CN115315256A - Methods of treating cancer with anti-TIGIT antagonist antibodies - Google Patents

Abstract

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

Description

Methods of treating cancer with anti-TIGIT antagonist antibodies

Cross reference to related patent applications

The present application claims the contents of U.S. patent application No. 62/966,448, filed on day 1/27 of 2020, U.S. patent application No. 62/985,822, filed on day 3/5 of 2020, U.S. patent application No. 62/994,272, filed on day 3/24 of 2020, international application No. PCT/US2020/024526, filed on day 30 of 2020, U.S. patent application No. 63/059,054, filed on day 31 of 2020, U.S. patent application No. 63/059,960, filed on day 4 of 2020, U.S. patent application No. 63/074,807, filed on day 4 of 2020, U.S. patent application No. 63/074,827, filed on day 4 of 2020, international application No. PCT/US2020, no. 2020/9415/2020, filed on day 9/30 of 2020, U.S. application No. 63/085,890, filed on day 23 of 2020, U.S. patent application No. 63/105,198, filed on day 11 of 2020, U.S. 16/2020, and U.S. 16/2020, application No. 16/16,2020, 6,2020, application No. 16, filed on day 3/16, and U.S. 2020, 16/18, which are incorporated by reference in their entireties.

Sequence listing

This application contains a sequence listing that has been submitted electronically in ASCII format and is incorporated by reference herein in its entirety. The ASCII copy was created at 25.1.2021, named 50474-206WO2 \/sequence \/Listing \/u 1 \/u 2021 \/u ST25 and was 30,641 bytes in size.

Technical Field

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

Background

Cancer is characterized by uncontrolled growth of cell subsets. Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 1400 million newly diagnosed cancer cases per year and over 800 million cancer deaths. Thus, cancer care represents a significant and increasing social burden.

Accordingly, there is an unmet need in the art for the development of effective immunotherapies and methods of administering the immunotherapies for the treatment of cancer.

Disclosure of Invention

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

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

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

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 a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, wherein the method is according to the methods provided herein.

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

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

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

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

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

In another aspect, the invention provides a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tirayleigh immuzumab (tiragolumab) and palbociclumab, wherein the palbociclumab is administered at a dose of between about 300mg to about 500mg every six weeks.

In another aspect, the invention provides a method for treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, and at about 10mg/m ² To about 10000mg/m ² The dosage in between is twice daily for 2 weeks/1 week off for three weeks of the antimetabolite administered orally.

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

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

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

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

In another aspect, the invention provides 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 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 for one or more dosing cycles, wherein the treatment prolongs Progression Free Survival (PFS) of the subject 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.

In another aspect, the invention provides a method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising 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 for one or more dosing cycles, wherein the treatment results in a median PFS of the population of subjects of 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, the method comprising administering to the subject or population of subjects a dosing regimen comprising 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 for one or more dosing cycles, wherein the treatment prolongs OS of the subject 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.

In another aspect, the invention provides a method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising 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 for one or more dosing cycles, wherein the treatment results in a median OS for the population of subjects of about 15.3 months to about 17.6 months.

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

In another aspect, the invention provides a method of treating a subject or population of subjects having ES-SCLC, the method comprising administering four initial dosing cycles followed by one or more dosing cycles to the subject or population of subjects, wherein (a) the four initial dosing cycles comprise administering tirylyumumab at a dose of about 600mg on day 1 of each initial dosing cycle, administering atezumab at a dose of about 1200mg on day 1 of each initial dosing cycle, administering carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each initial dosing cycle, and 100mg/m on days 1, 2, and 3 of each initial dosing cycle ² Administering etoposide; (b) The one or more additional dosing cycles comprise administering tenerriuzumab at a dose of about 600mg on day 1 of each additional dosing cycle and administering atelizumab at a dose of about 1200mg on day 1 of each additional dosing cycle, wherein the four initial dosing cycles and the one or more additional dosing cycles are each 21-day dosing cycles, and wherein the treatment prolongs PFS and/or OS of the subject or population of subjects compared to a treatment with atelizumab, carboplatin, and etoposide without tenerriuzumab.

In another aspect, the invention provides 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 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.

In another aspect, the invention provides a method of treating a subject or population of subjects with advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects a dosing regimen comprising four 21-day dosing cycles of telautumumab, atelizumab, carboplatin or cisplatin, and pemetrexed (pemetrexed), wherein on day 1 of each of the four 21-day dosing cycles, the telautumumab is administered at a dose of about 600mg every three weeks, the atelizumab is administered at a dose of about 1200mg every three weeks, the carboplatin is administered at a dose sufficient to achieve AUC =5mg/ml/min every three weeks or the cisplatin is administered at 75 mg/m/min every three weeks ² And pemetrexed is administered at a dose of about 500mg/m every three weeks ² Is administered.

In another aspect, the invention provides a method of treating a subject or population of subjects having advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects (i) four cycles of induction phase dosing of: a dose of about 600mg tirleiuzumab per three weeks, a dose of about 1200mg astuzumab per three weeks, a dose of carboplatin per three weeks sufficient to achieve an AUC =5mg/ml/min, and about 500mg/m per three weeks ² The dose of pemetrexed of (a); and (ii) one or more of the following maintenance phase dosing cycles: a dose of about 600mg every three weeks of tirleiuzumab, a dose of about 1200mg every three weeks of atuzumab, and about 500mg/m every three weeks ² Wherein one or more 21 day dosing cycles of the maintenance phase does not include administration of carboplatin, wherein the subject or population of subjects has not received prior systemic therapy for advanced non-squamous NSCLC.

In another aspect, the invention provides a method for treating a subject having resectable lung cancer, the method comprising administering to the subject one or more cycles of administration of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

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

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

In another aspect, the invention provides a method for treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of ibritumumab tirayleigh and atuzumab, wherein (I) at least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject (a) a dose of about 1200mg of ibritumumab tiuqu every three weeks; (b) A dose of about 1200mg of atuzumab as a neoadjuvant therapy every three weeks; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and at about 1000mg/m on days 1 and 8 of each dosing cycle ² The dose of gemcitabine of (a); (ii) The goal every three weeks was to achieve A of 6mg/mL/minUC dose of carboplatin and about 175mg/m every three weeks ² Or about 200mg/m ² The dose of paclitaxel of (a); or (iii) about 75mg/m every three weeks ² And about 1250mg/m on days 1 and 8 of each dosing cycle ² The dose of gemcitabine of (a); and (II) at least one of the dosing cycles comprises administering to the subject: a dose of between about 500mg to about 700mg every three weeks and a dose of between about 900mg to about 1500mg every three weeks of atuzumab as adjuvant therapy.

In another aspect, the invention provides a method for treating a subject or population of subjects having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject or population of subjects for one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

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

In another aspect, the invention provides a method for treating a subject having a cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg tireyueuzumab every three weeks, and a dose of about 1200mg atelizumab every three weeks.

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from breast cancer, the method comprising administering to the subject or population of subjectsAdministering to a population of subjects a dosing regimen comprising one or more cycles of dosing of: a dose of about 840mg of tenecteuzumab every four weeks, a dose of about 1680mg of atelizumab every four weeks, and a dosage of about 100mg/m ² The dosage of (a) was nab-paclitaxel administered for 3 weeks/withheld for 1 week.

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

In another aspect, the invention provides a method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising a dose of about 420mg tiregumab every two weeks, about 840mg atuzumab every two weeks, and (a) (i) about 125mg/m weekly for the first 12 weeks of the dosing regimen ² Nab-paclitaxel at a dose and carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks; and (ii) about 60mg/m biweekly between weeks 13 and 19 of the dosing regimen ² Of doxorubicin at a dose of about 600mg/m biweekly ² Cyclophosphamide and biweekly G-CSF or GM-CSF; or (b) (i) about 125mg/m weekly for the first 12 weeks of the dosing regimen ² The dose of nab-paclitaxel of (a); and (ii) about 60mg/m biweekly between weeks 13 and 19 of the dosing regimen ² Of doxorubicin at a dose of about 600mg/m biweekly ² Cyclophosphamide and biweekly G-CSF or GM-CSF; wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

In another aspect, the invention provides a method for treating a subject or population of subjects having SCCHN having a detectable PD-L1 expression level, 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 between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

In another aspect, the invention provides a method of selecting a therapy for a subject or population of subjects having SCCHN, the method comprising: (a) Detecting the protein expression level of PD-L1 in a tumor sample from a subject or population of subjects by an IHC assay using an anti-PD-L1 antibody suitable for staining; and (b) selecting a therapy for a subject or population of subjects having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of PD-1 axis binding antagonist between about 900mg to about 1500mg every three weeks and an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks.

In another aspect, the invention provides a method for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg tirayleigh immumab every three weeks, and a dose of about 1200mg atelizumab every three weeks.

In another aspect, the invention provides a method of treating a subject or population of subjects having hepatocellular carcinoma (HCC) 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 treatment for HCC.

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from HCC, the method comprising administering to the subject or population of subjects one or more cycles of administration of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist.

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from HCC, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg of tenecteukumab every three weeks, a dose of about 1200mg of atelizumab every three weeks, and a dose of about 15mg/kg of bevacizumab every three weeks.

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

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

In another aspect, the invention provides a method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of administration of: a dose of about 600mg tirleivuzumab every three weeks and a dose of about 1200mg atelizumab every three weeks, wherein the subject or subjects are not eligible for cisplatin.

In another aspect, the invention provides a method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of administration of: a dose of about 600mg tirayleigh-uzumab every three weeks, and a dose of about 1200mg atelizumab every three weeks, wherein the treatment is perioperative.

In another aspect, the invention provides a method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

In another aspect, the invention provides a method for treating a subject or population of subjects suffering from uc, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg tirayleigh immumab every three weeks, and a dose of about 1200mg atelizumab every three weeks.

In another aspect, the invention provides a method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a first dosing regimen, followed by a second dosing regimen, wherein (a) the first dosing regimen comprises one or more cycles of dosing of: a dose of about 600mg tireyueuzumab per three weeks and a dose of about 1200mg atelizumab per three weeks; and (b) the second dosing regimen comprises one or more of the following for the dosing cycle: a dose of about 1200mg of alemtuzumab every three weeks and (i) vildagliptin-enzitumumab (encortumab vedotin) administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (ii) govitegradn-shaxituzumab (sacituzumab govitecan) administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week, wherein the second dosing cycle is administered to the subject or population of subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity during the first dosing regimen.

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from pancreatic cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 28 day dosing cycle: a dose of about 420mg of tegraluretuzumab on days 1 and 15 of each 28-day dosing cycle, a dose of about 840mg of atelizumab on days 1 and 15 of each 28-day dosing cycle, about 1000mg/m on days 1, 8, and 15 of each 28-day dosing cycle ² And about 125mg/m on days 1, 8 and 15 of each 28-day dosing cycle ² Nab-paclitaxel at the dosage of (a).

In another aspect, the invention provides a method for treating a subject or population of subjects suffering from advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg on day 1 of each dosing cycle.

In another aspect, the invention provides a method of treating a subject or population of subjects having esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen of anti-TIGIT comprising one or more 21-day dosing cycles wherein the subject has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent, the antagonist antibody is administered at a dose of about 500mg to about 700mg on day 1 of each dosing cycle, and the PD-1 axis binding antagonist is administered at a dose of about 900mg to about 1500mg on day 1 of each dosing cycle.

In another aspect, the invention provides a method for treating a subject or population of subjects suffering from advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose of about 600mg of tiryleauuzumab on day 1 of each dosing cycle, a dose of about 1200mg of atuzumab on day 1 of each dosing cycle, about 80mg/m on day 1 of each dosing cycle ² And 800mg/m on days 1 to 5 of each 21-day cycle ² 5-fluorouracil at a dose of 24 hours, wherein cisplatin is omitted from the dosing regimen after six doses.

In another aspect, the invention provides a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosing regimen and a second dosing regimen, wherein (a) the first dosing regimen comprises one or more of the following for a 21-day dosing cycle: about 80mg/m on day 1 of each dosing cycle ² And 800mg/m on days 1 to 5 of each 21-day cycle ² 5-fluorouracil at a dose of 24 hours, in which cisplatin is omitted from the dosing regimen after six doses; and (b) the second dosing regimen comprises one or more of the following for a 21 day dosing cycle: at each one A dose of about 600mg of tirayleigh immuzumab on day 1 of the dosing cycle and a dose of about 1200mg of atelizumab on day 1 of each dosing cycle.

In another aspect, the invention provides a kit comprising a PD-1 axis binding antagonist and/or an 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 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, wherein the method is according to the methods provided herein.

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

Drawings

FIG. 1 is a flow chart showing the extension of phase Ib chemotherapy and the extension of phase Ib Q4W dosing.

FIG. 2 is a flow chart of the phase Ib test protocol. EOCG = eastern cooperative group of tumors; IHC = immunohistochemistry; PD-L1+ = programmed death ligand 1 positive; Q4W = every 4 weeks; RECIST v1.1= solid tumor efficacy standard, version 1.1; TFI = no treatment interval; TNBC = triple negative breast cancer.

FIG. 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 administered dose, MSI = microsatellite instability, MSS = microsatellite stability, 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.

