(a) an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
(b) an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);
(c) an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);
(d) an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);
(e) an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and
(f) an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). 7. The method according to any one of claims 1 to 6,
The anti-TIGIT antagonist antibody has the following light chain variable region framework regions (FR):
(a) FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
(b) FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
(c) a FR-L3 sequence comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and
(d) FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), and
The following heavy chain variable region FRs:
(a) FR-H1 comprising the amino acid sequence of X ₁ VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X ₁ is E or Q;
(b) FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);
(c) FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and
(d) FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). 8. The method according to any one of claims 1 to 7,
The anti-TIGIT antagonist antibody is:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or
(c) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. 9. The method according to any one of claims 1 to 8,
The method of claim 1, wherein the anti-TIGIT antagonist antibody is tyragolumab. 10. The method according to any one of claims 1 to 9,
The method of claim 1, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist. 11. The method according to any one of claims 1 to 10,
The method of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody. 12. The method according to any one of claims 1 to 11,
The method of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. 13. The method of claim 12,
The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636. 14. The method according to any one of claims 1 to 13,
The method of claim 1, wherein the PD-1 axis binding antagonist is atezolizumab. 12. The method according to any one of claims 1 to 11,
The method of claim 1, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody. 16. The method of claim 15,
Said anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, prolgolimab, camrelizumab, scintilimab, tislelizumab, torifalizumab Mab, dostalimab, retipanrimab, sasanrimab, fenfulimab, CS1003, HLX10, SCT-I10A, zimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21. 17. The method according to any one of claims 2 to 16,
A method comprising administering to the subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. 18. The method of claim 1 or 17,
The method of claim 1, wherein the non-platinum-based chemotherapeutic agent is a topoisomerase II inhibitor. 19. The method of claim 18,
wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331, in particular etoposide; Way. 20. The method of claim 18 or 19,
wherein the topoisomerase II inhibitor is administered at a dose of 100 mg/m ² . 21. The method according to any one of claims 17 to 20,
The method according to claim 1, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin. 22. The method according to any one of claims 17 to 21,
wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on the day of administration. 23. The method of any one of claims 1-22,
A method comprising a dosing regimen comprising an induction phase and a maintenance phase. 24. The method of claim 23,
wherein the induction phase comprises four initial dosing cycles and the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent are administered in each of the four initial dosing cycles. 25. The method of claim 23 or 24,
wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent and/or the non-platinum-based chemotherapeutic agent. 26. The method according to any one of claims 1 to 25,
wherein said treatment prolongs progression-free survival (PFS) of said subject compared to treatment without said anti-TIGIT antagonist antibody. 27. The method of any one of claims 1-26,
wherein said treatment prolongs overall survival of said subject compared to treatment without said anti-TIGIT antagonist antibody. 28. The method according to any one of claims 1 to 27,
The method of claim 1, wherein the cancer is lung cancer. 29. The method of claim 28,
The method of claim 1, wherein the lung cancer is small cell lung cancer (SCLC), in particular expanded stage SCLC (ES-SCLC). 29. The method of claim 28,
wherein the lung cancer is non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC). 29. The method of claim 28,
wherein the lung cancer is locally advanced unresectable or metastatic nonsquamous NSCLC. 29. The method of claim 28,
The method of claim 1, wherein the lung cancer is resectable lung cancer. 28. The method according to any one of claims 1 to 27,
The method of claim 1, wherein the cancer is cervical cancer. 28. The method according to any one of claims 1 to 27,
wherein the cancer is early triple negative breast cancer (eTNBC).
28. The method according to any one of claims 1 to 27,
The method of claim 1, wherein the cancer is head and neck cancer. 28. The method according to any one of claims 1 to 27,
wherein the cancer is liver cancer, in particular hepatocellular carcinoma (HCC). 28. The method according to any one of claims 1 to 27,
The method of claim 1, wherein the cancer is bladder cancer. 38. The method of claim 37,
wherein the cancer is urothelial cell carcinoma (UC), in particular metastatic urothelial cell carcinoma (mUC). 28. The method according to any one of claims 1 to 27,
wherein said cancer is pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC). 28. The method according to any one of claims 1 to 27,
The method of claim 1, wherein the cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer. 41. A kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to the method of any one of claims 1-40. 42. The method of claim 41,
A kit, further comprising one or more chemotherapeutic agents. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, comprising:
41. The method according to any one of claims 1 to 40, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist. 1. Use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having cancer, comprising:
41. Use according to the method of any one of claims 1-40. 45. The method of claim 44,
The use of claim 1, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations. 45. The method of claim 44,
The use of claim 1, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single dosage form. A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and at least one dosing cycle of a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks A method comprising A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks A method comprising the step of: 49. The method of claim 47 or 48,
The method further comprising administering to the subject one or more chemotherapeutic agents. 50. The method of claim 49,
A method comprising administering a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent to the subject. A method of treating a subject having cancer, comprising:
anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks, and an evacuation every 3 weeks A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a gold-based chemotherapeutic agent. 52. The method of claim 50 or 51,
A method comprising an induction phase and a maintenance phase. 53. The method of claim 52,
wherein the induction and maintenance phases each comprise one or more dosing cycles. 54. The method of claim 52 or 53,
wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent. 55. The method according to any one of claims 52 to 54,
The method of claim 1, wherein the maintenance phase does not include administration of the non-platinum-based chemotherapeutic agent. 56. The method of claim 55,
wherein said maintenance phase comprises one or more dosing cycles of anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks. A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and an anti-PD-1 antagonist antibody at a dose of about 100 mg to about 300 mg every 3 weeks wherein the anti-PD-1 antagonist antibody is pembrolizumab. A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising at least one dosing cycle of tiragolumab and pembrolizumab, wherein the pembrolizumab is administered at a dose of about 300 mg to about 500 mg every 6 weeks; Way. A method of treating a subject having cancer, comprising:
Anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, and 1 day every 3 weeks of 2 weeks dosing/1 week washout A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an antimetabolite at a dose of about 10 mg/m ² to about 10000 mg/m ² orally in two doses. A method of treating a subject having cancer, comprising:
one or more dosing cycles of anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, gemcitabine, and nap-paclitaxel A method comprising administering to the subject a dosing regimen comprising 50. The method of claim 49,
wherein the one or more chemotherapeutic agents are gemcitabine and nap-paclitaxel. A method of treating a subject having cancer, comprising:
Anti TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, and about 1 mg/kg to about 35 mg/kg every 3 weeks A method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of a kg dose of a VEGF antagonist. A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:
(a) the induction phase is an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks , and at least one dosing cycle of a non-platinum-based chemotherapeutic agent every 3 weeks; and
(b) said maintenance phase comprises at least one additional dosing cycle of said anti-TIGIT antagonist antibody every 3 weeks, said PD-1 axis binding antagonist every 3 weeks, and said non-platinum-based chemotherapeutic agent every 3 weeks, wherein said maintenance wherein the phase does not include administration of the platinum-based chemotherapeutic agent. A method of treating a subject having cancer, comprising:
administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:
(a) the induction phase is an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks, a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks, a platinum-based chemotherapeutic agent every 3 weeks , and at least one dosing cycle of a non-platinum-based chemotherapeutic agent every 3 weeks; and
(b) the maintenance phase comprises one or more additional dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 700 mg to about 1000 mg every 4 weeks and a PD-1 axis binding antagonist at a dose of about 1400 mg to 2000 mg every 4 weeks; , wherein the maintenance phase does not include administration of the platinum-based chemotherapeutic agent or the non-platinum-based chemotherapeutic agent. 57. The method of any one of claims 53-56, 63 and 64,
wherein the induction phase comprises 4 to 6 dosing cycles. 66. The method of any one of claims 50-56 and 63-65,
(a) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel; or
(c) the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is etoposide. 67. The method according to any one of claims 47 to 66,
wherein the cancer is a solid tumor. 68. The method according to any one of claims 47 to 67,
wherein the cancer is locally advanced or metastatic. 69. The method according to any one of claims 47 to 68,
wherein the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, stomach cancer, colorectal cancer, kidney cancer, kidney cancer, melanoma, or ovarian cancer.