Figure 4 is a flow chart of the study design of the extended cohort of phase Ib tenellumab and atelizumab, serial biopsy cohort, and Q4W dose extended cohort. CIT = cancer immunotherapy; DLT = dose-limiting toxicity; HNSCC = head and neck squamous cell carcinoma, IV = intravenous, MAD = maximum administered dose, MSI = microsatellite instability, MSS = microsatellite stability, MTD = maximum tolerated dose, NSCLC = non-small cell lung cancer, PD = disease progression; PD 1= programmed death 1; PD-L1= programmed death ligand 1; PK = pharmacokinetics, TIGIT = T cell immunoreceptors with Ig and ITIM domains. Remarking: limited to patients with tumors selected for PD-L1 and/or TIGIT. ^a Late stage, incurable and refractory tumor. Tirayleigh itumumab IV and atezumab 1200mg IV every 3 weeks. Only after IMC review of the safety data for phase Ia will be enrolled. Dose 3+3 was escalated with a DLT window of 21 days. Other intermediate doses of tirylereumab can be studied if they do not exceed the MTD. To obtain further safety, PK and PD data, the group can be recruited if the patient agrees to perform an optional serial biopsy. Evaluation of dose levels of over 1200mg of tiryleauuzumab would require protocol revisions with supporting justification. ^b Expansion can begin with a dose of ≦ MTD or MAD. ^c Up to about half of the patients in each cohort will be those who consented to optional consecutive biopsies. Patients with tumors approved for treatment with anti-PD-L1/PD-1 drugs by local regulatory authorities (e.g., NSCLC melanoma, renal cell carcinoma) can be included in the expanded cohort (indication-specific or serial biopsy) only if clinical trials of the combination of the test drug with anti-PD-L1 are considered to be acceptable treatment options. ^d Limited to patients who agree to perform optional serial biopsies (acceptable samples include core needle, resection, incision, punch and/or forceps biopsy samples). ^e In the Q4W dose extended queue, about completion will be achievedSafety import for 3 patients. IMC and researchers will thoroughly review all relevant security data from the security imports before proceeding to the group.

Figure 5 is a flow chart of a phase Ib chemotherapy extension cohort study design.

Figure 6 is a flow chart of a phase Ib non-chemotherapy extended cohort study design.

Figure 7 is a flow chart showing conditions for continued study treatment after progression. ECOG = eastern cooperative group of tumors; RECIST = evaluation criteria of efficacy of solid tumor.

Fig. 8 is a flowchart showing transition from phase Ia to phase Ib. AE = adverse event, DLT = dose-limiting toxicity, PD = disease progression.

Fig. 9 is a graph showing the pharmacokinetics of tenecteuzumab.

Fig. 10 is a series of graphs showing the pharmacodynamics of tirylereumab.

FIG. 11 is a graph showing > 10% of all adverse events in phase Ia Tirayleigh Euzumab dose-escalation studies. * AE grade 5 was malignancy progression (n = 3), independent of tiryleiguzumab.

FIG. 12 is a graph showing > 10% of all adverse events in phase Ib tenerayleigh unizumab and atuzumab dose escalation studies. * AE grade 5 were malignancy progression (n = 12) and pulmonary embolism (n = 2), independent of study drug.

Figure 13 is a graph showing tumor size reduction in a phase Ia tirayleigh uniuzumab dose escalation study.

Figure 14 is a graph showing tumor size reduction in phase Ib tirayleigh itumumab and atezumab dose escalation studies.

Figure 15 is a graph showing the reduction in size of CIT naive PD-L1 positive NSCLC tumors in phase Ib tirayleigh unizumab and atuzumab dose escalation studies.

Figure 16 is a graph showing the reduction in size of CIT naive PD-L1 positive NSCLC tumors over time in phase Ib tirayleigh itumumab and atezumab dose escalation studies.

FIG. 17 is a flow chart of a phase III protocol. 1L = one line; CE = carboplatin and etoposide; ECOG PS = eastern tumor cooperative group competence status; ES-SCLC = extensive small cell lung cancer; LDH = lactase dehydrogenase; RECIST = evaluation criteria for efficacy of solid tumor; ITT = intent-to-treat; PP = main population.

Figure 18 is a schematic of a study design showing parameters for selection of subjects, stratification criteria, randomization into treatment groups, and treatment endpoints.

Figure 19 is a schematic diagram showing the design of a GO42501 phase II clinical trial. Patients with resectable stage II, IIIA or selected stage IIIB (T3N 2) non-small cell lung cancer (NSCLC) who do not have an activating EGFR mutation (EGFR-), do not have an ALK fusion oncogene (ALK-), and have an eastern tumor cooperative group (ECOG) performance status of 0 or 1. Cohort a consisted of patients with high PD-L1. Patients in cohort a received treatment with atezumab (Atezo) and tegraleigh itumumab (Tira) once every three weeks (Q3W) for 4 cycles. Cohort B consisted of patients with any PD-L1 status. Patients in cohort B received Atezo, tira and platinum-based dual drug chemotherapy (Chemo) Q3W for 4 cycles. Chest Computed Tomography (CT) was performed after cycle 2 and cycle 4. Patients in both cohorts were operated on and assessed for Major Pathological Remission (MPR) and complete pathological remission (pCR). After surgery, patients in cohort a were treated with Atezo and Tira Q3W for 16 cycles or with Chemo Q3W for 4 cycles. Patients in cohort B were treated with Atezo and Tira Q3W for 16 cycles. For R1/R2 excision and/or ypN2, post-operative radiation therapy (PORT) may optionally be performed prior to adjunctive administration. And carrying out survival period follow-up.

Figure 20 is a flow chart showing patient enrollment in GO42501 phase II clinical trial. For cohort A (high PD-L1 patients; PD-L1 Tumor Proportion Score (TPS) ≥ 50%), 6 patients were used for safety introgression. If the surgical safety criteria are not met, then stop in group cohort A. If the surgical safety criteria are met, proceed to group cohort A. For cohort B (patients with any PD-L1 status), a safety import was performed using 6 patients with PD-L1 TPS < 50%. If the surgical safety criteria are not met, then stop in group cohort B. If the surgical safety criteria are met, continue into cohort B, and incorporate patients with cohort PD-L1 TPS < 50% and PD-L1 TPS ≧ 50%. After grouping B with more than 50% of 8 PD-L1 expressing tumors, grouping A with more than 50% PD-L1 TPS was continued.

FIG. 21 is a flow chart of a phase II protocol. 1L = one line; CDx = companion diagnosis; ECOG PS = eastern tumor cooperative kinetic status; IHC = immunohistochemistry; IRC = independent review board; PD-L1= programmed death ligand 1; Q3W = every 3 weeks; r = randomization; s/p = state after; IV = intravenous.

FIG. 22 is a flow chart of the phase Ib test protocol. TNBC = triple negative breast cancer; G-CSF = granulocyte colony stimulating factor; GM-CSF = granulocyte-macrophage colony stimulating factor; rand = randomization, pCR = pathology was completely alleviated, QW = weekly, Q2W = biweekly, Q3W = weekly.

FIG. 23 is a flow chart of the phase II protocol. HPV = human papilloma virus; IHC = immunohistochemistry; IV = intravenous; Q3W = every 3 weeks; PD-L1 low = TIC 10% -49%; PD-L1 height = TIC ≥ 50%; SCCHN = head and neck squamous cell carcinoma; RECIST = evaluation criteria of efficacy of solid tumor.

FIG. 24 is a schematic diagram showing the design of a Muscle Invasive Bladder Cancer (MIBC) cohort for the WO39613 phase Ib/II clinical trial. In the screening phase, MIBC patients who did not meet cisplatin use conditions and were either PD-L1 positive (+) (upper) or PD-L1 negative (-) (lower) were identified. After randomization (R), the patient was treated with alemtuzumab (Atezo; control) or alemtuzumab and tiryleigh Ewing mab (Tira).

Figure 25 is a schematic diagram showing the design of a metastatic urothelial cancer (mUC) cohort for a phase WO39613 Ib/II clinical trial. In the screening stage, patients with second-line locally advanced or metastatic UC who progressed during or after platinum-containing therapy and were initially treated with Cancer Immunotherapy (CIT) were identified. After randomization (R), patients were treated during phase 1 with: attuzumab (Atezo; control); alemtuzumab and vitin-Enfratuzumab (EV); alemtuzumab and nilapanib (niraparib) (Nira); alemtuzumab and Hu5F9-G4; attrituzumab and ibritumumab tiuxetan (Tira); alemtuzumab and govitikang-Shaxituzumab (SG); astuzumab and Tocilizumab (TCZ) ) (ii) a Alemtuzumab and RO7122290 (FAP-4-1 BBL); or RO7121661 (PD 1/TIM-3). ^a During phase 1, patients experiencing loss of clinical benefit (as determined by the investigator) or unacceptable toxicity may be eligible to receive a different combination of treatments at phase 2, provided they meet eligibility criteria. ^b The Atezo + Nira arm had 40 patients. ^c Patients receiving veltin-enfratuzumab at stage 1 did not receive veltin-enfratuzumab at stage 2, and patients receiving govitikang-saxituzumab at stage 1 did not receive govitikang-saxituzumab at stage 2; other patients who meet the condition of more than one treatment arm are assigned one treatment arm by the researcher. Once the Atezo + SG arm is open, the entry group of Atezo + EV arms will close. ^d The Atezo + RO7122290 (FAP-4-1 BBL) arm is only open in countries/regions outside the United states.

FIG. 26 is a graph showing Objective Remission Rate (ORR) (complete remission/partial remission (CR/PR); disease stabilization/disease progression (SD/PD); or unevaluable (NE)) from a CITYSCOPE test in patients with low or high PD-L1 TPS as assessed by the pharmDx 22C3 IHC assay (high TPS ≧ 50%; low TPS 1-49%); or has low or high PD-L1 Tumor Content (TC), as assessed by the CE-IVD VENTANA SP263 IHC assay (high TC ≧ 50%; low TC 1-49%).

FIG. 27A is a bar graph showing response rates (95% Confidence Intervals (CI)) from patients with ≧ 1% TPS from the CITYPE SCAPE assay, as measured using the 22C3 IHC assay.

FIG. 27B is a bar graph showing the response rate (95% CI) from a patient with ≧ 1% TC as measured using the SP263 IHC assay (and ≧ 1% TPS as measured using the 22C3 IHC assay) in a CITYSCOPE assay.

FIG. 28A is a graph showing progression free survival (percentage) for patients treated with Trirayleigh immuzumab and atlizumab (tira + atezo) or with placebo + atezo and having ≧ 1% TPS as measured using the 22C3 IHC assay from a CITYPE SCAPE test. The inset shows the median PFS in months (mo) and risk ratio (HR).

FIG. 28B is a graph showing progression free survival (in percent) for patients from the CITYPE SCAPE trial treated with Trypralyluzumab and atuzumab (tira + atezo) or treated with placebo + atezo and having ≧ 1% TC as measured using the SP263 IHC assay (and ≧ 1% TPS as measured using the 22C3 IHC assay). The inset shows the median PFS in months and HR.

FIG. 29A is a bar graph showing response rates (95% Confidence Intervals (CI)) from patients with ≧ 50% TPS from the CITYPE SCAPE assay, as measured using the 22C3 IHC assay.

FIG. 29B is a bar graph showing response rates (95% CI) from patients with > 50% TC from a CITYPE SCAPE assay as measured using the SP263 IHC assay.

FIG. 30A is a graph showing progression free survival (percentage) for patients from a CITYPE SCAPE trial treated with tiryleigh Euzumab and atlizumab (tira + atezo) or with placebo + atezo and having > 50% TPS as measured using a 22C3 IHC assay. The inset shows the median PFS in months and HR.

FIG. 30B is a graph showing progression free survival (percentage) of patients treated with tirayleigh immuzumab and atuzumab (tira + atezo) or with placebo + atezo from a CITYSCOPPE trial and having a TC of > 50% as measured using the SP263 IHC assay. The inset shows the median PFS in months and HR.

Detailed Description

The invention provides methods for treating cancer (e.g., 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))))); therapeutic methods and compositions for cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., 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 (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN), liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC), bladder cancer (e.g., MIBC, locally advanced UC or mcc), esophageal cancer, pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC), kidney or renal cancer (e.g., RCC), melanoma, ovarian cancer, gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC)). The present invention is based, at least in part, on the following findings: immunotherapy comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody, such as ibritumomab tiuxetan) in combination with a PD-1 axis binding antagonist, a VEGF antagonist, and/or a chemotherapeutic agent can be used to treat cancer. Also provided herein are compositions, uses and kits relating to such combination and/or dosing regimens.

I. General techniques

Those skilled in the art will generally readily understand and will generally use conventional methods for using the techniques and procedures described or referenced herein, such as, for example, sambrook et al, molecular Cloning: a Laboratory Manual version 3 (2001) Cold Spring Harbor Laboratory Press, cold Spring Harbor, N.Y.; current Protocols in Molecular Biology (edited by F.M. Ausubel et al, (2003)); methods in Enzymology series (Academic Press, inc.): and (3) PCR 2: a Practical Approach (m.j. Macpherson, b.d. Hames and g.r. Taylor editors (1995)), harlow and Lane editors (1988) Antibodies, a Laboratory Manual, and Animal Cell Culture (r.i. freshney editors (1987)); oligonucleotide Synthesis (m.j. gait editors, 1984); methods in Molecular Biology, human Press; cell Biology: a Laboratory Notebook (edited by J.E. Cellis, 1998) Academic Press; animal Cell Culture (r.i. freshney), editions, 1987); introduction to Cell and Tissue Culture (J.P.Mather and P.E.Roberts, 1998) Plenum Press; cell and Tissue Culture: laboratory Procedures (a.doyle, j.b.griffiths, and d.g.newell, editors, 1993-8) j.wiley and Sons; handbook of Experimental Immunology (d.m.weir and c.c.blackwell, eds.); gene Transfer Vectors for Mammalian Cells (J.M.Miller and M.P.Calos, eds., 1987); and (3) PCR: the Polymerase Chain Reaction, (Mullis et al, eds., 1994); current Protocols in Immunology (J.E.Coligan et al, eds., 1991); short Protocols in Molecular Biology (Wiley and Sons, 1999); immunobiology (c.a. 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, editions, oxford University Press, 2000); use Antibodies: a Laboratory Manual (E.Harlow and D.Lane (Cold Spring Harbor Laboratory Press, 1999), the Antibodies (M.Zantetti and J.D.Capra, eds., harwood Academic Publishers, 1995), and Cancer: principles and Practice of Oncology (V.T.DeVita et al, eds., J.B.Lippincott Company, 1993).

Definition of

It should be understood that aspects and embodiments of the invention described herein include aspects and embodiments that are referred to as "comprising," consisting of, "and" consisting essentially of. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

The term "about" as used herein refers to the usual range of error for the corresponding value as readily known to those of skill in the art. References herein to "about" a value or parameter include (and describe) aspects that relate to that value or parameter itself. 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 of converting information (e.g., gene coding and/or epigenetic information) into structures that exist and operate in a cell. Thus, as used herein, "expression" may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and/or polypeptide modification (e.g., post-translational modification of a polypeptide). Transcribed polynucleotides, translated polypeptides, or fragments of polynucleotide and/or polypeptide modifications (e.g., post-translational modifications of polypeptides) should also be considered as expressed, whether they are derived from transcripts generated by alternatively spliced or degraded transcripts, or from post-translational processing of polypeptides (e.g., by proteolysis). "expressed genes" include those that are transcribed into a polynucleotide, such as an mRNA, and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (e.g., transfer RNA and ribosomal RNA). The "amount" or "level" (e.g., expression level) of a biomarker can be measured by methods known to those skilled in the art and disclosed herein. The "amount" or "level" of a biomarker that is associated with an increased clinical benefit to an individual may, for example, be at a level detectable in a biological sample. In some aspects, the expression level or amount of the biomarker can be used to identify/characterize a subject having cancer who is likely to respond to or benefit from a particular therapy (e.g., a therapy comprising one or more dosing cycles of a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody, or a therapy comprising one or more dosing cycles of an anti-TIGIT antagonist antibody).

"increased expression," "increased expression level," "increased level," "elevated expression level," or "elevated level" refers to an increased expression or level of a biomarker in an individual relative to a control, such as one or more individuals not suffering from a disease or disorder (e.g., cancer) or an internal control (e.g., housekeeping biomarker).

"reduced expression", "reduced expression level", "reduced expression level", or "reduced level" refers to a reduced expression or reduced level of a biomarker in an individual relative to a control, such as one or more individuals not suffering from a disease or disorder (e.g., cancer) or an internal control (e.g., housekeeping biomarker). In some aspects, reduced expression is little or no expression.

The presence and/or expression levels/amounts of the various biomarkers described herein in a sample canFor analysis by a variety of methods, many of which are known in the art and understood by the skilled artisan, including but not limited to immunohistochemistry ("IHC"), western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, flow cytometry, fluorescence activated cell sorting ("FACS"), massARRAY, proteomics, blood-based quantitative assays (e.g., serum ELISA), biochemical enzyme activity determination, in Situ Hybridization (ISH), fluorescence In Situ Hybridization (FISH), southern blot analysis, northern blot analysis, whole genome sequencing, massively parallel DNA sequencing (e.g., next generation sequencing),

Polymerase Chain Reaction (PCR) (including quantitative real-time PCR (qRT-PCR) and other amplification type detection methods, such as branched DNA, SISBA, TMA, etc.), RNA-seq, microarray analysis, gene expression profiling and/or serial analysis of gene expression ("SAGE"), and any of a variety of assays that can be performed by protein, gene and/or tissue array analysis. Typical Protocols for assessing the status of genes and gene products can be found, for example, in Ausubel et al, eds 1995, latest Protocols In Molecular Biology, unit 2 (northern blotting), unit 4 (southern blotting), unit 15 (immunoblotting) and Unit 18 (PCR analysis). Multiplex immunoassays may also be used, such as those available from Rules Based Medicine or Meso Scale Discovery ("MSD").

"correlating" or "correlating" refers to comparing the performance and/or results of a first assay or protocol to the performance and/or results of a second assay or protocol in any manner. For example, the results of a first analysis or protocol may be used in performing 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. With respect to aspects of polypeptide analysis or protocols, the results of a polypeptide expression analysis or protocol can be used to determine whether a particular treatment regimen should be performed. With respect to aspects of polynucleotide analysis or protocols, the results of a polynucleotide expression analysis or protocol can be used to determine whether a particular treatment regimen should be performed.

As used herein, the phrase "significantly reduced" or "significantly different" means that there is a sufficiently high difference between two values (typically one value associated with a molecule and the other value associated with a reference/control molecule) such that one of skill in the art would consider it to be within the scope of the present invention to be comprised of the stated value (e.g., K) _D Value), the difference between the two values is statistically significant. Depending on the value of the reference/contrast molecule, for example, the difference between the two values is greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and/or greater than about 50%.

As used herein, the term "substantially similar" or "substantially the same" means that there is a sufficiently high degree of similarity between two numerical values (e.g., one numerical value is associated with an antibody described herein and the other numerical value is associated with a reference/control antibody) such that one skilled in the art would consider it to be within the context of the value described (e.g., K) _D Value), the difference between the two values has little biological and/or statistical significance. Depending on the value of the reference/control, for example, the difference between the two values is less than about 50%, less than about 40%, less than about 30%, less than about 20%, and/or less than about 10%.

The phrase "based on" as used herein means that information about one or more biomarkers is used to inform information provided on treatment decisions, package inserts or marketing/promotional guidelines, etc.

Unless otherwise indicated, the term "TIGIT" or "T cell immunoreceptor with Ig and ITIM domains" as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). 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. The term encompasses "full length," unprocessed TIGIT (e.g., full length human TIGIT having the amino acid sequence of SEQ ID NO: 30), as well as any form of TIGIT that is processed in a cell (e.g., processed human TIGIT without a signal sequence having the amino acid sequence of SEQ ID NO: 31). The term also encompasses naturally occurring TIGIT variants, e.g., splice variants or allelic variants. The amino acid sequence of exemplary human TIGIT can be found under UniProt accession number Q495 A1.

The terms "programmed death ligand 1" and "PD-L1" refer herein to a native sequence human PD-L1 polypeptide. The native sequence PD-L1 polypeptide is provided as Uniprot accession number Q9NZQ7 (SEQ ID NO: 32). For example, the native sequence PD-L1 may have an amino acid sequence as described in Uniprot accession number Q9NZQ7-1 (isoform 1). In another example, the native sequence PD-L1 may have an amino acid sequence as described in Uniprot accession number Q9NZQ7-2 (isoform 2). In yet another example, the native sequence PD-L1 may have an amino acid sequence as described in Uniprot accession number Q9NZQ7-3 (isoform 3). The term also encompasses naturally occurring PD-L1 variants, e.g., splice variants or allelic variants. PD-L1 is also known in the art as "programmed cell death 1 ligand 1", "PDCD 1LG 1", "CD 274", "B7-H", and "PDL 1".

The terms "PD-1" or "programmed cell death protein 1" herein, unless otherwise indicated, refer to any native PD-1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). PD-1 is also known in the art as CD279, PDCD1, and programmed cell death 1. The term also encompasses naturally occurring PD-1 variants, e.g., splice variants or allelic variants. The amino acid sequence of exemplary human PD-1 can be found under UniProt accession number Q15116.

Unless otherwise indicated, the term "PD-L2" or "programmed cell death 1 ligand 2" herein refers to any native PD-L2 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). PD-L2 is also known in the art as CD273 molecule, B7DC, and PDCD1L2. The term also encompasses naturally occurring PD-L2 variants, e.g., splice variants or allelic variants. The amino acid sequence of exemplary human PD-L2 can be found under UniProt accession number Q9BQ 51.

The term "antagonist" is used in the broadest sense and includes any molecule that partially or completely blocks, inhibits or neutralizes a biological activity of a native polypeptide disclosed herein. Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments (e.g., antigen-binding fragments), fragments or amino acid sequence variants of the native polypeptide, peptides, antisense oligonucleotides, small organic molecules, and the like. Methods of identifying a polypeptide antagonist can include contacting a 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 a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners to eliminate T cell dysfunction caused by signaling on the PD-1 signaling axis, resulting in restoration or enhancement of T cell function (e.g., proliferation, cytokine production, and/or target cell killing). As used herein, PD-1 axis binding antagonists 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 aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In another aspect, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In another aspect, the PD-1 axis binding antagonist is a PD-L2 binding antagonist.

The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with signaling resulting from the interaction of PD-1 with one or more of its binding partners (such as PD-L1 and/or PD-L2). PD-1 (programmed death 1) is also known in the art as "programmed cell death 1", "PDCD 1", "CD 279", and "SLEB 2". Exemplary human PD-1 is shown in UniProtKB/Swiss-Prot accession number Q15116. In some cases, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In particular aspects, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies and antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signaling resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one instance, the PD-1 binding antagonist reduces a negative co-stimulatory signal mediated by signaling through PD-1 mediated by or through a cell surface protein expressed on a T lymphocyte, thereby rendering the dysfunctional T cell less dysfunctional (e.g., increasing effector response to antigen recognition). In some cases, the PD-1 binding antagonist binds to PD-1. In some cases, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab (nivolumab), palivizumab (pembrolizumab), MEDI-0680 (AMP 514), PDR001 (spartalizumab), REGN2810 (cimiralizumab), BGB-108, palivizumab (prollimumab), carpriluzumab (camrelizumab), centilizumab (sintilimab), tiramizumab (tinlizumab), tiramizumab (tirliplizumab), terelizumab (toripimab), dolizumab (dostarolizumab), rituximab (retilinmab), and temelizumab (ritalinlizumab) Saxatilimab (sasanlimab), pinaprimab (penpulimab), CS1003, HLX10, SCT-110A, serpalimab (zimberlimab), batilinumab (balstiimab), jelinumab (genitmzumab), BI 754091, cetrelimab (cetrilimab), YBL-006, BATl306, HX008, bugliomab (budigalimab), AMG 404, CX-188, JTX-4014, 609A, sym021, LZM009, F520, SG001, AM0001, EN244C 8, ENUM 388D4, STI-103, AK-1110 and hAB21. In a particular aspect, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, the PD-1 binding antagonist is MK-3475 (palivizumab, previously known as pembrolizumab). In another specific aspect, the PD-1 binding antagonist is a PD-L2 fusion protein, e.g., AMP-224. In another specific aspect, the PD-1 binding antagonist is MEDI-0680. In another specific aspect, the PD-1 binding antagonist is PDR001 (sibatuzumab). In another specific aspect, the PD-1 binding antagonist is REGN2810 (cimetipril mab). In another particular aspect, the PD-1 binding antagonist is BGB-108. In another particular aspect, the PD-1 binding antagonist is palonolizumab. In another specific aspect, the PD-1 binding antagonist is carpriluzumab. In another specific aspect, the PD-1 binding antagonist is sediizumab. In another specific aspect, the PD-1 binding antagonist is tirizumab. In another particular aspect, the PD-1 binding antagonist is tereprinimab. 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, that is capable of binding PD-1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-1. For example, an anti-PD-1 antagonist antibody can reduce, block, inhibit, eliminate, or interfere with a signaling molecule resulting from the interaction of PD-1 with one or more of its binding partners (such as PD-L1 and/or PD-L2). One of ordinary skill in the art will appreciate that in some cases, an anti-PD-1 antagonist antibody can antagonize one P-1 activity without affecting the other PD-1 activity. For example, an anti-PD-1 antagonist antibody for use in certain methods or uses described herein is an anti-PD-1 antagonist antibody that antagonizes PD-1 activity in response to one of its binding partners (e.g., PD-L1 or PD-L2) but does not affect or minimally affects any other PD-1 interaction. In one aspect, for example, an anti-PD-1 antagonist antibody binds to an unrelated, non-PD-1 protein to less than about 10% of the extent of binding of the antibody to PD-1 as measured by a Radioimmunoassay (RIA). In certain aspects, an anti-PD-1 antagonist antibody that binds PD-1 has a dissociation constant (KD) of less than or equal to 1 μ M, less than or equal to 100nM, less than or equal to 10nM, less than or equal to 1nM, less than or equal to 0.1nM, less than or equal to 0.01nM or less than or equal to 0.001nM (e.g., 10 nM) ^{- 8} M or less, e.g. 10 ^-8 M to 10 ^-13 M, e.g. 10 ^-9 M to 10 ^-13 M). In certain aspects, an anti-PD-1 antagonist antibody binds to a PD-1 epitope 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 pabulizumab (previously known as pembrolizumab). In one aspect, the anti-PD-1 antagonist antibody is nivolumab.

The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates, or interferes with signaling resulting from the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and/or B7-1). In some cases, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In particular aspects, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and/or B7-1. In some cases, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere 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). In one instance, the PD-L1 binding antagonist reduces negative costimulatory signals mediated by signaling through PD-L1 mediated by or through cell surface proteins expressed on T lymphocytes, thereby rendering dysfunctional T cells less dysfunctional (e.g., increasing effector response to antigen recognition). In some cases, the PD-L1 binding antagonist binds to PD-L1. In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include adzuzumab, MDX-1105, MEDI4736 (Dewar umab), MSB0010718C (Avelumab), SHR-1316, CS1001, envolumizumab (envafolimab), TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, coxilimab (cosibelimab), lodalizumab), 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 atelizumab, MDX-1105, MEDI4736 (devoluumab), or MSB0010718C (avizumab). In a particular aspect, the PD-L1 binding antagonist is MDX-1105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (devolizumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (avizumab). In other aspects, the PD-L1 binding antagonist can be a small molecule, e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041, which in some cases can be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atelizumab, sold as tecentrijtm. Astuzumab is described in the following documents: WHO drug information (international drug substance non-patent name), proposed INN: manifest 112, volume 28, phase 4, published on day 16 of 2015, month 1 (see page 485). In another specific aspect, 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 that is capable of binding PD-L1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-L1. For example, an anti-PD-L1 antagonist antibody can reduce, block, inhibit, eliminate, or interfere with a signaling molecule resulting from the interaction of PD-L1 with one or more of its binding partners (such as PD-1 and/or B7-1). One of ordinary skill in the art will appreciate that in some cases, an anti-PD-L1 antagonist antibody can antagonize one P-L1 activity without affecting the other PD-L1 activity. For example, an anti-PD-L1 antagonist antibody for use in certain methods or uses described herein is an anti-PD-L1 antagonist antibody that antagonizes PD-L1 activity in response to one of its binding partners (e.g., PD-1 or B7-1) but does not affect or minimally affects any other PD-L1 interaction. In one aspect, for example, an anti-PD-L1 antagonist antibody binds to an unrelated, non-PD-L1 protein to less than about 10% of the extent of binding of the antibody to PD-L1, as measured by a Radioimmunoassay (RIA). In certain aspects, an anti-PD-L1 antagonist antibody that binds to PD-L1 has a dissociation constant (KD) of less than or equal to 1 μ M, less than or equal to 100nM, less than or equal to 10nM, less than or equal to 1nM, less than or equal to 0.1nM, less than or equal to 0.01nM or less than or equal to 0.001nM (e.g., 10 nM) ^-8 M or less, e.g. 10 ^-8 M to 10 ^-13 M, e.g. 10 ^-9 M to 10 ^-13 M). In certain aspects, an anti-PD-L1 antagonist antibody binds to a PD-L1 epitope that is conserved between PD-L1 from different species or an epitope on PD-L1 that allows cross-species reactivity. In one aspect, the anti-PD-L1 antagonist antibody is atelizumab.