70. The method of claim 69,
The method of claim 1, wherein the cancer is lung cancer. 71. The method of claim 70,
wherein the lung cancer is NSCLC, in particular locally advanced unresectable NSCLC. 72. The method of claim 71,
wherein said NSCLC is stage IIIB NSCLC. 73. The method of any one of claims 70-72,
wherein the lung cancer is relapsed or metastatic NSCLC. 74. The method of claim 73,
wherein said NSCLC is stage IV NSCLC. 75. The method of claim 74,
wherein the subject has not been previously treated for stage IV NSCLC. 71. The method of claim 70,
wherein the lung cancer is small cell lung cancer (SCLC). A method of treating a subject or population of subjects having lung cancer, the method comprising:
administering to said subject or population of subjects a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor; , wherein the treatment prolongs progression-free survival (PFS) of the subject compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without the anti-TIGIT antagonist antibody . A method of treating a population of subjects having lung cancer, the method comprising:
administering to said subject population a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor; wherein the treatment results in a median PFS of the subject population of from about 8.2 months to about 9.2 months. 79. The method of claim 77 or 78,
wherein said treatment prolongs overall survival (OS) of said subject or population of subjects compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody; Way. 80. The method according to any one of claims 77 to 79,
wherein the treatment prolongs the PFS of the subject or population of subjects by at least about 2.4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , Way. 81. The method of claim 80,
wherein said treatment reduces the PFS of said subject or population of subjects by at least about 3 months to about 4 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. How to extend by months. A method of treating a subject or population of subjects having lung cancer, the method comprising:
administering to said subject or population of subjects a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor; , wherein said treatment prolongs the OS of said subject compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. A method of treating a population of subjects having lung cancer, the method comprising:
administering to said subject population a dosing regimen comprising at least one dosing cycle of an effective amount of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor; wherein the treatment results in a median OS of the subject population of from about 15.3 months to about 17.6 months. 84. The method of any one of claims 79-83,
wherein the treatment prolongs the OS of the subject or population of subjects by at least about 3.3 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of the anti-TIGIT antagonist antibody. , Way. 84. The method of any one of claims 79-83,
wherein said treatment reduces the OS of said subject or population of subjects by at least about 3 months to about 5.3 as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor in the absence of said anti-TIGIT antagonist antibody. How to extend by months. 86. The method of any one of claims 77-85, wherein
wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered in each of four initial dosing cycles. 87. The method of any one of claims 77-86,
wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are further administered in one or more additional cycles after the fourth initial dosing cycle. 88. The method of claim 87,
wherein said platinum-based chemotherapeutic agent and said topoisomerase II inhibitor are omitted from each of one or more additional dosing cycles. 89. The method according to any one of claims 77 to 88,
wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide. 90. The method according to any one of claims 77 to 89,
wherein the lung cancer is small cell lung cancer (SCLC). 91. The method of claim 90,
wherein the SCLC is extended SCLC (ES-SCLC). 92. The method of claim 91,
The method of claim 1, wherein the subject or subjects is naive for treatment for ES-SCLC. 93. The method of any one of claims 77-92, wherein
The method of claim 1, wherein the subject or subjects do not have the presence or history of brain metastases. 94. The method according to any one of claims 77 to 93,
The method of claim 1, wherein the lung cancer is not selected for PD-L1 expression. 94. The method according to any one of claims 77 to 93,
wherein the lung cancer is selected for PD-L1 expression. 96. The method of claim 95,
wherein the lung cancer is selected for PD-L1 expression by a detectable expression level of PD-L1. 97. The method of any one of claims 77-96,
wherein the lung cancer is metastatic. 98. The method of claim 97,
The method of claim 1, wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal glands. 99. The method of claim 97 or 98,
The method of claim 1, wherein the lung cancer has not metastasized to the brain. 101. The method of any one of claims 77-99,
wherein the treatment results in a complete response (CR) or a partial response (PR). A method of treating a subject or population of subjects having SCLC comprising:
Anti TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on day 1 of each dosing cycle, atezolizumab at a dose of about 900 mg to about 1500 mg on day 1 of each dosing cycle, Day 1 of each dosing cycle Carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min, and 1 of a 100 mg/m ² dose of etoposide on each of Days 1, 2, and 3 of each dosing cycle. administering to said subject or population of subjects at least one 21 day dosing cycle, wherein said treatment is compared to treatment with atezolizumab, carboplatin, and etoposide without said anti-TIGIT antagonist antibody to said subject or prolonging the PFS and/or OS of the subject population. A method of treating a subject or population of subjects having ES-SCLC comprising:
administering to the subject or population of subjects one or more additional dosing cycles following four initial dosing cycles, wherein:
(a) said four initial dosing cycles are tiragolumab at a dose of about 600 mg on day 1 of each initial dosing cycle, atezolizumab at a dose of about 1200 mg on day 1 of each initial dosing cycle, each initial dosing cycle Carboplatin in ^a dose sufficient to achieve AUC = 5 mg/ml/min on Day 1 of administering etoposide; and
(b) said one or more additional dosing cycles comprises administering a dose of about 600 mg of tiragolumab on Day 1 of each additional dosing cycle and a dose of about 1200 mg of Atezolizumab on Day 1 of each additional dosing cycle. including,
wherein said four initial dosing cycles and said one or more additional dosing cycles are each 21 day dosing cycle, wherein said treatment is compared to treatment with atezolizumab, carboplatin, and etoposide without said tiragolumab to prolong the PFS and/or OS of the subject or population of subjects. A method of treating a subject or population of subjects having lung cancer, the method comprising:
a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a first chemotherapeutic agent that is a platinum-based chemotherapeutic agent, and a second chemotherapeutic agent that is a non-platinum-based chemotherapeutic agent; A method comprising administering to 104. The method of claim 103,
The method of claim 1, wherein the lung cancer has not been assessed for PD-L1 expression. 105. The method of claim 103 or 104,
The method of claim 1, wherein the subject or subjects is not determined to have a fraction of PD-L1 positive tumor cells greater than or equal to 50%. 107. The method of claim 105,
The method of claim 1 , wherein the subject or subjects is determined to have a fraction of PD-L1 positive tumor cells of less than 50%. 107. The method of claim 105 or 106,
wherein said PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein said anti-PD-L1 antibody is SP263 or 22C3. 108. The method of any one of claims 103-107,
The method of claim 1, wherein the subject or subjects do not have an epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) genomic tumor abnormality. 109. The method of any one of claims 103-108,
The method of claim 1, wherein said subject or subjects has not received prior systemic therapy for said lung cancer. 110. The method of any one of claims 103-109,
wherein the lung cancer is locally advanced lung cancer. 112. The method of any one of claims 103-110,
wherein the lung cancer is NSCLC, in particular locally advanced unresectable or metastatic nonsquamous NSCLC. 112. The method of claim 111,
wherein said nonsquamous NSCLC is stage IV nonsquamous NSCLC. 113. The method of any one of claims 103-112,
wherein the dosing regimen includes an induction phase comprising 4 dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum-based chemotherapeutic agent, and the non-platinum-based chemotherapeutic agent include each dosing cycle of the induction phase. administered on the first day of 114. The method of claim 113,
wherein the dosing regimen comprises a maintenance phase after the induction phase, wherein the maintenance phase includes one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the non-platinum chemotherapeutic agent are the maintenance phases. administered on Day 1 of each dosing cycle of the phase. 115. The method of claim 114,
wherein the one or more dosing cycles of the maintenance phase do not include administration of the platinum-based chemotherapeutic agent. 116. The method of any one of claims 103-115,
The method of claim 1, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed. A method of treating a subject or population of subjects having advanced nonsquamous NSCLC, comprising:
administering to said subject or population of subjects a dosing regimen comprising four 21-day dosing cycles for tiragolumab, atezolizumab, carboplatin or cisplatin, and pemetrexed, wherein said tiragolumab comprises: is administered at a dose of about 600 mg every 3 weeks, the atezolizumab is administered at a dose of about 1200 mg every 3 weeks, and the carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min every 3 weeks. or, the cisplatin is administered at a dose of 75 mg/m ² every 3 weeks, and the pemetrexed is administered at a dose of about 500 mg/m ² every 3 weeks on the first day of each of four 21-day dosing cycles. , Way. A method of treating a subject or population of subjects having advanced nonsquamous NSCLC, comprising:
To said subject or population of subjects:
(i) tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, carboplatin in a dose sufficient to achieve AUC = 5 mg/ml/min every 3 weeks, and 3 4 cycles of induction dosing for pemetrexed at a dose of about 500 mg/m ² per week; and
(ii) one or more maintenance phase dosing cycles of tyragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and pemetrexed at a dose of about 500 mg/m 2 every 3 weeks. administering, wherein at least one 21-day dosing cycle of said maintenance phase does not comprise administration of said carboplatin;
wherein the subject or population of subjects has not received prior systemic therapy for advanced nonsquamous NSCLC. 119. The method of any one of claims 103-118,
wherein the treatment prolongs the PFS of the subject or population of subjects by at least about 3.5 months or about 4.7 months. 119. The method of any one of claims 103-118,
wherein said treatment results in a median PFS of a population of subjects from about 12.5 months to about 14.7 months. 119. The method of any one of claims 103-118,