The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates or interferes with signaling resulting from the interaction of PD-L2 with its one or more binding partners (such as PD-1). PD-L2 (programmed death ligand 2) is also known in the art as "programmed cell death 1 ligand 2", "PDCD 1LG 2", "CD 273", "B7-DC", "Btdc" and "PDL 2". Exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot accession number Q9BQ 51. In some cases, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In particular aspects, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signaling resulting from the interaction of PD-L2 with one or more of its binding partners, such as PD-1. In one aspect, the PD-L2 binding antagonist reduces negative costimulatory signals mediated by or by cell surface proteins expressed on T lymphocytes that cause less dysfunctional T cells by PD-L2 mediated signaling (e.g., increase 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 immunoadhesin.

Other examples of PD-1 axis binding antagonists include cimeprinizumab, palivizumab, carpriclizumab, certilizumab, tirezlizumab, tereprinizumab, dolaprimab, revelizumab, sibatuzumab, saralazumab, pinaprizumab, CS1003, HLX10, SCT-110A, SHR-1316, CS1001, envorlizumab, TQB2450, ZKAB001, LP-002, serpalizumab, batilizumab, geminlizumab, BI 754091, celizumab, YBL-006, BAT1306, HX008, CX-072, IMC-KL-001, KL-A167, brilizumab, jagliomab, BI 754091, celizumab, YBL-006, BAT1306, HX008, CX-072, IMC-KL-001, buglilizumab AMG 404, CX-188, JTX-4014, 609A, sym021, LZM009, F520, SG001, APL-502, cochlizumab, lodalizumab, 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, INCB090, KD036, KY, LYN192, MT-6035, VXM10, YBL-007, ABSK041, 7003, JS-003, and HS-636.

For purposes herein, "attritumab" is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin that binds PD-L1 and comprises the amino acid sequence of SEQ ID NO:28 and SEQ ID NO:29, and a light chain sequence of seq id no. Atelizumab comprises a single amino acid substitution (asparagine to alanine) at position 297 on the heavy chain (N297A), using EU numbering of amino acid residues in the Fc region, which results in a non-glycosylated antibody with minimal binding to the Fc receptor. Alemtuzumab is also described in the following documents: WHO drug information (international pharmaceutical substance non-patent name), proposed INN: manifest 112, volume 28, phase 4, published on day 16 of 2015, month 1 (see page 485).

As used herein, "pabolizumab" is a recombinant humanized monoclonal IgG4 antibody directed against human cell surface receptor PD-1. Pertuzumab is also described in the following references: WHO drug information (international drug substance non-patent name), proposed INN: manifest 72, volume 28, phase 3, published in 2014 (see page 407).

As used herein, "ibrinouzumab" is derived from a fully human IgG1/κ MAb in Open Monoclonal Technology (OMT) rats, which binds TIGIT and comprises the amino acid sequence of SEQ ID NO:33 and the heavy chain sequence of SEQ ID NO:34, or a light chain sequence thereof. Tirayleigh itumumab comprises two N-linked glycosylation sites in the Fc domain (N306). Tiryleryitumumab is also described in the following documents: WHO drug information (international drug substance non-patent name), proposed INN: manifest 117, volume 31, phase 2, published in 2017, 7/month 7 (see page 343).

As used herein, "bevacizumab" is a recombinant humanized monoclonal antibody that recognizes all VEGF isoforms, which is described in the following references: WHO drug information (international pharmaceutical substance non-patent name), proposed INN: manifest 83, volume 14, phase 2, published in 2000 (see page 107). Bevacizumab comprises SEQ ID NO: x and SEQ ID NO: the light chain variable region sequence of X.

The term "anti-TIGIT antagonismAgent antibody "refers to an antibody or antigen-binding fragment or variant thereof that is capable of binding TIGIT with sufficient affinity to substantially or completely inhibit the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody can block signaling through PVR, PVRL2, and/or PVRL3, thereby restoring the functional response (e.g., proliferation, cytokine production, target cell killing) by the T cell from a dysfunctional state to antigenic stimulation. For example, anti-TIGIT antagonist antibodies can block signaling through the PVR without affecting the PVR-CD226 interaction. One of ordinary skill in the art will appreciate 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 certain methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of a PVR interaction, a PVRL3 interaction, or a PVRL2 interaction, e.g., does not affect or minimally affects any other TIGIT interaction. In one aspect, the extent of binding of an anti-TIGIT antagonist antibody to an unrelated, non-TIGIT protein is less than about 10% of the extent of binding of the antibody to TIGIT, e.g., as determined by a Radioimmunoassay (RIA). In certain aspects, the dissociation constant (K) of an anti-TIGIT antagonist antibody that binds to TIGIT _D ) Is ≤ 1 μ M, ≦ 100nM, ≦ 10nM, ≦ 1nM, ≦ 0.1nM, ≦ 0.01nM, or ≦ 0.001nM (e.g., 10 nM) ^-8 M or less, e.g. 10 ^-8 M to 10 ^-13 M, e.g. 10 ^-9 M to 10 ^-13 M). In certain aspects, the anti-TIGIT antagonist antibody binds a TIGIT epitope that is conserved between TIGIT from different species or an epitope on TIGIT that permits cross-species reactivity. In some aspects, the anti-TIGIT binding antibody has intact Fc-mediated effector functions (e.g., ibritumumab tiuxetan, vibolimab (vibostolimab), etiglimab, EOS084448, or TJ-T6). In some aspects, the anti-TIGIT binding antibody has enhanced Fc-mediated effector function (e.g., SGN-TGT). In other aspects, the anti-TIGIT binding antibody lacks Fc-mediated effector function (e.g., dommaralimab, BMS-986207, ASP8374, or COM 902). In some aspects, the anti-TIGIT binding antibody is an IgG1 class antibody (e.g., tiryleigh ewolizumab, veborrelizumabAnti, domplanimab, BMS-986207, etiglimaliab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6 or AB 308). In other aspects, the anti-TIGIT binding antibody is an IgG4 class antibody (e.g., ASP8374 or COM 902). In one aspect, the anti-TIGIT antagonist antibody is securititumumab.

As used herein, "administering" means administering to the subject a compound (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a VEGF antagonist, or a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))) or a composition (e.g., a pharmaceutical composition, e.g., comprising an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a chemotherapeutic agent (e.g., methods of dosing a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel) and/or a topoisomerase II inhibitor (e.g., doxorubicin)), an antibody-drug conjugate (ADC) (e.g., vilin-emritumab or govericin-shacetotuzumab) and/or a Colony Stimulating Factor (CSF) (e.g., pegylated filgrastim (pegfilgrastim), filgrastim (filgrastim), or sargrastim (sargrastimstim)). The compounds and/or compositions used in the methods described herein can be administered via the following routes: for example, intravenous (e.g., by intravenous infusion), subcutaneous, intramuscular, intradermal, transdermal, intraarterial, intraperitoneal, intralesional, intracranial, intraarticular, intraprostatic, intrapleural, intratracheal, intranasal, intravitreal, intravaginal, intrarectal, topical, intratumoral, intraperitoneal, subconjunctival, intravesicular, mucosal, intrapericardial, intraumbilicus, intraocular, oral, topical, by inhalation, by injection, by infusion, by continuous infusion, by local perfusion bathing target cells directly, by catheter, by lavage, by cream, or in lipid composition. The method of administration may vary depending on a variety of factors (e.g., the compound or composition to be administered and the severity of the condition, disease or disorder to be treated).

A "fixed" or "fixed" dose of a therapeutic agent (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a VEGF antagonist, a chemotherapeutic (e.g., a platinum-based chemotherapeutic or a non-platinum-based chemotherapeutic), an ADC (e.g., viltine-enrotuzumab or govittacine-shacetuzumab), or a CSF (e.g., pegylated filgrastim, or sargrastim)) means administered to a patient without regard to the patient's weight or Body Surface Area (BSA). Thus, a fixed or fixed dose is not a mg/kg dose or mg/m ² The dosage is provided, but rather is provided in an absolute amount of the therapeutic agent (e.g., an absolute amount of the therapeutic agent in mg).

As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of the individual or cell being treated during the course of the clinical pathology. Desirable therapeutic effects include slowing or decreasing the rate of disease progression, slowing or alleviating the disease state, and ameliorating or improving the prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are reduced or eliminated, including but not limited to reducing the proliferation (or destruction) of cancer cells, reducing symptoms resulting from the disease, increasing the quality of life of a person suffering from the disease, reducing the dose of other drugs required to treat the disease, slowing the progression of the disease, and/or prolonging survival of the individual. For example, treatment includes effective cancer treatment with an effective amount of a therapeutic agent (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a VEGF antagonist, a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent), an ADC (e.g., viltine-enrotuzumab or govietzetuzumab), and/or a CSF (e.g., pegylated filgrastim, filgrastim or sargrastim)) or a combination of therapeutic agents. Treatment herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. The treatment may be a first line treatment (e.g., the patient may have not previously been treated or received prior systemic therapy), or a second or subsequent line of treatment.

As used herein, "in combination with" or "in synergy with" refers to a treatment regimen that includes administration of a PD-1 axis binding antagonist (e.g., attrituzumab), VEGF antagonist, chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent), ADC (e.g., vildagliptin or govittac-shaxituzumab), and/or CSF (e.g., pegylated filgrastim, filgrastim or sargrastim) and anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleighumab). Thus, "in combination with" means that one treatment modality is administered to a patient before, during, or after another treatment modality is administered to the patient.

A drug that is administered "concurrently" with one or more other drugs is administered within the same treatment cycle, on the same day as treatment with the one or more other drugs, and optionally concurrently with the one or more other drugs. For example, for cancer treatment given every 3 weeks, the concurrently administered drugs are each administered on day 1 of the 3-week cycle.

As used herein, the term "perioperative treatment" refers to treatment administered before and after surgery. Perioperative treatment may include administration of neoadjuvant therapy prior to surgery (e.g., cystectomy) and administration of therapy (e.g., adjuvant therapy) after surgery. For example, perioperative treatment can include neoadjuvant therapy (e.g., anti-TIGIT antagonist antibody and PD-1 axis binding antagonist neoadjuvant therapy) administered after diagnosis and before surgery (e.g., cystectomy) (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15 weeks or more) and therapy (e.g., adjuvant therapy (e.g., tig anti-it antagonist antibody and PD-1 axis binding antagonist adjuvant therapy) after surgery (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14, 15 weeks or more after surgery).

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

The term "dysfunction" in immune dysfunction refers to a state of reduced immune response to antigen stimulation.

The term "dysfunction" as used herein also includes impaired ability to render antigen recognition refractory (refractory) or unresponsive, in particular, to translate antigen recognition into downstream T cell effector functions such as proliferation, production of cytokines (e.g., gamma interferon) and/or target cell killing.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by uncontrolled growth of cells. Cancers include solid tumor cancers and non-solid tumor cancers as well as locally advanced or metastatic cancers (e.g., locally advanced or metastatic tumors). Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, urothelial Cancer (UC), including locally advanced and metastatic UC (mUC), bladder cancer (e.g., muscularis Invasive Bladder Cancer (MIBC) and non-muscularis invasive bladder cancer (NMIBC), e.g., BCG-refractory NMIBC), MIBC Urothelial Bladder Cancer (UBC); kidney or renal cancer (e.g., renal Cell Carcinoma (RCC)); cancer of the urinary tract; lung cancer such as Small Cell Lung Cancer (SCLC), including extensive-stage SCLC (ES-SCLC), non-small cell lung cancer (NSCLC), including squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), adenocarcinoma of the lung, or squamous cell carcinoma (e.g., epithelial squamous cell carcinoma (e.g., lung squamous cell carcinoma)); pancreatic cancer (e.g., pancreatic Ductal Adenocarcinoma (PDAC), e.g., metastatic PDAC); <xnotran> (, SCCHN, , / PD-L1 SCCHN (HNSCC); (OC); ; ; ; (GC) (, (GEJ) , ; ; ; ; , , HER2+ (TNBC (, TNBC (eTNBC), (ER-), (PgR-) HER2 (HER 2-)); , (CRPC); ; ; , ; (, (PDAC)); ; (, IVB , , , / PD-L1 ); ; (, (HCC), , HCC / HCC); ; ; ; (CRC; , (MSS) (MSI) (MSI-Low) CRC); ; ; ; ; ; ; ; ; , </xnotran> Including superficial spreading melanoma, malignant freckle melanoma, acro melanoma and nodular melanoma; multiple myeloma and B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small Lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-split cell NHL; large disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Fahrenheit macroglobulinemia); chronic Lymphocytic Leukemia (CLL); acute Lymphocytic Leukemia (ALL); acute Myeloid Leukemia (AML); hairy cell leukemia; chronic Myeloid Leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndrome (MDS), as well as abnormal vascular proliferation associated with maternal patches (phakomatases), edema (such as that 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 has not become undetectable or benign after a previous therapy.

As used herein, "IVB stage cervical cancer" refers to cervical cancer classified as such using a cervical cancer staging system (e.g., the international association of obstetrics and gynecology (FIGO) staging system). In some aspects, cervical cancer is classified as stage IVB if it has metastasized to distant organs (including the parenchyma of the spleen or liver) or to the inguinal and extraabdominal lymph nodes.

As used herein, the term "recurrent cervical cancer" refers to cervical cancer that has been detected or has recurred after initial treatment with surgery, radiation therapy and/or chemotherapy.

The term "TNBC" refers to breast cancer that lacks ER, PR, and HER2 expression. The term "eTNBC" refers to T2-4d TNBC (e.g., cT2-cT4, cN0-cN3, and cM 0).

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

As used herein, "urothelial cancer" and "UC" refer to a type of cancer that commonly occurs in the urinary system, including Muscularis Invasive Bladder Cancer (MIBC) and muscularis invasive urothelial cancer (UTUC). UC is also known in the art as Transitional Cell Carcinoma (TCC).

The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, as well as all pre-cancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder" and "tumor" are not mutually exclusive herein.

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 sample, 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 escape is attenuated and the tumor is recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

As used herein, "metastasis" refers to the spread of cancer from its primary site to other parts of the body. Cancer cells can detach from the primary tumor, infiltrate into lymphatic and blood vessels, circulate in the bloodstream, and grow (metastasize) in distant foci of normal tissue elsewhere in the body. Metastasis may be localized or distant. Metastasis is a continuous process, dependent on the shedding of tumor cells from the primary tumor, passing through the bloodstream, and stopping at a distance. At the new site, the cells establish a blood supply and can grow to form life threatening masses. 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 (e.g., causes cell death or destruction, inhibits proliferation, or otherwise inhibits or prevents cell function). Cytotoxic agents include, but are not limited to, radioisotopes (e.g., 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); chemotherapeutic agents or drugs (e.g., methotrexate, doxorubicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunomycin, or other intercalating agents); a growth inhibitor; enzymes and fragments thereof such as nucleolytic enzymes; (ii) an antibiotic; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and various anti-tumor or anti-cancer agents disclosed below. Exemplary cytotoxic agents may be selected from the group consisting of antimicrotubule 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, LDH-a inhibitors; inhibitors of fatty acid biosynthesis; inhibitors of cell cycle signaling; HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors. In one instance, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one instance, the cytotoxic agent is an antagonist of EGFR, e.g., N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (e.g., erlotinib). In one instance, cytotoxicity The agent is a RAF inhibitor, e.g., a BRAF and/or CRAF inhibitor. In one instance, the RAF inhibitor is vemurafenib (vemurafenib). In one instance, the cytotoxic agent is a PI3K inhibitor.

"chemotherapeutic agents" include chemical compounds useful for the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (b)

Genes of tek/OSI pharm.), bortezomib (

Ganxi pharmaceuticals (Millennium pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (Zygosaccharide)

Astrazeneca, sunitinib (AstraZeneca), and

Pfizer/Sugen) letrozole (C)

Novartis (Novartis)), imatinib mesylate (i.e., (ii)) and (ii) pharmaceutically acceptable salts thereof

Novak), finafloxacin ester (a)

Norwalk), oxaliplatin: (A)

Sirofil (Sanofi)), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus,

wheet (Wyeth)), lapatinib (a) (b)

The GSK572016 (human resource K) is provided with a plurality of holes, kulansu Schk (Glaxo Smith Kline)), lonafami (Lonafami) (SCH 66336), sorafenib (R) (Ixaprid)

Bayer laboratory (Bayer Labs)), gefitinib (Gefitinib (Gefitinib)

Astrazep), AG1478; alkylating agents such as thiotepa and

cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzotepa, carboquone, meturedpa, and uredpa; ethyleneamines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; annonaceous acetogenins (especially bullatacin and bullatacin); camptothecin (including topotecan and irinotecan); bryostatins; a caristatin (callystatin); CC-1065 (including its synthetic analogs of adozelesin, cartezisin and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); adrenal corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5 α -reductase (including finasteride and dutasteride); vorinostat, romidepsin, pantoprazole, valproic acid, moxystat (mocetinostat), dolastatin (dolastatin); aldesleukin, talc, ducamycin (including synthetic analogs KW-2189 and CB1-TM 1); eleutherobin (eleutherobin); (ii) coprinus atramentarius alkali; sarcandra glabra alcohol (sarcodictyin); sponge chalone; nitrogen mustards, such as chlorambucil, chlorophenylpiperazine, chlorophenylphosphoramide, estramustine, ifosfamide, mechlorethamine hydrochloride, melphalan, neomustard (novembichin), benzene mustard cholesterol, prednisetum, trofosfamil (trofosfami) de), uramustine (uracil mustard); nitrosoureas such as carmustine, chlorourethrine, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ 1I and calicheamicin ω 1I (Angew chem. Intl. Ed. Engl.199433: 183-186); daptomycin (dynemicin), including daptomycin a; bisphosphonates, such as clodronate, esmolosine, and also neocarcinostatin chromophores and related chromoproteins enediyne antibiotics, aclacinomycin (acarinomycin), actinomycin (actinomycin), anthranilic (authramycin), azaserine (azaserine), bleomycin, actinomycin (cactinomycin), carubicin (carabicin), carminomycin (caminomycin), carcinophilin (carzinophilin), chromomycin (chromomycin), dactinomycin, daunomycin, diterol (detorubicin), 6-azido-5-oxo-L-norleucine,

(doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, isoxabixin, idarubicin, maccellomycin (marcellomomycin); mitomycins, such as mitomycin C, mycophenolic acid, nogomycin, olivomycin, pelomycin, methylmitomycin, puromycin, triiron doxorubicin (queamycin), rodoricin (rodorubicin), streptonigrin, streptozotocin, tubercidin, ubenimex, netostatin, 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, thioguanine (thiamirine), thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifradine, enocitabine, floxuridine; androgens such as carpoterone, drostandrosterone propionate, epitioandrostanol, meperidine, testolactone; anti-adrenaline medicine Substances such as aminoglutethimide, mitotane, troostitan; folic acid replenishers such as leucovorin; acetic acid glucurolactone; an aldphosphoramide glycoside; (ii) aminolevulinic acid; eniluracil; amsacrine; doubly-branched betuzucil; a bisantrene group; edatrexate (edatraxate); desphosphamide (defofamine); colchicine; imine quinone; ilonidine (elfosmithine); ammonium etiolate; an epothilone; ethydine; gallium nitrate; a hydroxyurea; lentinan; lonidamine (lonidainine); maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol (mopidarnol); diamine nitracridine (nitrarine); pentostatin; methionine mustard (phenamett); pirarubicin; losoxantrone (losoxantrone); podophyllinic acid; 2-ethyl hydrazine; (ii) procarbazine;

polysaccharide complex (JHS Natural Products, eugene, oreg.); lezoxan; rhizomycin (rhizoxin); schizophyllan (sizofuran); a germanium spiroamine; alternanoic acid tenuazonic acid; a tri-imine quinone; 2,2',2 "-trichlorotriethylamine; trichothecene toxins (especially T-2 toxin, veracurin a, myrmecin a, and nigella sativa); urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; gatifloxacin (gacytosine); arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes (taxanes), e.g. taxanes

(Taxol; department of precious cancers of Otsumadam, princeton, N.J., of Princeton, N.J.),

(hydrogenated castor oil free (Cremophor)), albumin engineered nanoparticle formulations of paclitaxel (e.g., nanoparticle albumin engineered paclitaxel (nab-paclitaxel)) (American pharmaceutical partners of shore berg, illinois (American)Pharmaceutical Partners, schaumberg, ill.)) and

(docetaxel, docetaxel; sirolimus-ampheta (Sanofi-Aventis)); chlorambucil;

(gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;

(vinorelbine); nuntoron (novantrone); (ii) teniposide; edatrexed; daunomycin; aminopterin; capecitabine

Ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agents also include (i) anti-hormonal agents that act to modulate or inhibit hormonal effects on tumors, such as anti-estrogen agents and Selective Estrogen Receptor Modulators (SERMs), including, for example, tamoxifen (including

Tamoxifen citrate), raloxifene, droloxifene, iodoxifen (iodoxyfene), 4-hydroxytamoxifene, troloxifene, raloxifene (keoxifene), LY117018, onapristone and

(toremifene citrate); (ii) Aromatase inhibitors which inhibit the enzyme aromatase, which modulate the production of estrogen by the adrenal gland, such as 4 (5) -imidazoles, aminoglutarimides, beta-adrenergic agonists, and beta-adrenergic agonists,

(megestrol acetate),

(exemestane; pyroxene), formestane (formastane), fadrozole,

(vorozole),

(letrozole; noval) and

(anastrozole; asricon); (iii) Anti-androgens such as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, bemeili, fluoxymesterone, all trans retinoic acid, fenretinide, and troxacitabine (1, 3-dioxolane nucleoside cytosine analogs); (iv) Protein kinase inhibitors (e.g., anaplastic lymphoma kinase (Alk) inhibitors such as AF-802 (also known as CH-5424802 or Alectonib), (v) lipid kinase inhibitors, (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways implicated by abnormal cell proliferation, such as, for example, PKC-alpha, ralf, and H-Ras, (vii) ribozymes, such as VEGF expression inhibitors (e.g.,

) And inhibitors of HER2 expression; (viii) Vaccines, such as gene therapy vaccines, e.g.

And

rIL-2; topoisomerase 1 inhibitors, such as

rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agents also include "platinum-based" chemotherapeutic agents, also referred to herein as "platinum agents," which comprise organic compounds containing platinum as an integral part of the molecule. Typically, the platinum-based chemotherapeutic agent is a coordination complex of platinum. Platinum-based chemotherapeutic agents are sometimes referred to in the art as "platinum-based agents". Examples of platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthroline (phenonthrolidin), picoplatin (picoplatin), lipoplatin (lipoplatin), and satraplatin (satraplatin). The platinum-based chemotherapeutic (e.g., cisplatin or carboplatin) can be administered in combination with one or more additional chemotherapeutic agents, such as a nucleoside analog (e.g., gemcitabine), an antimetabolite (e.g., pemetrexed or gemcitabine), or a taxane (e.g., paclitaxel or nab-paclitaxel).

The term "eligible for treatment with platinum-based chemotherapy" refers to a subject eligible for treatment with platinum-based chemotherapy, whether at the discretion of the attending clinician or according to established criteria for platinum-based chemotherapy as is known in the art.

Chemotherapeutic agents also include "non-platinum-based chemotherapeutic agents," which as used herein refers to chemotherapeutic agents other than "platinum-based". As used herein, the terms "non-platinum chemotherapeutic agent" and "non-platinum agent" are used interchangeably. Exemplary non-platinum chemotherapeutic agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331), taxanes (e.g., paclitaxel (e.g., albumin engineered paclitaxel, also known as nanoparticle-albumin bound paclitaxel (nab-paclitaxel)), docetaxel (docetaxel), larotaxel (larotaxel), cabazitaxel (cabazitaxel), milataxel (tesetaxel), tesetaxel (tesetaxel), and/or oraxel). Exemplary non-platinum chemotherapeutic agents also include alkylating agents (e.g., cyclophosphamide).

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

As used herein, a "taxane" is a diterpene that can bind to tubulin, promote microtubule assembly and stabilization, and/or prevent microtubule depolymerization. Included herein are taxanes including the taxane class of 10-deacetylbaccatin III and/or derivatives thereof. Exemplary taxanes include, but are not limited to, paclitaxel (i.e.,

CAS # 33069-62-4), docetaxel (i.e.,

CAS # 114977-28-5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or oraxaxel. In some aspects, the taxane is an albumin-coated nanoparticle (e.g., nab-paclitaxel, i.e., paclitaxel)

And/or nab-docetaxel, ABI-008). In some aspects, the taxane is nab-paclitaxel

In some aspects, the taxane is formulated in

In (e.g.,

) And/or a tween such as polysorbate 80 (e.g.,

). In some aspects, the taxane is a liposome-encapsulated taxane. In some aspects, the taxane is a prodrug form and/or a conjugated form of the taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel polyaniline, and/or linoleyte carbonate-paclitaxel).In some aspects, paclitaxel is formulated to be substantially free of surfactant (e.g., in the absence of CREMAPHOR and/or tween, such as

Paclitaxel).

As used herein, an "antimetabolite" is a chemotherapeutic agent that interferes with and inhibits (in whole or in part) endogenous (normal) metabolic processes within a cell (e.g., a cancer cell). Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.

Chemotherapeutic agents also include dexamethasone, interferon, colchicine, chlorpheniramine (metoprine), cyclosporin, amphotericin, metronidazole, alemtuzumab (alemtuzumab), alitretinoin (alitretinin), allopurinol (allopurinol), amifostine (amifostine), arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene (bexarotene), cladribine, clofarabine (clofarabine), darbepoetin alpha (darbepoetin alfa), dinil (denileukin), dexrazoxane (dexrazoxane), epoetin alpha (epoetin alfa), erlotinib, filgrazine, histretinomycin acetate (histreetin acetate), ibritumomab (ibritumomab), interferon alpha-2 a, interferon alpha-2 b lenalidomide (lenalidomide), levamisole, mesna (mesna), methoxsalen, nandrolone (nandrolone), nelarabine (nelabane), nofetomab (nofetumomab), opprey interleukin (oprevekin), palifermin (palifermin), pamidronate (pamidronate), pegase (pegademase), pemetrase (pegaspragase) PEGylated filgrastim, pemetrexed disodium, mithramycin (plicamycin), porfimer sodium (porfimer sodium), quinacrine (quinacrine), rasburicase (rasburicase), sargrastim, temozolomide (temozolomide), VM-26, 6-TG, toremifene (toremifene), tretinoin (tretinoin), ATRA, valrubicin (valrubicin), and combinations thereof, zoledronate (zoledronate) and zoledronic acid (zoledronic acid) and their pharmaceutically acceptable salts.