wherein the treatment prolongs the OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months. 119. The method of any one of claims 103-118,
wherein said treatment results in a median OS in the subject population of about 27.5 months to about 32.0 months. A method of treating a subject with resectable lung cancer, comprising:
administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks How to. A method of treating a subject having lung cancer, comprising:
administering to said subject one or more dosing cycles of an anti TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein at least one of said dosing cycles is from about 500 mg to about 700 mg of an antibiotic every 3 weeks. A method comprising administering to the subject as neoadjuvant treatment a TIGIT antagonist antibody and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks. 125. The method of claim 124,
At least once in said dosing cycle administering to said subject as adjuvant treatment a dose of about 500 mg to about 700 mg of an anti-TIGIT antagonist antibody every 3 weeks and a dose of about 900 mg to about 1500 of a PD-1 axis binding antagonist every 3 weeks A method comprising the step of: 127. The method of claim 124 or 125,
The method of claim 1, wherein the lung cancer is resectable lung cancer. 127. The method of any one of claims 123-126,
The method of claim 1, wherein the lung cancer is early stage lung cancer. 127. The method of any one of claims 123 to 127,
The method of claim 1, wherein the lung cancer is stage II, IIIA, or IIIB lung cancer. 129. The method according to any one of claims 123 to 128,
The method of claim 1, wherein the subject is eligible for a curative-purpose RO resection. 130. The method according to any one of claims 123 to 129,
The method of claim 1, wherein the subject has never received prior therapy for lung cancer. 130. The method of claim 130,
wherein the prior therapy is immunotherapy, chemotherapy, or radiotherapy. 132. The method of any one of claims 123-131,
wherein the subject is eligible for platinum-based chemotherapy. 134. The method according to any one of claims 123 to 132,
wherein the first dosing cycle is initiated prior to surgery. 134. The method of claim 133,
at least 1, 2, 3, or 4 dosing cycles are completed prior to the surgery. 134. The method of claim 133 or 134,
and 4 dosing cycles are completed prior to the surgery. 136. The method of any one of claims 123 to 135,
at least one dosing cycle is initiated after surgery. 137. The method of claim 136,
16 dosing cycles are completed after said surgery. 137. The method of any one of claims 133 to 137,
wherein the operation is lobectomy, lobectomy, bilobectomy, or pneumonectomy. 139. The method of any one of claims 123 to 138,
The method further comprising radiation therapy. 140. The method of claim 139,
The method of claim 1, wherein the radiation therapy is post-surgery radiation therapy. 140. The method of any one of claims 123-140,
The method further comprising administering one or more chemotherapeutic agents. 142. The method of claim 141,
wherein the one or more chemotherapeutic agents are administered post-surgery. 143. The method of claim 142,
The method of claim 1, wherein the one or more chemotherapeutic agents are administered in 4 dosing cycles after the surgery. 144. The method of any one of claims 141 to 143,
wherein the at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. 145. The method of claim 144,
(a) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is pemetrexed;
(b) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is gemcitabine;
(c) the platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is paclitaxel;
(d) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed; or
(e) the platinum-based chemotherapeutic agent is cisplatin and the non-platinum-based chemotherapeutic agent is gemcitabine. 145. The method of any one of claims 123-145,
wherein said treatment results in an increase in the MPR rate as compared to a baseline major pathological response rate (MPR). 147. The method of claim 146,
The reference MPR ratio is:
(a) a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody; and/or
(b) the MPR rate of a population of subjects who have ever received treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab. 147. The method according to any one of claims 123 to 147,
wherein the treatment results in an increase in the pathological complete response (pCR) and/or pCR ratio compared to a baseline pCR ratio. 149. The method of claim 148,
The reference pCR ratio is:
(a) a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody; and/or
(b) cisplatin and docetaxel or the pCR ratio of a population of subjects that have ever received treatment comprising cisplatin, docetaxel, and bevacizumab. 149. The method of any one of claims 123-149, wherein
wherein said treatment results in an increase in EFS compared to a baseline event-free survival (EFS) period. 150. The method of claim 150,
The reference EFS period is:
(a) a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody; and/or
(b) the duration of EFS in a population of subjects who have ever received treatment comprising cisplatin and docetaxel or cisplatin, docetaxel, and bevacizumab. A method of treating a subject with resectable lung cancer, comprising:
Tiragolumab at a dose of about 600 mg every 3 weeks, Atezolizumab at a dose of about 1200 mg every 3 weeks, and:
(a)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min or an AUC of 6 mg/mL/min every 3 weeks; or
(ii) cisplatin at a dose of about 75 mg/m ² every 3 weeks; and
(b)
(i) pemetrexed at a dose of about 500 mg/m ² every 3 weeks or gemcitabine at a dose of about 1000 mg/m ² or about 1250 mg/m ² on days 1 and 8 of each dosing cycle; or
(ii) administering to the subject one or more dosing cycles for paclitaxel at a dose of about 175 mg/m ² or about 200 mg/m ² every 3 weeks. A method of treating a subject having lung cancer, comprising:
administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein:
(I) at least one of said dosing cycles is neoadjuvant treatment and to said subject:
(a) tyragolumab at a dose of about 1200 mg every 3 weeks;
(b) atezolizumab at a dose of about 1200 mg every 3 weeks as neoadjuvant treatment; and
(c)
(i) carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks and gemcitabine at a dose of about 1000 mg/m ² on days 1 and 8 of each dosing cycle;
(ii) carboplatin at a dose targeted to achieve an AUC of 6 mg/mL/min every 3 weeks and paclitaxel at a dose of about 175 mg/m ² or about 200 mg/m ² every 3 weeks; or
(iii) administering cisplatin at a dose of about 75 mg/m ² every 3 weeks and gemcitabine at a dose of 1250 mg/m ² on days 1 and 8 of each dosing cycle; and
(II) administering to the subject as adjuvant treatment at least one of said dosing cycles is tiragolumab at a dose of about 500 mg to about 700 mg every 3 weeks and atezolizumab at a dose of about 900 mg to about 1500 mg every 3 weeks A method comprising the step of 154. The method according to any one of claims 123 to 153,
A method, wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP263 is determined. 154. The method of claim 154,
The method, wherein the detectable protein expression level of PD-L1 is at least 50% of the PD-L1 positive tumor cell fraction. 107. The method of any one of claims 70, 103-110, and 123-155, wherein
The method of claim 1, wherein the lung cancer is NSCLC. 157. The method of claim 156,
wherein the NSCLC is squamous NSCLC. 157. The method of claim 156,
wherein the NSCLC is non-squamous NSCLC. 70. The method of claim 69,
The method of claim 1, wherein the cancer is cervical cancer. A method of treating a subject or population of subjects having cervical cancer having a detectable expression level of PD-L1, the method comprising:
administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method comprising steps. A method of selecting therapy for a subject having cervical cancer comprising:
(a) detecting the protein expression level of PD-L1 on tumor cells from a tumor sample from said subject by IHC analysis using an anti-PD-L1 antibody suitable for staining; and
(b) an anti-TIGIT antagonist antibody administered at a dose of about 500 mg to about 700 mg every 3 weeks based on PD-L1 expression on tumor cells detected for said subject having a detectable expression level of PD-L1, and selecting a regimen comprising one or more dosing cycles of a PD-1 axis binding antagonist administered at a dose of about 900 mg to about 1500 mg every 3 weeks. 162. The method of claim 160 or 161,
The method of claim 1, wherein the cervical cancer is squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma. 163. The method of any one of claims 160 to 162,
wherein the cervical cancer is stage IVB, metastatic, recurrent, or persistent. 164. The method of any one of claims 160 to 163,
The method of claim 1, wherein the cervical cancer is metastatic and/or recurrent PD-L1 positive cervical carcinoma. 165. The method of any one of claims 160 to 164,
The subject or subjects have received at least one line of prior therapy. 167. The method of any one of claims 160 to 165,
The subject or subjects have received two lines of prior therapy. 166. The method of any one of claims 160 to 166,
wherein the subject or subjects have received more than two lines of prior therapy. 165. The method of any one of claims 160 to 164,
The method of claim 1, wherein the subject or subjects have not received prior therapy. 169. The method of any one of claims 165-168,
wherein said prior therapy is chemotherapy, surgery and/or radiation therapy. 169. The method of any one of claims 160 and 162-169,
wherein said treatment elicits a clinical response. 170. The method of claim 170,
wherein the clinical response is an increase in the objective response rate (ORR) of the subject population as compared to a baseline ORR. 172. The method of claim 171,
wherein said baseline ORR is the median ORR of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody. 170. The method of claim 170,
wherein the baseline ORR is at least about 14.6% to about 26%. 170. The method of claim 170,
wherein the clinical response is CR or PR. 175. The method of any one of claims 170-174,
The clinical response is an increase in the subject's PFS compared to a baseline progression-free survival (PFS) period, an increase in the subject's DOR compared to a baseline duration of response (DOR) period, or an increase in the subject's DOR compared to a baseline overall survival (OS) period compared to a baseline overall survival (OS) period. an increase in the subject's OS. 175. The method of claim 175:
(a) said baseline PFS duration is the median duration of PFS in a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;
(b) said baseline DOR duration is the median DOR duration of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or
(c) the baseline OS duration is the median OS duration of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody. A method of treating a subject having cervical cancer having a detectable expression level of PD-L1, the method comprising:
A method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. 178. The method of any one of claims 160-177,
wherein the subject is identified as likely to benefit from treatment based on PD-L1 expression on the detected tumor cells. 178. The method of any one of claims 160-178,
The method of claim 1, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP263. 180. The method of any one of claims 160 to 179,