The chemotherapeutic agent further comprises hydrocortisone (hydrocort)isonone), hydrocortisone acetate (hydrocortisone acetate), cortisone acetate (cortisone acetate), hydrocortisone mercaptonate (tixocortol pivalate), triamcinolone acetonide (triamcinolone acetonide), triamcinolone acetonide (triamcinolone alcohol), mometasone (mometasone), amcinonide (amcinonide), budesonide (budesonide) desonide, fluocinonide, betamethasone, sodium betamethasone phosphate, dexamethasone, sodium dexamethasone, fluocortolone, and the like hydrocortisone-17-butyrate (hydrocortisone-17-butyrate), hydrocortisone-17-valerate (hydrocortisone-17-acetate), alclomesone dipropionate (acetomethasone dipropionate), betamethasone valerate (betamethasone valerate), betamethasone dipropionate (betamethasone dipropionate), prednisone ester (prednicarbate), clobetasone-17-butyrate (clobetasone-17-butyrate), clobetasol-17-propionate (clobetamethasone-17-propionate), fluorometholone caproate (cacolone propionate), fluorometholone pivalate (fluocinolone pivalate) and fluprednide acetate (fluprednidene acetate); immunoselective anti-inflammatory peptides (imsaids), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer (FEG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, cyclosporine (cyclosporin A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide minocycline (leflunomide aminocycline), sulfasalazine, tumor necrosis factor alpha (TNF alpha) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as arbitux (Orencia), interleukin 6 (IL-6) blockers such as tolytuzumab (Tortula)

Interleukin 13 (IL-13) blockers such as lerizumab; interferon alpha (IFN) blockers, such as rolizumab (rotalizumab); beta 7Integrin blockers such as rhuMAb β 7; igE pathway blockers, such as anti-M1 primers; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTal/beta 2 blockers, such as anti-lymphotoxin alpha (LTa); radioisotopes (e.g., at211, I131, I125, Y90, re186, re188, sm153, bi212, P32, pb212 and radioactive isotopes of Lu); miscellaneous research reagents such as thioplatinum, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol,

) (ii) a Beta-lapachone (beta-lapachone); lapachol; colchicine; betulinic acid; acetyl camptothecin, scopolectin (scopolectin), and 9-aminocamptothecin); podophyllotoxin; tegafur

Bexarotene

Bisphosphonates, e.g. clodronates (such as

Or

) Etidronate

NE-58095 zoledronic acid/zoledronic acid salt

Alendronate

Pamidronic acidSalt (I)

Tillofosinate (tirudronate)

Or risedronate

And epidermal growth factor receptor (EGF-R); vaccines, e.g.

A vaccine; perhafos (perifosine), COX-2 inhibitors (e.g., celecoxib or etoxib), proteosome inhibitors (e.g., PS 341); CCI-779; tipifarnib (Tipifarnib) (R11577); orafenib (orafenaib), ABT510; bcl-2 inhibitors, such as orlimesen sodium (oblimersen sodium)

Pixantrone (pixantrone); farnesyl transferase inhibitors such as lonafarnib (SCH 6636, sarasrtm); and pharmaceutically acceptable salts, acids or derivatives of any of the above; and combinations of two or more of the above, such as CHOP, an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone; and FOLFOX, an abbreviation for treatment regimen of oxaliplatin (ELOXATINTM) in combination with 5-FU and folinic acid.

Chemotherapeutic agents also include nonsteroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of cyclooxygenase enzymes. 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, and lornoxicam), fenamic acid derivatives (such as mefenamic acid, meclofenamic acid, flufenamic acid, tosylate), and COX-2 inhibitors (such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, and valdecoxib). NSAIDs may be useful for alleviating symptoms of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylitis, psoriatic arthritis, reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, post-operative pain, mild to moderate pain due to inflammation and tissue injury, fever, ileus, and renal colic.

Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or interact directly with EGFR and prevent or reduce its signaling activity, and are alternatively referred to as "EGFR antagonists. Examples of such agents include small molecules that bind to EGFR. EGFR antagonists include small molecules such as U.S. Pat. nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 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: the compounds described in WO98/14451, WO98/50038, WO99/09016 and WO 99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib,

gene tack/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-acrylamido, N- [4- [ (3-chloro-4-fluorophenyl) amino)]-7- [3- (4-morpholinyl) propoxy]-6-quinazolinyl]-, dihydrochloride, feverfew); ZD1839, gefitinib (

4- (3 '-chloro-4' -fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline, aliskiren); ZM 105180 ((6-amino-4- (3-methylphenyl-amino) -quinazoline, jiekang (Zeneca)); BIBX-1382 (N8- (3-chloro-4-fluoro-phenyl) -N2- (1-methyl-piperidin-4-yl) -pyrimidinyl [5,4-d ]Pyrimidine-2, 8-diamine, boringer Invitrogen (Boehringer Ingelheim)); PKI-166 ((R) -4- [4- [ (1-phenylethyl) amino)]-1H-pyrrolidone [2,3-d ]]Pyrimidin-6-yl]-phenol);(R) -6- (4-hydroxyphenyl) -4- [ (1-phenylethyl) amino group]-7H-pyrrolo [2,3-d]Pyrimidines); CL-387785 (N- [4- [ (3-bromophenyl) amino)]-6-quinazolinyl]-2-butyneamide); EKB-569 (N- [4- [ (3-chloro-4-fluorophenyl) amino group)]-3-cyano-7-ethoxy-6-quinolinyl]-4- (dimethylamino) -2-butenamide) (wheaten); AG1478 (feverfew); AG1571 (SU 5271; feverine); dual EGFR/HER2 tyrosine kinase inhibitors, such as lapatinib (R: (R))

GSK572016 or N- [ 3-chloro-4- [ (3-fluorophenyl) methoxy]Phenyl radical]2- [ 6 ] [ [5 (methylsulfonyl) ethyl ] ethyl]Amino group]Methyl radical]-2-furyl radical]-4-quinazolinamines).

Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR-targeting agents described in the preceding paragraph; insulin receptor tyrosine kinase inhibitors, including anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802 (also known as CH-5424802 or Alletinib), ASP3026, X396, LDK378, AP26113, crizotinib

And ceritinib

Small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from the pharmaceutical company martial arts (Takeda); CP-724, 714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (feverfew and OSI); dual HER inhibitors, such as EKB-569 (available from hewlett-packard), which can preferentially bind EGFR but inhibit both HER2 and EGFR overexpressing cells; lapatinib (GSK 572016; available from Kurarin Schker), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Nowa corporation); pan-HER inhibitors such as canatinib (CI-1033; pharmacia); raf-1 inhibitors, such as the antisense agent available from ISIS pharmaceuticals for inhibiting Raf-1 signaling ISIS-5132; non-HER targeted TK inhibitors such as imatinib mesylate (b: (b))

Available from the Puerarin Schker company); multi-targeted tyrosine kinase inhibitors, such as sunitinib (C: (B))

Available from pfeiri); VEGF receptor tyrosine kinase inhibitors, such as vartanib (PTK 787/ZK222584, available from Nowa/pioneer company (Schering AG)); CI-1040, a MAPK extracellular regulated kinase I inhibitor (available from Famex corporation); quinazolines, such as PD 153035,4- (3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4- (phenylamino) -7H-pyrrolo [2,3-d]A pyrimidine; curcumin (diformylmethane, 4, 5-bis (4-fluoroanilino) phthalimide); tyrosine containing nitrothiophene moieties; PD-0183805 (Warner-Lambert, inc.); antisense molecules (e.g., molecules that bind to HER-encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tyrosine phosphorylation inhibitors (U.S. Pat. No. 5,804,396); ZD6474 (asixicam); PTK-787 (Nowa/Pioneer); pan HER inhibitors such as CI-1033 (pyroxene); affinitac (ISIS 3521; imatinib mesylate

PKI166 (noval corporation); GW2016 (glatiramer inc); CI-1033 (pfeiffer); EKB-569 (Whitman); sematinib (pyrosorib); ZD6474 (asixicam); PTK-787 (Nowa/Pioneer); INC-1C11 (Imclone), rapamycin (sirolimus,

) (ii) a Or in any of the following patent publications: U.S. Pat. No. 5,804,396, WO 1999/09016 (American Cyanamid), WO 1998/43960 (American Cyanamid), WO 1997/38983 (Warner Lambert), WO 1999/06378 (Warner Lambert), WO 1999/06396 (Warner Lambert), WO 1996/30347 (Pfizer, inc), WO 1996/33978 (Zeneca), WO 1996/3397 (Zeneca), and WO 1996/33980 (Zeneca).

The term "anthracycline" relates to a chemotherapeutic agent, an anticancer agent used to induce apoptosis, preferably by inhibiting DNA recombination in topoisomerase II. Examples include doxorubicin (adriamycin), daunorubicin (daunorubicin), epirubicin, idarubicin, daunorubicin (rhodomycin), pirarubicin, valrubicin (valrubicin), N-trifluoroacetyl doxorubicin-14-pentanoic acid, aclarubicin, morpholino doxorubicin (morpholino-DOX), cyanomorpholino doxorubicin (cyanomorpholino-DOX), 2-pyrrolino doxorubicin (2-PDOX), 5-iminodaunorubicin, mitoxantrone, and aclarubicin A (aclarubicin)). In some aspects, the anthracycline is administered in combination with an alkylating agent, e.g., doxorubicin in combination with cyclophosphamide (treatment with AC).

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

An "effective amount" of a compound, e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a VEGF antagonist, a chemotherapeutic (e.g., a platinum-based chemotherapeutic or a non-platinum-based chemotherapeutic), an ADC (e.g., vildagliptin or govitin-shaxituzumab), or a CSF (e.g., pegylated filgrastim, filgrastim or sargrastim), at least to a minimum amount to achieve a desired therapeutic outcome, such as a measurable increase in overall survival or progression-free survival of a particular disease or condition (e.g., 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 an expected response in the subject. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include, for example, elimination or reduction of risk, lessening of severity, or delaying onset of the disease, which includes biochemical, histological, and/or behavioral symptoms of the disease, complications thereof, and intermediate pathological phenotypes that arise during the course of disease development. For therapeutic use, beneficial or desired results include clinical results, such as a reduction or delay in one or more symptoms caused by the disease (e.g., cancer-related pain, symptomatic bone-related events (SSE)), a reduction in symptoms (e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, inappetence, constipation, diarrhea, or general level of physical mood, cognitive or social functioning) according to european cancer research and treatment organization quality of life questionnaire (EORTC QLQ-C30), a reduction in pain measured by, for example, a 10-point pain severity (measured at its worst), an increase in quality of life for a person with the disease, a reduction in the dosage of other drugs required to treat the disease, such as enhancing the effect of another drug via targeting, delaying the progression of the disease (e.g., progression free or imaging free progression (rPFS)), a delay in clinical progression of confirmed disease (e.g., progression of cancer-related pain, performance related events, delay in progression of disease (e.g., survival in eastern cohort group (ecps)), and a prolongation of the clinical outcome of life of the disease (e.g., a general cancer-related pain, cancer-related event, a systemic cancer therapy, a cancer-related cancer, a cancer-related event, a cancer-related group (ecps), and/or a general cancer-related therapy. In the case of cancer or tumors, an effective amount of the drug may reduce the number of cancer cells; reducing tumor size; inhibit (i.e., slow to some extent or expect to stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and expect to stop) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more symptoms associated with the condition to some extent. The effective amount may be administered one or more times. For the purposes of the present invention, an effective amount of a drug, compound or pharmaceutical composition is an amount sufficient for direct or indirect prophylaxis or treatment. As understood in the clinical setting, 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. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and administration of an effective amount of a single agent may be considered if the desired result can be achieved or achieved in combination with one or more other agents. In some aspects, beneficial or desired results are a reduction in lung cancer-related symptoms according to the health-related quality of life (HRQoL) questionnaire, as assessed by the lung cancer Symptoms (SILC) scale (e.g., time to exacerbation (TTD) of cough, dyspnea, and chest pain) and/or time to delay progression to lung-specific antigens).

"immunogenicity" refers to the ability of a particular substance to elicit an immune response. Tumors are immunogenic and increasing tumor immunogenicity aids in the elimination of tumor cells by immune response. Examples of enhancing tumor immunogenicity include, but are not limited to, treatment with TIGIT and/or PD-L1 antagonists (e.g., anti-TIGIT antagonist antibodies and/or anti-PD-L1 antibodies).

An "individual response" or "response" can be assessed using any endpoint that indicates a benefit to the subject, including, but not limited to, (1) inhibition of disease progression to some extent (e.g., cancer progression, such as lung cancer (e.g., small Cell Lung Cancer (SCLC), which includes extensive-stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), including squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), lung adenocarcinoma), UC, e.g., bladder cancer (e.g., MIBC), urothelial Bladder Cancer (UBC), pancreatic cancer (e.g., pancreatic Ductal Adenocarcinoma (PDAC), e.g., metastatic PDAC), kidney or renal cancer (e.g., renal Cell Carcinoma (RCC)), melanoma, head and neck cancer (e.g., head and Neck Squamous Cell Carcinoma (HNSCC)), ovarian Cancer (OC), gastric Cancer (GC) (e.g., gastroesophageal junction (GEJ) cancer), hepatocellular carcinoma (HCC), colorectal cancer (CRC; e.g., CRC with microsatellite stability (MSS) and microsatellite instability (MSI) Low (MSI-Low) or breast cancer (e.g., HER2+ breast cancer and Triple Negative Breast Cancer (TNBC), which are estrogen receptor negative (ER-, receptor-negative (gR-) and HER 2-negative (HER-) 2, HER-negative breast cancer, including slow down and complete stop; (2) tumor size reduction; (3) Inhibit (i.e., reduce, slow, or completely stop) cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) Inhibit (i.e., reduce, slow, or stop altogether) metastasis; (5) Relieve to some extent one or more symptoms associated with a disease or disorder (e.g., cancer); (6) Increasing or extending the length of survival, including overall survival and progression-free survival; and/or (9) reduce mortality at a given time point after treatment.