wherein the detectable expression level of PD-L1 is greater than or equal to 5% of tumor associated immune cells (TICs) in the sample from the subject. 178. The method of any one of claims 160-178,
The method of claim 1, wherein the PD-L1 expression level is detected using anti-PD-L1 antibody 22C3. 180. The method of any one of claims 160 to 179,
wherein the detectable expression level of PD-L1 has a composite positive score (CPS) of 1 or greater in a sample from the subject. 70. The method of claim 69,
The method of claim 1, wherein the cancer is breast cancer. A method of treating a subject or population of subjects having breast cancer, the method comprising:
One or more dosing cycles of tiragolumab at a dose of about 840 mg every 4 weeks, atezolizumab at a dose of about 1680 mg every 4 weeks, and nap-paclitaxel at a dose of about 100 mg/m ² of 3 weeks dosing/1 week off A method comprising administering to the subject or population of subjects a dosing regimen comprising 185. The method of claim 183 or 184,
The method of claim 1, wherein the breast cancer is triple negative breast cancer (TNBC). 185. The method of claim 185,
wherein the TNBC is unresectable locally advanced or metastatic TNBC. 189. The method of any one of claims 183 to 186,
The method of claim 1, wherein the subject or subjects has not received prior systemic therapy for metastatic breast cancer. 189. The method of any one of claims 183 to 187,
wherein said treatment results in an ORR in at least about 53% to at least about 67.5% of the subject population. 189. The method according to any one of claims 183 to 188,
wherein said treatment results in a median OS in the subject population of about 25.0 months. A method of treating a subject having early triple negative breast cancer (eTNBC), comprising:
administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 300 mg to about 600 mg every two weeks and one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 600 mg to about 1200 mg every two weeks A method comprising the step of 190. The method of claim 190,
The method further comprising administering to the subject one or more chemotherapeutic agents. 192. The method of claim 191,
The method of claim 1, wherein the at least one chemotherapeutic agent is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent. 190. The method of claim 190,
(a) at least one dosing cycle of said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) said anti-TIGIT antagonist antibody, said PD-1 axis binding antagonist, a topoisomerase II inhibitor, an alkylating agent, and granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) The method further comprising administering one or more dosing cycles of 194. The method of claim 192 or 193,
wherein the alkylating agent is cyclophosphamide. 194. The method of claim 194,
wherein the cyclophosphamide is administered at a dose of about 600 mg/m ² . 194. The method of any one of claims 190-192, 194 and 195, wherein
further administering G-CSF or GM-CSF to the subject. 197. The method of claim 193 or 196,
The G-CSF is pegfilgrastim or filgrastim, the method. 197. The method of claim 197,
The G-CSF is pegfilgrastim, the method. 199. The method of claim 198,
The method of claim 1, wherein the pegfilgrastim is administered at a dose of about 6 mg. 199. The method of any one of claims 191, 192, and 194-199, wherein
further administering to the subject the one or more chemotherapeutic agents and/or one or more subsequent doses of G-CSF or GM-CSF. 201. The method of any one of claims 191, 192, and 194-200, wherein
wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are administered once every week, once every 2 weeks, or once every 3 weeks, respectively. 202. The method of any one of claims 192-201, wherein
The platinum-based chemotherapeutic agent is administered every 3 weeks, the taxane is administered weekly, the topoisomerase II inhibitor is administered every 2 weeks, the alkylating agent is administered every 2 weeks, and the G-CSF or GM- CSF is administered every two weeks. 202. The method of any one of claims 192-202, wherein
wherein said taxane or said taxane and said platinum-based chemotherapeutic agent are administered during the first 12 weeks of said dosing regimen. 203. The method of any one of claims 192-203, wherein
wherein the topoisomerase II inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered for 13 to 19 weeks of a dosing regimen. 204. The method of any one of claims 190-204,
The total duration of said dosing regimen is 19 weeks. 205. The method of any one of claims 190-205,
A neoadjuvant treatment, a method. 206. The method of any one of claims 190-206, wherein
wherein surgery is performed after said dosing regimen. 208. The method of claim 207,
wherein said surgery is performed between 2 and 6 weeks after the last dose of said dosing regimen. 209. The method of claim 207 or 208,
wherein the surgery comprises a mastectomy. 209. The method of any one of claims 207-209,
wherein the surgery comprises axillary lymph node surgery. 212. The method of any one of claims 192-210, wherein
wherein the topoisomerase II inhibitor is doxorubicin. 212. The method of any one of claims 192-210, wherein
wherein the taxane is nap-paclitaxel, the platinum-based chemotherapeutic agent is carboplatin, and the topoisomerase II inhibitor is doxorubicin. 223. The method of claim 211 or 212,
The method of claim 1, wherein doxorubicin is administered at a dose of about 60 mg/m ² . A method of treating a subject having eTNBC comprising:
Tiragolumab at a dose of about 420 mg every 2 weeks, Atezolizumab at a dose of about 840 mg every 2 weeks, and:
(a)
(i) nap-paclitaxel at a dose of about 125 mg/m ² every week for the first 12 weeks of the dosing regimen and carboplatin at a dose targeted to achieve an AUC of 5 mg/mL/min every 3 weeks; and
(ii) doxorubicin at a dose of about 60 mg/m ² every 2 weeks, cyclophosphamide at a dose of about 600 mg/m ² every 2 weeks, and G-CSF every 2 weeks or GM-CSF; or
(b)
(i) nap-paclitaxel at a dose of about 125 mg/m ² weekly for the first 12 weeks of said dosing regimen; and
(ii) doxorubicin at a dose of about 60 mg/m ² every 2 weeks, cyclophosphamide at a dose of about 600 mg/m ² every 2 weeks, and G-CSF every 2 weeks or administering to the subject a dosing regimen comprising GM-CSF;
and surgery between 2 and 6 weeks after the last dose of the dosing regimen. 214. The method of any one of claims 184-214,
wherein a detectable protein expression level of PD-L1 is determined in a tumor sample from said subject determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142. 225. The method of claim 215,
The method of claim 1, wherein the proportion of tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (ICs) in the tumor sample is at least 1%. 217. The method of any one of claims 190-216,
wherein the eTNBC is presented as T2-4d TNBC. 218. The method of any one of claims 190-217,
wherein the eTNBC is presented as cT2-cT4, cN0-cN3, and cM0 TNBC. 218. The method of any one of claims 190 to 218,
wherein the subject has not been previously treated for eTNBC. 221. The method of any one of claims 190 to 219,
wherein the treatment results in a pathological complete response (pCR). 221. The method of any one of claims 190-220, wherein
wherein the treatment results in an increase in overall survival (OS) or event-free survival (EFS).
70. The method of claim 69,
The method of claim 1, wherein the cancer is head and neck cancer. 223. The method of claim 222,
The method of claim 1, wherein the head and neck cancer is squamous cell carcinoma (SCCHN) of the head and neck. A method of treating a subject or population of subjects having SCCHN having a detectable expression level of PD-L1, the method comprising:
administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks A method comprising steps. A method of selecting a therapy for a subject or population of subjects with SCCHN comprising:
(a) detecting the protein expression level of PD-L1 in a tumor sample from said subject or population of subjects by IHC analysis using an anti-PD-L1 antibody suitable for staining; and
(b) a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks and 3 weeks based on PD-L1 expression detected for said subject or population of subjects having a detectable expression level of PD-L1 selecting a regimen comprising at least one dosing cycle of an anti TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg per time. A method of treating a subject having SCCHN having a detectable expression level of PD-L1 comprising:
A method comprising administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. 227. The method of any one of claims 224 to 226,
wherein the subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1. 227. The method according to any one of claims 223 to 227,
wherein the SSCHN is human papillomavirus (HPV) positive. 223. The method of any one of claims 223 to 228,
wherein the SSCHN is HPV negative. 229. The method of claim 228 or 229,
HPV status is determined by p16 IHC, in situ hybridization, or PCR. 234. The method of any one of claims 223 to 230,
wherein the SCCHN is recurrent and/or metastatic SCCHN. 232. The method according to any one of claims 222 to 231,
The method of claim 1, wherein the subject or subjects have not received prior therapy. 232. The method of claim 232,
wherein said prior therapy is prior systemic therapy for recurrent and/or metastatic disease. 224. The method of any one of claims 222-224 and 226-233,
wherein said treatment results in CR or PR. 224. The method of any one of claims 222-224 and 226-233,
wherein the treatment results in an increase in the ORR of the subject population as compared to a baseline objective response rate (ORR). 234. The method of claim 235,
wherein said baseline ORR is the median ORR of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody. 237. The method of claim 235 or 236,
wherein the baseline ORR is at least about 19% to about 36%. 223. The method of any one of claims 222-224 and 226-237, wherein
The treatment comprises an increase in PFS of the subject or population of subjects as compared to a baseline progression-free survival (PFS) period, an increase in the DOR of the subject or population of subjects as compared to a baseline duration of response (DOR), or a baseline overall survival (OS) ) causes an increase in OS of the subject or population of subjects compared to a period of time. 238. The method of claim 238:
(a) said baseline PFS duration is the median duration of PFS in a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;
(b) said baseline DOR duration is the median DOR duration of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody; or
(c) the baseline OS duration is the median OS duration of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody. 238. The method of claim 238,
wherein the baseline DOR period is at least about 6.7 months to about 23.4 months. 238. The method of claim 238,
wherein the baseline OS duration is at least about 11.6 months to about 14.9 months. 25. The method of any one of claims 224 to 241,
wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1 determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody SP263. 252. The method of claim 242,
The detectable protein expression level of PD-L1 is in the tumor sample:
(a) at least 5%;
(b) at least 5% and less than 20%; or
(c) at least 20% tumor associated immune cells (TICs). 24. The method of any one of claims 224 to 243,
wherein the subject or population of subjects is identified as likely to benefit from treatment based on PD-L1 expression on the detected tumor cells.