As used herein, "pathological complete remission" (pCR) is defined as the proportion of patients in which residual invasive cancer is absent from a completely resected specimen. In the context of breast cancer, "pathological complete remission" or "pCR" refers to the eradication of a tumor (ypT 0/ypN 0) from the breast and lymph nodes.

As used herein, in the context of Urothelial Cancer (UC), the "pathological degradation rate" is defined as the proportion of patients that reach pT1pN0 at cystectomy.

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

As used herein, "partial remission" or "PR" means a reduction in the sum of the target lesions at baseline by at least 30% with reference to the longest diameter (SLD) of the lesion.

As used herein, "objective remission rate" (ORR) refers to the sum of the Complete Remission (CR) rate and the Partial Remission (PR) rate.

As used herein, "duration of objective remission" (DOR) is defined as the time from the first appearance of the recorded objective remission to disease progression, or death for any reason within 30 days after the last dose of treatment, whichever occurs first.

By "sustained response" is meant a sustained effect on reducing tumor growth after cessation of treatment. For example, the tumor size may remain the same or smaller than the size at the beginning of the dosing phase. In some aspects, the duration of the sustained response is at least the same as the duration of treatment, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the duration of treatment, or longer.

"effective response" of a subject to drugs and treatments or "responsiveness" of a subject and similar phrases refer to conferring a clinical or therapeutic benefit to a subject at risk for or suffering from a disease or disorder, such as cancer. In one aspect, such benefits include one or more of the following: extending survival (including overall survival and progression-free survival); results in objective remission (including CR or PR); or ameliorating the signs or symptoms of cancer.

A subject "not effectively responding" to treatment refers to a patient who does not have any of the following: extending survival (including overall survival and progression-free survival); results in objective remission (including CR or PR); or ameliorating the signs or symptoms of cancer.

The term "survival" refers to the patient remaining alive and includes overall survival as well as progression-free survival.

As used herein, "overall survival" and "OS" refer to the length of time a patient remains alive from the date of diagnosis or the beginning of treatment for a disease (e.g., cancer). For example, the OS may be defined as the time from randomization to death for any reason.

As used herein, "overall survival" refers to the percentage of subjects in a group that survive after a particular duration, e.g., after six 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 recorded recurrence of the disease or death from any cause.

As used herein, "event-free lifetime" (EFS) is defined as the time from randomization to any of the following events (whichever occurs first): disease progression (e.g., the progression of exclusion surgery 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 treated disease (e.g., cancer) does not worsen. Progression-free survival can include the amount of time a patient has experienced CR or PR, as well as the amount of time a patient has experienced stable disease.

As used herein, "disease stable" or "SD" refers to a target lesion that is neither sufficiently diminished to comply with CR or PR, nor sufficiently increased to comply with PD, with reference to the minimum SLD since the start of treatment.

As used herein, "disease progression" or "PD" refers to an increase in the sum of the longest diameter of the target lesion (SLD) of at least 20% with reference to the minimum SLD recorded since the initiation of treatment or the presence of one or more new lesions.

As used herein, "major pathological remission" (MPR) is defined as residual viable tumor ≦ 10% upon surgical resection of the primary tumor.

As used herein, "delaying progression" of a disorder or disease means delaying, impeding, slowing, delaying, stabilizing and/or delaying the progression of the disease or disorder (e.g., cancer). Such delays may be of varying lengths of time, depending on the medical history and/or the subject to be treated. It will be apparent to those skilled in the art that a sufficient or significant delay may actually encompass prevention, as the subject will not suffer from the disease. For example, in advanced cancers, the development of Central Nervous System (CNS) metastases may be delayed.

As used herein, the term "reducing or inhibiting cancer recurrence" refers to reducing or inhibiting tumor or cancer recurrence or tumor or cancer progression.

"reduce or inhibit" refers to the ability to cause an overall reduction of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more. Reducing or inhibiting can refer to the symptoms of the condition being treated (e.g., cancer), the presence or size of metastases, or the size of the primary tumor.

By "extending survival" is meant increasing the overall survival or progression-free survival of a treated patient relative to a patient that is not treated (e.g., relative to a patient that is not treated with a drug), or relative to a patient that does not express a biomarker at a specified level and/or relative to a patient that is treated with an approved anti-tumor agent. Objective remission refers to measurable remission, including CR or PR.

The term "detecting" is used herein in the broadest sense to include qualitative and quantitative measurements of target molecules. Detection involves merely identifying the presence of the target molecule in the sample and determining whether the target molecule is present at detectable levels in the sample. Detection may be direct or indirect.

As used herein, a "PD-L1 positive tumor cell fraction" is the relative, post-staining, in the context of an Immunohistochemistry (IHC) assay, e.g., an IHC assay that stains PD-L1 with antibodies SP142, SP263, 22C3, or 28-8All live tumor cells present in the sample, the percentage of live tumor cells showing partial or complete membrane staining (excluding cytoplasmic staining) at any intensity. Thus, a PD-L1 IHC SP263 (Ventana) assay can be used, for example, to calculate a PD-L1 positive tumor cell fraction by the formula PD-L1 positive tumor cell fraction = (PD-L1 positive tumor number cells)/(total number of PD-L1 positive and PD-L1 negative tumor cells), where cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) by PD-L1 is excluded from the assessment and scoring. It is understood that any given diagnostic PD-L1 antibody may correspond to a particular IHC assay protocol and/or scoring term that may be used to derive a PD-L1 positive tumor cell fraction. For example, PD-L1 positive tumor cell fractions can be used separately on Benchmark ULTRA

Detection, enVision Flex on AutostainerLink 48, and EnVision Flex on Benchmark ULTRA

Detection and amplification or EnVision Flex on AutostainerLink 48 was derived from tumor cell samples stained with SP263, 22C3, SP142, or 28-8. In another example, the fraction of PD-L1 positive tumor cells can be calculated according to the above formula using the PD-L1 IHC 22C3 pharmDx assay (Dako). The skilled artisan will appreciate that the sensitivity may differ between different PD-L1 antibodies used in IHC assays. For example, only about 64% of samples that satisfy 1-tc or 25-tc threshold (as defined by staining with 28-8 or 22C3 and SP263, respectively) satisfy the threshold when stained with SP 142. Hirsch et al, journal of scientific Oncology 2016, 12 (2): 208-222. As used herein, the terms PD-L1 positive tumor cell fraction and "tumor proportion score" (TPS) are used interchangeably.

As used herein, the "Ventana SP142 IHC assay" is performed according to the Ventana PD-L1 (SP 142) assay package insert (Tucson, AZ: ventana Medical Systems, inc.), which is incorporated herein by reference in its entirety.

As used herein, the "Ventana SP263 IHC assay" is performed according to the Ventana PD-L1 (SP 263) assay package insert (Tucson, AZ: ventana Medical Systems, inc.), which is incorporated herein by reference in its entirety.

As used herein, the "pharmDx 22C3 IHC assay" is performed according to the PD-L1 IHC 22C3 pharmDx packaging insert (Carpinteria, CA: dako, agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

As used herein, the "pharmDx 28-8 IHC assay" is performed according to the PD-L1 IHC 28-8 pharmDx packaging insert (Carpinteria, CA: dako, agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

As used herein, "tumor infiltrating immune cells" refers to any immune cells present in a tumor or sample thereof. Tumor infiltrating immune cells include, but are not limited to, intra-tumor immune cells, peri-tumor immune cells, other tumor stromal cells (e.g., fibroblasts), or any combination thereof. Such tumor infiltrating immune cells can be, for example, T lymphocytes (such as CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other myeloid lineage cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., dendritic cells), histiocytes, and natural killer cells.

As used herein, the term "biomarker" refers to an indicator that can be detected in a sample, e.g., a predictive, diagnostic, and/or prognostic indicator, e.g., PD-L1, ctDNA, or a cytokine (e.g., a cytokine associated with T cell activation and/or lymphocyte subpopulations). Biomarkers can be used as indicators of particular subtype diseases or disorders (e.g., cancer) that have certain, molecular, pathological, histological, and/or clinical characteristics. In some aspects, the biomarker is a gene. Biomarkers include, but are not limited to, polypeptides, polynucleotides (e.g., DNA (e.g., ctDNA) and/or RNA), polynucleotide copy number alterations (e.g., DNA copy number), polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrate 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 (e.g., one or more cytokines associated with T cell activation and/or lymphocyte subpopulations). In some aspects, the biomarker is a cell (e.g., an immune cell, e.g., a T cell subpopulation, e.g., 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 (e.g., 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" refers herein to a gene or set of genes that encode proteins whose activities are essential for maintaining cell function, and housekeeping genes are typically similarly present in all cell types.

As used herein, "circulating tumor DNA" and "ctDNA" refer to DNA of tumor origin that is not associated with cells in the circulatory system. ctDNA is a cell-free DNA (cfDNA) that may be derived from tumor cells or Circulating Tumor Cells (CTCs). ctDNA may be found, for example, in the bloodstream of a patient or in a biological sample (e.g., blood, serum, plasma, or urine) obtained from a patient. In some aspects, ctDNA may include aberrant mutations (e.g., patient-specific variants) and/or methylation patterns.

The term "antibody" includes monoclonal antibodies (including full length antibodies having an immunoglobulin Fc region), polyclonal antibodies, antibody compositions having polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies), diabodies, and single chain molecules, as well as antibody fragments, including antigen-binding fragments, such as Fab, F (ab') ₂ And Fv as long as they exhibit the desired biological activity. The term "immunoglobulin" (Ig) is used herein in connection with antibodiesMay be used interchangeably. In one instance, the antibody is a full length monoclonal antibody.

As used herein, the term IgG "isotype" or "subclass" refers to any subclass of immunoglobulin defined by the chemical and antigenic characteristics of the constant regions of the immunoglobulin.

Antibodies (immunoglobulins) can be classified into different classes according to the amino acid sequence of their heavy chain constant domains. Immunoglobulins are largely divided into five classes: igA, igD, igE, igG, and IgM, and some of them can be further divided into subclasses (isotypes), e.g., igG1, igG2, igG3, igG4, igA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, γ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and generally described, for example, in the following documents: abbas et al, cellular and mol immunology, 4 th edition (w.b. saunders, co., 2000). The antibody may be part of a larger fusion molecule formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides.

The basic 4 chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. IgM antibodies consist of 5 elementary heterotetramer units and an additional polypeptide called the J chain and contain 10 antigen binding sites, while IgA antibodies contain 2-5 elementary 4 chain units that can combine with the J chain, polymerizing to form multivalent complexes. In the case of IgG, the 4-chain unit is typically about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while 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 bonds. Each H chain has a variable domain at the N-terminus (V) _H ) Followed by three constant domains (C) _H ) (for each of the alpha and gamma chains) and four C _H Domains (for μ and ε isoforms). Each L chain has a variable domain at the N-terminus (V) _L ) And the other end has a constant domain. V _L And V _H Alignment, and C _L To the first constant domain (C) of the heavy chain _H 1) And (6) aligning. It is believed that particular amino acid residues form an interface between the light and heavy chain variable domains. V _H And V _L Together form a single antigen binding site. For the structure and properties of antibodies of different classes see, e.g., basic and Clinical Immunology, 8 th edition, daniel P.Stits, abba I.Terr and Tristram G.Parslow (eds.), appleton &Lange, norwalk, CT,1994, page 71 and chapter 6. The L chain from any vertebrate can be assigned to one of two distinctly different types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain. Immunoglobulins can be assigned to different classes or isotypes based on the amino acid sequence of their heavy chain constant domains (CH). There are five classes of immunoglobulins: igA, igD, igE, igG and IgM, which have heavy chains called α, δ, ε, γ and μ, respectively. The γ and α classes are further divided into subclasses based on the relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: igG1, igG2A, igG2B, igG3, igG4, igA1, and IgA2.

The term "hypervariable region" or "HVR" as used herein refers to the various regions of an antibody variable domain which are hypervariable in sequence and which determine the antigen-binding specificity, e.g., "complementarity determining regions" ("CDRs").

Typically, an antibody comprises six CDRs; three in VH (CDR-H1, CDR-H2, CDR-H3) and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:

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

(b) CDRs present at amino acid residues 24 to 34 (L1), 50 to 56 (L2), 89 to 97 (L3), 31 to 35b (H1), 50 to 65 (H2) and 95 to 102 (H3) (Kabat et al, sequence of Proteins of Immunological Interest, 5 th edition, public Health Service, national Institutes of Health, bethesda, MD (1991)); and

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

Unless otherwise indicated, the CDRs are determined according to the methods described by Kabat et al (supra). One skilled in the art will appreciate that the CDR names can also be determined according to the methods described by Chothia (supra), mcCallum (supra), or any other scientifically accepted nomenclature system.

"framework" or "FR" refers to residues of the variable domain other than the Complementarity Determining Regions (CDRs). The FRs of a variable domain typically consist of the following four FR domains: FR1, FR2, FR3 and FR4. Thus, CDR and FR sequences typically occur in VH (or VL) as follows: FR1-CDR-H1 (CDR-L1) -FR2-CDR-H2 (CDR-L2) -FR3-CDR-H3 (CDR-L3) -FR4.

The term "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat" and variations thereof refers to the numbering system of heavy or light chain variable domains used in antibody compilation as in the Kabat et al reference above. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids, which correspond to a shortening or insertion of the FR or HVR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion (e.g., residue 52a according to Kabat numbering) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c according to Kabat numbering, etc.) after heavy chain FR residue 82. The Kabat numbering of residues for a given antibody can be determined by aligning the antibody sequences to regions of homology of "standard" Kabat numbered sequences.