70. The method of claim 69,
The method of claim 1, wherein the cancer is liver cancer. 245. The method of claim 245,
The method of claim 1, wherein the liver cancer is hepatocellular carcinoma (HCC). A method of treating a subject or population of subjects having hepatocellular carcinoma (HCC), the method comprising:
A method comprising administering to the subject or population of subjects one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject or population of subjects has not received prior systemic therapy for HCC. . 247. The method of claim 247,
The method of claim 1, further comprising administering a VEGF antagonist to the subject or population of subjects. A method of treating a subject or population of subjects having HCC comprising:
A method comprising administering to the subject or population of subjects one or more dosing cycles of an anti TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist. 249. The method of claims 248 and 249,
The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks. 250. The method of any one of claims 247-250, wherein
wherein the anti-TIGIT antagonist antibody is administered at a dose of about 500 mg to about 700 mg every 3 weeks. 252. The method of any one of claims 247-251,
The method of claim 1, wherein the PD-1 axis binding antagonist is administered at a dose of about 900 mg to about 1500 mg every 3 weeks. 252. The method of claim 248 or 249,
The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 1 mg/kg to about 20 mg/kg every two weeks. 252. The method of claim 253,
The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 10 mg/kg every two weeks. 254. The method of claim 254,
The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg, about 7.5 mg/kg, or about 10 mg/kg every two weeks. 257. The method of any one of claims 247-249 and 253-255, wherein
wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300 mg to about 800 mg every two weeks. 257. The method of any one of claims 247-249 and 253-256, wherein
The method of claim 1, wherein the PD-1 axis binding antagonist is administered at a dose of about 200 mg to about 1200 mg every two weeks. 252. The method of claims 247-249,
wherein the anti-TIGIT antagonist antibody is administered at a dose of about 700 mg to about 1000 mg every 4 weeks. 258. The method of any one of claims 247-249 and 258,
The method of claim 1, wherein the PD-1 axis binding antagonist is administered at a dose of about 1400 mg to about 2000 mg every 4 weeks. 262. The method of any one of claims 247 to 259,
wherein the HCC is locally advanced or metastatic HCC. 260. The method of any one of claims 247 to 260,
wherein the HCC is unresectable HCC. 27. The method of any one of claims 247 to 261,
wherein the subject or subjects is determined to have sufficient liver function. 262. The method of claim 262,
wherein said sufficient liver function is characterized by Child-Pugh class A. 267. The method of any one of claims 247 to 263,
wherein the subject or HCC tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1. 267. The method of any one of claims 247 to 264,
A method comprising administering to the subject or population of subjects at least four dosing cycles. 261. The method of claim 261,
and administering to the subject or population of subjects at least 16 dosing cycles. A method of treating a subject or population of subjects having HCC comprising:
administering to the subject one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks, atezolizumab at a dose of about 1200 mg every 3 weeks, and bevacizumab at a dose of about 15 mg/kg every 3 weeks. A method comprising steps. 267. The method of any one of claims 249-267,
The method of claim 1, wherein the subject or subjects have not received prior systemic treatment for HCC. 269. The method of any one of claims 247 to 268,
wherein said treatment results in a median PFS in the subject population of at least about 5.6 months to at least about 6.83 months. 70. The method of claim 69,
wherein the cancer is bladder cancer. 270. The method of claim 270,
wherein the bladder cancer is muscle invasive bladder cancer (MIBC). A method of treating a subject or population of subjects having MIBC comprising:
administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks and, the subject is ineligible for treatment with a platinum-based chemotherapeutic agent. A method of treating a subject or population of subjects having MIBC comprising:
administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist every 3 weeks And, the treatment is a treatment before and after surgery, the method. 274. The method of claim 272 or 273,
The method of claim 1, wherein the subject or subjects have a creatinine clearance of less than 60 mL/min. 275. The method of any one of claims 272-274,
The method of claim 1, wherein the subject or subjects have a hearing loss of grade 2 or greater. 275. The method of any one of claims 272-275,
The method of claim 1 , wherein the subject or subjects have grade 2 or greater neuropathy. 279. The method of any one of claims 272-276,
The method of claim 1, wherein the subject or subjects refused treatment with a platinum-based chemotherapeutic agent. 277. The method of any one of claims 272 or 274-277,
The method of claim 1, wherein the platinum-based chemotherapeutic agent is cisplatin. 279. The method of any one of claims 272-278,
wherein the MIBC is surgically feasible. 279. The method of claim 279,
The method further comprising surgery. 280. The method of claim 280,
at least one dosing cycle is initiated prior to the surgery. 280. The method of claim 280,
at least 1, 2, or 3 dosing cycles are completed prior to the surgery. 289. The method of any one of claims 280 to 282,
at least one dosing cycle is initiated between 4 and 6 weeks post surgery. 283. The method of claim 283,
1 to 17 dosing cycles are completed after said surgery. 289. The method of any one of claims 280-284,
wherein the surgery is cystectomy and/or lymphadenectomy. 289. The method of any one of claims 272-285,
wherein the treatment results in a pathological complete response (pCR). 297. The method of any one of claims 272-286,
wherein the treatment is an increase in relapse-free survival (RFS) of the subject or subjects as compared to a baseline RFS duration, an increase in event-free survival (EFS) of the subject or subjects compared to a baseline EFS duration, or an increase in the event-free survival (EFS) of the subject or subjects compared to a baseline OS duration, or compared to a baseline OS duration. causing an increase in overall survival (OS) in the subject or subjects. 289. The method of claim 287:
(a) said baseline RFS duration is the median RFS duration of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody;
(b) said baseline EFS duration is the median duration of EFS in a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody; or
(c) the baseline OS duration is the median OS duration of a population of subjects receiving treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody. 289. The method of any one of claims 272-288,
wherein the treatment results in pathological downstaging. A method of treating a subject or population of subjects having MIBC comprising:
administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks, wherein the subject or subjects are cisplatin ineligible In, way. A method of treating a subject or population of subjects having MIBC comprising:
administering to said subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks, wherein said treatment is perioperative treatment. , Way. 302. The method of any one of claims 272-291,
wherein said treatment results in an ORR in at least about 13.4% to at least about 15% of the subject population. 302. The method of any one of claims 272-292,
wherein said treatment results in a median OS in the subject population of about 7.9 months to about 8.6 months. 294. The method of any one of claims 272-293,
wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142 is determined. 295. The method of claim 294,
The method of claim 1, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction in which the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (IC) is 5% or more. 270. The method of claim 270,
The method of claim 1, wherein the bladder cancer is urothelial cell carcinoma (UC). 297. The method of claim 296,
wherein the UC is metastatic urothelial cell carcinoma (mUC). A method of treating a subject or population of subjects having mUC, comprising:
administering a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg every 3 weeks and a PD-1 axis binding antagonist at a dose of about 900 mg to about 1500 mg every 3 weeks to the subject or subject. A method comprising administering to a population. 298. The method of claim 298,
The method of claim 1, wherein the subject or subjects have not received prior cancer immunotherapy. 302. The method of claim 298 or 299,
wherein the treatment is a second line treatment. 300. The method of any one of claims 298-300,
wherein the mUC progresses during or after platinum containing therapy. 302. The method of any one of claims 298-301,
and administering a second dosing regimen to the subject or population of subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity. 302. The method of claim 302,
wherein the second dosing regimen comprises one or more dosing cycles of a PD-1 axis binding antagonist and an antibody-drug conjugate (ADC). 303. The method of claim 303,
The method of claim 1, wherein the ADC is (a) enfortumab vedotin or (b) sacituzumab gobitecan. 305. The method of claim 304,
(a) enfortumab vedotin is administered at a weekly dose of 1.25 mg/kg on a 2-week dosing/week break, or (b) sacituzumab gobitecan is administered at 10 mg/week on a 2-week dos/week break Administered in kg dose. A method of treating a subject or population of subjects having mUC, comprising:
A method comprising administering to the subject or population of subjects one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks. A method of treating a subject or population of subjects having mUC, comprising:
administering to the subject or population of subjects a first dosage regimen followed by a second dosage regimen, wherein:
(a) said first dosing regimen comprises one or more dosing cycles of tiragolumab at a dose of about 600 mg every 3 weeks and atezolizumab at a dose of about 1200 mg every 3 weeks; and
(b) said second dosing regimen comprises at least one dosing cycle of atezolizumab at a dose of about 1200 mg every 3 weeks, and (i) enfortumab vedotin is administered at 1.25 weekly doses of 2 weeks on/1 week off. is administered at a mg/kg dose, or (ii) sacituzumab gobitecan is administered at a weekly 10 mg/kg dose of 2 weeks dosing/1 week off, wherein said second dosing regimen is wherein said subject or population of subjects The method is administered to the subject or population of subjects after experiencing disease progression or unacceptable toxicity during a first dosing regimen. 312. The method of any one of claims 298-307,
wherein said treatment results in an ORR in at least about 13.4% to at least about 31% of the subject population. 309. The method of any one of claims 298-308,
wherein said treatment results in a median OS of the subject population of about 7.9 months to about 16.3 months. 70. The method of claim 69,
The method of claim 1, wherein the cancer is pancreatic cancer. A method of treating a subject or population of subjects having pancreatic cancer, the method comprising:
Tiragolumab at a dose of about 420 mg on days 1 and 15 of each 28-day dosing cycle, atezolizumab at a dose of about 840 mg on days 1 and 15 of each 28-day dosing cycle, each 28 days. Gemcitabine at a dose of about 1000 mg/m ² on days 1, 8, and 15 of the dosing cycle, and about 125 mg/m ² on days 1, 8, and 15 of each 28-day dosing cycle A method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 28-day dosing cycles of a dose of nap-paclitaxel. 312. The method of claim 310 or 311,
wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). 312. The method of claim 312,
wherein the PDAC is a metastatic PDAC. 314. The method according to any one of claims 310 to 313,
The method of claim 1, wherein the subject or subjects have not received prior systemic therapy for metastatic PDAC. 314. The method of any one of claims 310-314,
wherein said treatment results in an ORR in at least about 41.7% to about 46.7% of the subject population. 315. The method of any one of claims 310-315,
wherein said treatment results in an increase in ORR of at least about 20% compared to treatment comprising gemcitabine and nap-paclitaxel without an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist. 316. The method of any one of claims 310-316,
wherein said treatment results in a median PFS in the subject population of at least about 5.5 months to about 7 months. 312. The method of any one of claims 310 to 317, wherein
wherein said treatment results in a median OS in the subject population of at least about 8.5 months to about 10.6 months. 70. The method of claim 69,
wherein the cancer is esophageal cancer. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, the method comprising:
One or more times 21 of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. A method comprising administering to the subject or population of subjects a dosing regimen comprising one dosing cycle. A method of treating a subject or population of subjects having esophageal cancer, the method comprising:
One or more times 21 of an anti-TIGIT antagonist antibody at a dose of about 500 mg to about 700 mg on Day 1 of each dosing cycle and a dose of about 900 mg to about 1500 mg of a PD-1 axis binding antagonist on Day 1 of each dosing cycle. A method comprising administering to the subject or population of subjects a dosing regimen comprising one dosing cycle, wherein the subject or subjects have previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. 320. The method of claim 320,
The method of claim 1, wherein the subject or subjects has previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. 323. The method of claim 321 or 322,
wherein said subject or subjects experienced disease progression or unacceptable toxicity during said prior treatment. 320. The method of claim 320,
The 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. 325. The method of claim 324,
wherein said platinum-based chemotherapeutic agent is omitted from said dosing regimen after 6 doses. 325. The method of any one of claims 321 to 325,
The method of claim 1, wherein the platinum-based chemotherapeutic agent is cisplatin. 326. The method of claim 326,
The method of claim 1 wherein cisplatin is administered at a dose of about 80 mg/m ² on Day 1 of each dosing cycle. 321. The method of any one of claims 321 to 327,
The method of claim 1, wherein the non-platinum-based chemotherapeutic agent is an antimetabolites. 339. The method of claim 328,
wherein the antimetabolite is 5-fluorouracil. 329. The method of claim 329,
5-fluorouracil is administered at a dose of about 800 mg/m ² /24 hours on days 1-5 of each 21-day cycle. 335. The method of any one of claims 321 to 330,
The method of claim 1, wherein the esophageal cancer is advanced or metastatic esophageal cancer. 335. The method of claim 320 or 331,
The method of claim 1, wherein the subject or subjects has not received prior treatment for metastatic esophageal cancer. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, the method comprising:
Tiragolumab at a dose of about 600 mg on Day 1 of each dosing cycle, atezolizumab at a dose of about 1200 mg on Day 1 of each dosing cycle, at a dose of about 80 mg/m ² on Day 1 of each dosing cycle administering to the subject or population of subjects a dosing regimen comprising one or more 21-day dosing cycles of cisplatin, and 5-fluorouracil at a dose of about 800 mg/m ² /24 hours on days 1-5 of each 21-day cycle. administering, wherein cisplatin is omitted from the dosing regimen after 6 doses. A method of treating a subject or population of subjects having advanced or metastatic esophageal cancer, the method comprising:
administering a first dosage regimen and a second dosage regimen to the subject or population of subjects, wherein:
(a) said first dosing regimen is cisplatin at a dose of about 80 mg/m ² on day 1 of each dosing cycle and 5 at a dose of 800 mg/m ² /24 hour on days 1-5 of each 21 day cycle. - one or more 21 day dosing cycles of fluorouracil, wherein cisplatin is omitted from said dosing regimen after 6 doses; and
(b) said second dosing regimen is one or more 21 day dosing cycles of tiragolumab at a dose of about 600 mg on day 1 of each dosing cycle and atezolizumab at a dose of about 1200 mg on day 1 of each dosing cycle A method comprising 35. The method of any one of claims 321 to 334,
wherein the treatment results in an ORR in at least about 14% of the subject population. 335. The method of any one of claims 47 to 335,
The anti-TIGIT antagonist antibody has the following hypervariable regions (HVR):
HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);
HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);
HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);
HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);
HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and
A method comprising an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). 336. The method of claim 336,
The anti-TIGIT antagonist antibody has the following light chain variable region framework regions (FR):
FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);
FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);
FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and
FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). 336. The method of claim 336,
The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FRs:
FR-H1 comprising the amino acid sequence of X ₁ VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X ₁ is E or Q;
FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);
FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and
FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). 339. The method of claim 338,
X ₁ is E; 339. The method of claim 338,
X ₁ is Q. 340. The method of any one of claims 336-340,
The anti-TIGIT antagonist antibody is:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:19; or
(c) a VH domain as in case (a) and a VL domain as in case (b). 34. The method of any one of claims 336 to 341,
The anti-TIGIT antagonist antibody is:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and
(b) a VL domain comprising the amino acid sequence of SEQ ID NO:19. The method of any one of claims 336-339, 341, and 342, wherein
The anti-TIGIT antagonist antibody is:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and
(b) a VL domain comprising the amino acid sequence of SEQ ID NO:19. 34. The method of any one of claims 336-339 and 341-343, wherein
The anti-TIGIT antagonist antibody is:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 33; and
(b) a light chain comprising the amino acid sequence of SEQ ID NO:34. 335. The method of any one of claims 336 to 344,
wherein the anti-TIGIT antagonist antibody is a monoclonal antibody. 345. The method of any one of claims 336-345,
wherein the anti-TIGIT antagonist antibody is a human antibody. 346. The method of any one of claims 336-346,
wherein the anti-TIGIT antagonist antibody is a full length antibody. 347. The method of any one of claims 336-347,
wherein the anti-TIGIT antagonist antibody has a prototypical Fc-mediated agonist function. 335. The method of any one of claims 336-339 and 341-348, wherein
The method of claim 1, wherein the anti-TIGIT antagonist antibody is tyragolumab. 346. The method of any one of claims 336-346,
wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab') ₂ fragment. 349. The method of any one of claims 336-349, wherein
wherein the anti-TIGIT antagonist antibody is an IgG class antibody. 351. The method of claim 351
wherein the IgG class antibody is an IgG1 subclass antibody. 335. The method of any one of claims 336 to 352,
wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. 355. The method of claim 353,
The method of claim 1, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 355. The method of claim 354,
wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. 355. The method of claim 355,
wherein the PD-L1 binding antagonist inhibits PD-L1 from binding to PD-1, B7-1, or both PD-1 and B7-1. 356. The method of any one of claims 354 to 356,
The method of claim 1, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody. 358. The method of claim 357,
The anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001, enbapoliumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL -A167, APL-502, Cosibelimab, Rhodafoliumab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003 , YBL-007, or HS-636. 358. The method of claim 358,
The method of claim 1, wherein the anti-PD-L1 antagonist antibody is atezolizumab. 358. The method of claim 357,
The anti-PD-L1 antagonist antibody has the following HVRs:
HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);
HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);
HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22);
HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);
HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and
A method comprising an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO:25). 360. The method of claim 360,
The anti-PD-L1 antagonist antibody is:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26;
(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:27; or
(c) a VH domain as in case (a) and a VL domain as in case (b). 361. The method of claim 361,
The anti-PD-L1 antagonist antibody is:
(a) a VH domain comprising the amino acid sequence of SEQ ID NO:26; and
(b) a VL domain comprising the amino acid sequence of SEQ ID NO:27. 362. The method of claim 362,
The anti-PD-L1 antagonist antibody is:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO:28; and
(b) a light chain comprising the amino acid sequence of SEQ ID NO:29. 37. The method of any one of claims 360 to 363,
The method of claim 1, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody. 375. The method of any one of claims 360 to 364,
The method of claim 1, wherein the anti-PD-L1 antagonist antibody is a humanized antibody. 365. The method of claim 364 or 365,
wherein the anti-PD-L1 antagonist antibody is a full length antibody. 36. The method of any one of claims 360-365,
wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, scFv, and (Fab') ₂ fragments. 370. The method of any one of claims 360-366,
wherein the anti-PD-L1 antagonist antibody is an IgG class antibody. 368. The method of claim 368,
wherein the IgG class antibody is an IgG1 subclass antibody. 355. The method of claim 353,
The method of claim 1, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist. 370. The method of claim 370,
wherein the PD-1 binding antagonist inhibits PD-1 from binding to one or more of its ligand binding partners. 371. The method of claim 371,
wherein the PD-1 binding antagonist inhibits PD-1 from binding to PD-L1, PD-L2, or both PD-L1 and PD-L2. 373. The method of any one of claims 370 to 372,
The method of claim 1, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody. 373. The method of claim 373,
Said anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, semiflimab, BGB-108, prolgolimab, camrelizumab, scintilimab, tislelizumab, torifalizumab Mab, dostalimab, retipanrimab, sasanrimab, fenpulimab, CS1003, HLX10, SCT-I10A, gimberelimab, valstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21. 373. The method of any one of claims 370 to 372,
The method of claim 1, wherein the PD-1 binding antagonist is an Fc fusion protein. 375. The method of claim 375,
The Fc fusion protein is AMP-224, the method. 107. The method of any one of claims 77-101, 103-116, 119-122, and 247-249, wherein
and administering said anti-TIGIT antagonist antibody to said subject or population of subjects at a dose of about 500 mg to about 700 mg every three weeks. 57, 59, 60, 62-64, 101, 123-151, 160, 161, 224, 225, 247 325. The method of any one of claims 255-255, 272-289, 298-305, 320-332, and 377, wherein
and administering the anti-TIGIT antagonist antibody to the subject at a dose of about 600 mg every 3 weeks. 84. The method of any one of claims 77, 78, 82, and 83, wherein
and administering said anti TIGIT antagonist antibody to said subject or population of subjects at a dose of about 700 mg to about 1000 mg every 4 weeks. 58. The method of any one of claims 47, 56, 64, 258, and 379, wherein
and administering the anti-TIGIT antagonist antibody to the subject at a dose of about 840 mg every 4 weeks. 87. The method of any one of claims 77, 78, 82, 83, and 256, wherein
and administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of about 300 mg to about 600 mg every two weeks. 249. The method of any one of claims 48, 190-213, 215-221, 256, and 381, wherein
and administering the anti-TIGIT antagonist antibody to the subject at a dose of about 420 mg every two weeks. 339. The method according to any one of claims 47 to 382,
wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose. 107. The method of any one of claims 77-100, 103-116, 119-122, and 243-245, wherein
and administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of about 900 mg to about 1500 mg every three weeks. 272 The method of any one of claims-289, 298-305, 320-332, and 384, wherein
administering the PD-1 axis binding antagonist to the subject at a dose of about 1200 mg every 3 weeks. 84. The method of any one of claims 77, 78, 82, and 83, wherein
and administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of about 1400 mg to about 2000 mg every 4 weeks. 57. The method of any one of claims 47, 56, 64, 259, and 386,
administering the PD-1 axis binding antagonist to the subject at a dose of about 1680 mg every 4 weeks. 78. The method of any one of claims 77, 78, 82, 83, and 257, wherein
and administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of about 600 mg to about 1200 mg every two weeks. 249. The method of any one of claims 48, 190-213, 215-221, 257, and 388,
administering the PD-1 axis binding antagonist to the subject at a dose of about 840 mg every two weeks. 389. The method of any one of claims 47-389,
The method of claim 1, wherein the dose of the PD-1 axis binding antagonist is a fixed dose. 59. The method of claim 58,
A method comprising administering to the subject pembrolizumab at a fixed dose of about 400 mg every 6 weeks. 163. The method of any one of claims 51, 57, 59, 60, 62, 77, 78, 82, 83, 103, and 161. ,
wherein each period of said one or more dosing cycles is 21 days. 57. The method of any one of claims 47, 56, 64, 77, 184 to 189, and 253 to 259,
wherein each period of said one or more dosing cycles is 28 days. 404. The method according to any one of claims 47 to 393,
administering said anti-TIGIT antagonist antibody to said subject or population of subjects on about Day 1 of each of said one or more dosing cycles. 395. The method of any one of claims 47-394,
administering the PD-1 axis binding antagonist to the subject or population of subjects on about Day 1 of each of the one or more dosing cycles. 256. The method of claim 256,
administering said anti-TIGIT antagonist antibody to said subject on about 15 days of each of said one or more dosing cycles. 257. The method of claim 257,
administering the PD-1 axis binding antagonist to the subject on about day 15 of each of the one or more dosing cycles. 399. The method according to any one of claims 47 to 397,
and administering the PD-1 axis binding antagonist to the subject or population of subjects prior to the anti TIGIT antagonist antibody. 399. The method of claim 398,
a first observation period following administration of the PD-1 axis binding antagonist. 399. The method of claim 399,
The method of claim 1, wherein the first observation period is from about 30 minutes to about 60 minutes in length. 401. The method of claim 399 or 400,
a second observation period following administration of said anti-TIGIT antagonist antibody. 401. The method of claim 401,
and the second observation period is between about 30 minutes and about 60 minutes in length. 399. The method according to any one of claims 47 to 397,
administering the PD-1 axis binding antagonist to the subject or population of subjects concurrently with the anti-TIGIT antagonist antibody. 404. The method of any one of claims 47 to 403,
and administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist intravenously to the subject or population of subjects. 404. The method of claim 404,
administering the PD-1 axis binding antagonist to the subject or population of subjects as an intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes. 405. The method of claim 404 or 405,
and administering said anti-TIGIT antagonist antibody to said subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or 60 ± 10 minutes. 104. The method of any one of claims 47-103 and 105-406, wherein
A method, wherein the level of PD-L1 expression in the subject or a tumor sample obtained from subjects is determined. 407. The method of claim 407,
wherein the subject or a tumor sample obtained from subjects is determined to have a detectable expression level of PD-L1. 408. The method of claim 408,
wherein the detectable expression level of PD-L1 is a detectable protein expression level of PD-L1. 409. The method of claim 409,
The method of claim 1, wherein the detectable protein expression level of PD-L1 is determined by immunohistochemical (IHC) analysis comprising staining with an anti-PD-L1 antibody suitable for staining. 410. The method of claim 410,
An anti-PD-L1 antibody suitable for said staining is an anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. 420. The method of claim 410 or 411,
wherein the detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a PalmDx 28-8 IHC assay. . 103. The method of any one of claims 47-102, 159, 181-223, and 245-335,
wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP263 is determined. 189. The method of any one of claims 47-189, 222-269, and 296-335, wherein
wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody SP142 is determined. 189. The method of any one of claims 47-189, and 222-335, wherein
wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 22C3 is determined. 104. The method of any one of claims 47-103 and 105-335, wherein
wherein the detectable protein expression level of PD-L1 determined by IHC analysis comprising staining with anti-PD-L1 antibody 28-8 is determined. 413. The method of claim 413,
wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% of tumor associated immune cells (TICs) in the tumor sample. 413. The method of claim 413,
wherein the detectable protein expression level of PD-L1 has a TIC of at least 5% and less than 20% in the tumor sample. 413. The method of claim 413,
wherein the detectable protein expression level of PD-L1 has a TIC of at least 10% in the tumor sample. 413. The method of claim 413,
wherein the detectable protein expression level of PD-L1 has a TIC of at least 20% in the tumor sample. 413. The method of claim 413,
wherein the detectable protein expression level of PD-L1 has a TIC of at least 10% and less than 50% in the tumor sample. 413. The method of claim 413,
wherein the detectable protein expression level of PD-L1 has a TIC of at least 50% in the tumor sample. 416. The method of any one of claims 413, 415, and 416,
The method of claim 1, wherein the detectable protein expression level of PD-L1 is greater than or equal to 1% of the PD-L1 positive tumor cell fraction. 416. The method of any one of claims 413, 415, and 416,
The method of claim 1, wherein the detectable protein expression level of PD-L1 is greater than or equal to 30% in the fraction of PD-L1 positive tumor cells. 416. The method of any one of claims 413, 415, and 416,
wherein the detectable protein expression level of PD-L1 is greater than or equal to 1% and less than 50% of a fraction of PD-L1-positive tumor cells in the tumor sample. 416. The method of any one of claims 413, 415, and 416,
The method, wherein the detectable protein expression level of PD-L1 is at least 50% of the PD-L1 positive tumor cell fraction. 414. The method of claim 414,
wherein the PD-L1-positive tumor cell fraction is a proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating immune cells (ICs). 414. The method of claim 414,
The method of claim 1, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is at least 1%. 414. The method of claim 414,
The method of claim 1, wherein the proportion of tumor area occupied by PD-L1-expressing tumor invasive IC is at least 5%. 415. The method of claim 415,
The method of claim 1, wherein the detectable protein expression level of PD-L1 has a composite positive score (CPS) of 1 or more. 415. The method of claim 415,
The method, wherein the detectable protein expression level of PD-L1 has a CPS of 10 or more. 415. The method of claim 415,
The method, wherein the detectable protein expression level of PD-L1 has a CPS of 20 or more. 427. The method of any one of claims 427 to 429,
wherein the IHC assay is a Ventana SP142 IHC assay. 408. The method of claim 408,
wherein the detectable expression level of PD-L1 is a detectable nucleic acid expression level of PD-L1. 434. The method of claim 434,
The detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof. 335. The method of any one of claims 47 to 335,
wherein the treatment results in an increase in overall survival (OS) of the subject as compared to a baseline OS duration and/or an increase in progression-free survival (PFS) in the subject compared to a baseline PFS duration. 436. The method of claim 436:
(a) said baseline OS duration is the median OS duration of a population of subjects receiving treatment with a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without an anti-PD-1 axis binding antagonist; and/or
(b) the baseline PFS duration is the median PFS duration of a population of subjects receiving treatment with a PD-1 axis binding antagonist without anti-TIGIT antagonist antibody or treatment with an anti-TIGIT antagonist antibody without anti-PD-1 axis binding antagonist. 149. The method of any one of claims 49, 141, and 190, wherein
The method of claim 1, wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents. 438. The method of claim 438,
The method of claim 1, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin. 71. The method of claim 66, 89, 116, 145, 212, and 439,
wherein the carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min or AUC=6 mg/ml/min. 173. The method of claim 66, 116, 145, 147, 149, 151, 278, and 326,
wherein the cisplatin is administered at a dose of about 75 mg/m ² or 80 mg/m ² . 438. The method of any one of claims 438 to 441,
The method of claim 1, wherein the one or more non-platinum-based chemotherapeutic agents are antimetabolites, taxanes, or topoisomerase II inhibitors. 60. The method of claim 59 or 442,
wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil. 147. The method of any one of claims 66, 116, 145, and 443,
The method of claim 1, wherein the pemetrexed is administered at a dose of about 500 mg/m ² . 64. The method of any one of claims 60, 61, 145, 316, and 443,
wherein the gemcitabine is administered at a dose of about 1000 mg/m ² or about 1250 mg/m ² . 443. The method of claim 59 or 443,
The method of claim 1, wherein the antimetabolite is capecitabine. 447. The method of claim 443 or 446,
The method of claim 1, wherein the capecitabine is administered at a dose of about 1250 mg/m ² . 203. The method of any one of claims 193, 202, 203, and 442-447,
The method of claim 1, wherein the taxane is paclitaxel or nap-paclitaxel. 69. The method of any one of claims 66, 145, and 448, wherein
wherein the paclitaxel is administered at a dose of about 175 mg/m ² or about 200 mg/m ² . 62. The method of any one of claims 60, 61, 212, 316, and 448, wherein
wherein the nap-paclitaxel is administered at a dose of about 100 mg/m ² . 74. The method of any one of claims 77, 78, 82, 83, 192, 193, and 442 to 450,
wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331. 69. The method of any one of claims 66, 89, and 451, wherein
wherein the etoposide is administered at a dose of about 100 mg/m ² . 45. The method of any one of claims 438 to 452,
The one or more chemotherapeutic agents are each administered once every week, once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, twice every 4 weeks, or 3 times every 4 weeks. , Way. 45. The method of any one of claims 438 to 453,
The method of claim 1, wherein the one or more chemotherapeutic agents are administered on Day 1 of one or more dosing cycles. 45. The method of any one of claims 443-454,
wherein the gemcitabine is administered three times every four weeks. 455. The method of any one of claims 443 to 455,
wherein the gemcitabine is administered on days 1, 8, and/or 15 of one or more dosing cycles. 456. The method of any one of claims 443 to 456,
wherein the capecitabine is administered daily for 2 weeks. 45. The method of any one of claims 443 to 457,
wherein the capecitabine is administered on days 1 to 14 of one or more dosing cycles. 459. The method of any one of claims 448 to 458,
wherein the nap-paclitaxel is administered 3 times every 4 weeks. 459. The method of any one of claims 448 to 459,
wherein said nap-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles. 460. The method of any one of claims 451-460,
wherein the etoposide is administered on days 1 to 3 every 3 weeks. 47. The method of any one of claims 451 to 461,
wherein the etoposide is administered on days 1-3 of one or more dosing cycles. 47. The method of any one of claims 438 to 462,
wherein said one or more chemotherapeutic agents are administered prior to said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody. 47. The method of any one of claims 438 to 463,
wherein said one or more chemotherapeutic agents are administered after said PD-1 axis binding antagonist and/or said anti-TIGIT antagonist antibody. 475. The method of any one of claims 438 to 464,
The method of claim 1, wherein the one or more chemotherapeutic agents are administered intravenously or orally. 65. The method of any one of claims 62, 248, and 249, wherein
The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 5 mg/kg to about 25 mg/kg every 3 weeks. 470. The method of claim 250 or 466,
The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 10 mg/kg to about 20 mg/kg every 3 weeks. 467. The method of claim 467,
The method of claim 1, wherein the VEGF antagonist is administered at a dose of about 15 mg/kg every 3 weeks. 65. The method of any one of claims 62, 248 to 250, 253 to 255, and 466 to 468,
The method of claim 1, wherein the VEGF antagonist is an anti-VEGF antibody. 469. The method of claim 469,
The anti-VEGF antibody is bevacizumab, the method. 62. The method of any one of claims 62, 248-250, and 253-255, wherein
The method of claim 1, wherein the anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the VEGF antagonist is bevacizumab. 62. The method of any one of claims 62, 248 to 250, 253 to 255, and 466 to 471,
and administering the VEGF antagonist to the subject on Day 1 of one or more dosing cycles. 256. The method of any one of claims 253-255,
and administering the VEGF antagonist to the subject on day 15 of one or more dosing cycles. 62. The method of any one of claims 62, 248 to 250, 253 to 255, and 466 to 471,
The method of claim 1, wherein the VEGF antagonist is administered intravenously. 474. The method of claim 474,
wherein the VEGF antagonist is administered to the subject as an intravenous infusion over 90 ± 15 minutes. 62. The method of any one of claims 62, 248 to 250, 253 to 255, and 466 to 475,
A method comprising administering to the subject the PD-1 axis binding antagonist prior to the VEGF antagonist, and the VEGF antagonist prior to the anti-TIGIT antagonist antibody. 476. The method of claim 476,
A method comprising a first observation period after administration of the PD-1 axis binding antagonist, a second observation period after administration of the VEGF antagonist, and a third observation period after administration of the anti-TIGIT antagonist antibody. 479. The method of claim 477,
wherein the first observation period, the second observation period, and the third observation period are each from about 30 minutes to about 120 minutes in length. 112, 117, 118, 152, 153, 177, 184, 214, 226, 267, 290, 291, 306 333. The method of any one of claims, 307, 311, 333, and 334, wherein
wherein tiragolumab and atezolizumab are combined in an IV bag prior to administration. 479. The method of any one of claims 47 to 479,
wherein the subject is a human. A PD-1 axis binding antagonist and/or anti-TIGIT for treating a subject having cancer according to the method of any one of claims 47-160, 162-224, and 226-480. A kit comprising an antagonist antibody. PD for use in combination with an anti TIGIT antagonist antibody to treat a subject having cancer according to the method of any one of claims 47-160, 162-224, and 226-480. - A kit comprising a -1 axis binding antagonist. 482. The method of claim 482,
The kit further comprising an anti-TIGIT antagonist antibody. 49. The method of any one of claims 481 to 483,
The anti-TIGIT antagonist antibody is tyragolumab, the kit. 49. The method of any one of claims 481 to 484,
The kit, wherein the PD-1 axis binding antagonist is atezolizumab. Claims 47-160, 162-224, and 226-480 for use in combination with a PD-1 axis binding antagonist to treat a subject having cancer according to the method of any one of claims 47-160, 162-224, and 226-480. A kit comprising a TIGIT antagonist antibody. 486. The method of claim 486,
A kit, further comprising a PD-1 axis binding antagonist. 49. The method of claim 486 or 487,
The kit, wherein the PD-1 axis binding antagonist is atezolizumab. 497. The method of any one of claims 486-488,
The anti-TIGIT antagonist antibody is tyragolumab, the kit. 49. The method of any one of claims 486 to 489,
A kit, further comprising one or more chemotherapeutic agents. 490. The method of claim 490,
wherein the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents. 491. The method of claim 491,
wherein the at least one platinum-based chemotherapeutic agent is carboplatin or cisplatin. 495. The method of claim 491 or 492,
wherein the at least one non-platinum-based chemotherapeutic agent is an antimetabolite, a taxane, or a topoisomerase II inhibitor. 493. The method of claim 493,
wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil. 495. The method of claim 493 or 494,
wherein the taxane is paclitaxel or nap-paclitaxel. 495. The method of any one of claims 493-495,
wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticin, aurintricarboxylic acid, or HU-331. 497. The method of any one of claims 481-496,
A kit, further comprising a VEGF antagonist. 497. The method of claim 497,
The VEGF antagonist is an anti-VEGF antibody, kit. 497. The method of claim 498,
The anti-VEGF antibody is bevacizumab, the kit. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject or population of subjects having cancer, comprising:
The method comprises an anti-TIGIT antagonist antibody and an anti-PD-1 axis binding antagonist according to any one of claims 47-160, 162-224, and 226-480. 1. Use of an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject or population of subjects having cancer, comprising:
Use according to any one of claims 47 to 160, 162 to 224, and 226 to 480, wherein the treatment is according to the method. 501. The method of claim 501,
The use of claim 1, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations. 501. The method of claim 501,
The use of claim 1, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single dosage form.

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