When referring to residues in the variable domain (approximately residues 1 to 107 for the light chain and residues 1 to 113 for the heavy chain), the Kabat numbering system is commonly used (e.g., kabat et al, "Sequences of Proteins of Immunological Interest", 5 th edition, department of U.S. department of health and public service, national institute of health, betesday, maryland (1991)). When referring to residues in the constant region of an immunoglobulin heavy chain, the "EU numbering system" or "EU index" (e.g., the EU index reported by Kabat et al, supra) is typically used. "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody.

The term "variable" means that certain fragments of the variable domains vary widely between the sequences of the antibodies. The V domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the entire span of the variable domain. Instead, it is concentrated in three segments called hypervariable regions (HVRs) in the light and heavy chain variable domains. The more highly conserved portions of the variable domains are called the Framework Regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, predominantly in the beta sheet structure, connected by three HVRs, which form loops connecting and in some cases forming part of the beta sheet structure. The HVRs in each chain are held tightly together by the FR region and, together with the HVRs in the other chain, contribute to the formation of the antigen-binding site of the antibody (see Kabat et al, sequences of Immunological Interest, fifth edition, national Institute of Health, bethesda, md. (1991)). The constant domains are not directly involved in binding of the antibody to the antigen, but exhibit a variety of effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity.

The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of heavy and light chains may be referred to as "VH" and "VL", respectively. These domains are usually the most variable part of an antibody (relative to other antibodies of the same class) and contain an antigen binding site.

"framework" or "FR" refers to variable domain residues other than the hypervariable region (HVR) residues. The FRs of a variable domain typically consist of the following four FR domains: FR1, FR2, FR3 and FR4. Thus, HVR and FR sequences typically occur in the VH (or VL) as follows: FR1-H1 (L1) -FR2-H2 (L2) -FR3-H3 (L3) -FR4.

The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, rather than an antibody fragment. In particular, intact antibodies include those having heavy and light chains that include an Fc region. The constant domain can be a native sequence constant domain (e.g., a human native sequence constant domain) or an amino acid sequence variant thereof. In some cases, an intact antibody may have one or more effector functions.

"naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabeled. Naked antibodies may be present in pharmaceutical compositions.

An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen binding and/or variable regions of an intact antibody. Examples of antibody fragments include Fab, fab ', F (ab') ₂ And Fv fragments; a diabody; linear antibodies (see U.S. Pat. No. 5,641,870, example 2, zapata et al, protein Eng.8 (10): 1057-1062[1995 ]]) (ii) a Single chain antibody molecules and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments (referred to as "Fab" fragments) and a residual "Fc" fragment (the name of which reflects its ability to crystallize readily). Fab fragments consist of the entire L chain as well as the variable region domain of the H chain (V) _H ) And a first constant domain of a heavy chain (C) _H 1) And (4) forming. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen binding site. Pepsin treatment of antibodies produced a single large F (ab') ₂ Fragments which correspond approximately to two disulfide-linked Fab fragments which have different antigen-binding activity and are still capable of crosslinking antigen. Fab 'fragments differ from Fab fragments in that the Fab' fragments are at C _H 1 domain has added to it additional residues at the carboxy terminus, including one or more cysteines from the antibody hinge region. Fab '-SH is the designation herein for Fab' in which the cysteine residues of the constant domains carry a free thiol group. F (ab') ₂ Antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines in between. Other chemical couplings of antibody fragments are also known.

The Fc fragment contains the carboxy terminal portions of two H chains linked together by disulfide bonds. The effector functions of antibodies are determined by sequences in the Fc region, which are also recognized by Fc receptors (fcrs) present on certain types of cells.

"functional fragments" of an antibody of the invention comprise a portion of an intact antibody, typically including the antigen binding or variable region of an intact antibody or the Fc region of an antibody which retains or has modified FcR binding capability. Examples of antibody fragments include linear antibodies; single chain antibody molecules and multispecific antibodies formed from antibody fragments.

"Fv" is the smallest antibody fragment that contains the entire antigen recognition and binding site. The fragment consists of a dimer of a heavy chain variable region domain and a light chain variable region domain in tight, non-covalent association. Six hypervariable loops (3 loops for each of the H and L chains) are generated by the folding of these two domains, which contribute amino acid residues to achieve antigen binding, and the antibody has antigen binding specificity. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although with a lower affinity than the entire binding site.

"Single chain Fv", also abbreviated as "sFv" or "scFv", is a polypeptide comprising a V linked into a single polypeptide chain _H And V _L Antibody fragments of antibody domains. Preferably, the sFv polypeptide is at V _H And V _L The structural domains further comprise polypeptide connecting groups, so that the sFv forms a required antigen binding structure. For an overview of sFv see The Pharmacology of Monoclonal Antibodies by Pluckthun, 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 a constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxy terminus of the heavy chain. However, the antibody 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. Thus, an antibody produced by a host cell by expression of a particular nucleic acid molecule encoding a full-length heavy chain may comprise the full-length heavy chain, or the antibody may comprise a cleaved variant of the full-length heavy chain. This may be the case where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Thus, the C-terminal lysine (Lys 447) or the C-terminal glycine (Gly 446) and lysine (Lys 447) of the Fc region may or may not be present. If not otherwise indicated, the amino acid sequence of the heavy chain comprising the Fc region is indicated herein as having no C-terminal lysine (Lys 447). In one aspect, a heavy chain comprising an Fc region as specified herein is comprised in an antibody according to the disclosure, the heavy chain comprising an additional C-terminal glycine-lysine dipeptide (G446 and K447). In one aspect, a heavy chain comprising an Fc region as specified herein is comprised in an antibody according to the disclosure, the heavy chain comprising an additional C-terminal glycine residue (G446). In one aspect, a heavy chain comprising an Fc region as specified herein is comprised in an antibody according to the disclosure herein, the heavy chain comprising an additional C-terminal lysine residue (K447). In one aspect, the Fc region contains a single amino acid substitution of the heavy chain N297A. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al, sequences of Proteins of Immunological Interest, 5 th edition, public Health Service, national Institutes of Health, bethesda, MD, 1991.

"Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. In addition, a preferred FcR is one that binds an IgG antibody (gamma receptor) and includes Fc γ RI, fc γ RII and Fc γ RIII subclasses, including allelic and alternatively spliced forms of these receptors, and Fc γ RII receptors including Fc γ RIIA ("activating receptor") and Fc γ RIIB ("inhibitory receptor"), which have similar amino acid sequences, differing primarily in their cytoplasmic domains. The activating receptor Fc γ RIIA comprises in its cytoplasmic domain an immunoreceptor tyrosine-based activation motif (ITAM). The inhibitory receptor Fc γ RIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see M.

Annu, rev, immunol.15:203-234 (1997)). For reviews on FcR see: ravatch and Kine, annu.rev.immunol.9:457-92 (1991); capel et al, immunolmethods 4:25-34 (1994); and de Haas et al, j.lab.clin.med.126:330-41 (1995). The term "FcR" herein encompasses other fcrs, including those to be identified in the future.

The term diabodies refers to small antibody fragments prepared by construction of an sFv fragment (see preceding paragraph), where at V _H And V _L The domains have short linkers (about 5-10 residues) between them, thereby effecting inter-chain pairing but not intra-chain pairing of the V domains, resulting in a bivalent fragment, i.e., a fragment with two antigen binding sites. Bispecific diabodies are heterodimers of two "cross" sFv fragments, where the V of both antibodies _H And V _L The domains are located on different polypeptide chains. Diabodies are described in more detail in, for example, 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) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, and the remainder of one or more chains is identical with or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. nos. 4,816,567 morrison et al, proc.natl.acad.sci.usa,81:6851-6855 (1984)). Chimeric antibodies of interest herein include

An antibody, wherein the antigen binding region of the antibody is derived from an antibody produced by, for example, immunization of cynomolgus monkey with an antigen of interest. As used herein, "humanized antibodies" are used as a subset of "chimeric antibodies".

"class" of antibodies meansThe heavy chain of an antibody has a type of constant domain or constant region. There are five major classes of antibodies: igA, igD, igE, igG and IgM, and some of them may be further divided into subclasses (isotypes), e.g. IgG ₁ 、IgG ₂ 、IgG ₃ 、IgG ₄ 、IgA ₁ And IgA ₂ . The heavy chain constant domains corresponding to different classes of immunoglobulins are referred to as α, δ, ε, γ, and μ, respectively.

"affinity" refers to the strength of the sum of the non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen, such as TIGIT, PD-L1, or VEGF). As used herein, unless otherwise specified, "binding affinity" refers to intrinsic binding affinity that reflects a 1:1 interaction. The affinity of a molecule X for its partner Y can generally be determined by the dissociation constant (K) _D ) And (4) showing. Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary aspects for measuring binding affinity are described below.

A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human and/or made using any of the techniques disclosed herein for making human antibodies. This definition of human antibody specifically excludes humanized antibodies comprising non-human antigen binding residues. Human antibodies, including phage display libraries, can be generated using a variety of techniques known in the art. Hoogenboom and Winter, j.mol.biol.,227:381 (1991); marks et al, j.mol.biol.,222:581 (1991). Also useful in methods for preparing human Monoclonal Antibodies are Cole et al, monoclonal Antibodies and Cancer Therapy, alan R.Liss, p.77 (1985); boerner et al, j.immunol.,147 (1): 86-95 (1991). See also van Dijk and van de Winkel, curr, opin, pharmacol, 5:368-74 (2001). Human antibodies can be made by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to an antigen challenge but for which the endogenous locus has failed, e.g., immunizing a XENOMOUSE (see, e.g., for xenomice) ^TM U.S. Pat. nos. 6,075,181 and 6,150,584 to technology). See also, for example, li et al, proc.natl.acad.sci.usa,103:3557-3562 (2006) pertain to human antibodies produced by human B-cell hybridoma technology.

A "humanized" form of a non-human (e.g., murine) antibody is a chimeric antibody comprising minimal sequences derived from non-human immunoglobulins. In one aspect, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues from a recipient HVR (as defined below) are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and/or capacity. In some cases, framework ("FR") residues of a human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies may comprise residues that are not present in the recipient antibody or the donor antibody. These modifications can be made to further improve antibody performance, such as binding affinity. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions to improve antibody properties, e.g., binding affinity, isomerization, immunogenicity, and the like. The number of these amino acid substitutions in the FR is usually not more than 6 in the H chain and not more than 3 in the L chain. The humanized antibody will also optionally comprise at least a portion of an immunoglobulin constant region (Fc), which is typically a human immunoglobulin. For more details see, e.g., jones et al, nature 321:522-525 (1986); riechmann 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. 105-115 (1998); harris, biochem. Soc. Transactions 23:1035-1038 (1995); hurle and Gross, curr.op.biotech.5:428-433 (1994); and U.S. 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 a cell or cell culture in which it is expressed. Contaminant components of their natural environment are materials that would normally interfere with diagnostic or therapeutic uses for polypeptides, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some aspects, the antibody is purified to greater than 95% or 99% purity as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis), or chromatography (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessing antibody purity, see, e.g., flatman et al, j.chromatogr.b848:79-87 (2007). In a preferred aspect, the antibody will be purified (1) to an extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by using a rotary cup sequencer, or (2) to be homogeneous as determined by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or preferably silver staining. Isolated antibodies include antibodies in situ within recombinant cells, since at least one component of the polypeptide's natural environment will not be present. Typically, however, an isolated polypeptide will be prepared by at least one purification step.

The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies (e.g., containing naturally occurring mutations or produced during the manufacture of a monoclonal antibody preparation, such variants typically being present in minor amounts). In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the modifier "monoclonal" indicates that the characteristics of the antibody are 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 invention can be prepared by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods that utilize transgenic animals comprising all or part of a human immunoglobulin locus.

As used herein, the terms "bind", "specific binding" or "having specificity" refer to a measurable and reproducible interaction, such as binding between a target and an antibody, which determines the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically binds to a target (which may be an epitope) is an antibody that binds to that target with greater affinity, avidity, more readily, and/or for a longer duration than it binds to other targets. In one aspect, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target, e.g., as measured by Radioimmunoassay (RIA). In some aspects, the dissociation constant (K) of an antibody that specifically binds to a target _D ) Is less than or equal to 1 mu M, less than or equal to 100nM, less than or equal to 10nM, less than or equal to 1nM or less than or equal to 0.1nM. In certain aspects, the antibody specifically binds to an epitope on the protein that is conserved among proteins of different species. In another aspect, specific binding may include, but is not required to be, exclusive binding. The term as used herein may be displayed by, for example, a molecule having a dissociation constant with the target, K _D Is 10 ^-4 M or lower, alternatively 10 ^-5 M or lower, alternatively 10 ^-6 M or lower, alternatively 10 ^-7 M or lower, alternatively 10 ^-8 M or lower, alternatively 10 ^-9 M or lower, alternatively 10 ^-10 M or lower, alternatively 10 ^-11 M or lower, alternatively 10 ^-12 M or lower; or K _D In the range of 10 ^-4 M to 10 ^-6 M or 10 ^-6 M to 10 ^-10 M or 10 ^-7 M to 10 ^-9 And M. Affinity and K as understood by the skilled person _D The values are inversely related. High affinity for antigen is through low K _D The value is measured. In one aspect, the term "specifically binds" refers to binding of a molecule to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or epitope of the polypeptide.

"percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with amino acid residues in a reference polypeptide sequence, after aligning the candidate sequence with the reference polypeptide sequence and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without regard to any conservative substitutions as part of the sequence identity. Alignments to determine percent amino acid sequence identity can be performed in a variety of ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine appropriate parameters for aligning the sequences, including any algorithms required to achieve maximum alignment over the full length of the sequences being compared. However, for purposes herein, the sequence comparison computer program ALIGN-2 was used to generate values for% amino acid sequence identity. The ALIGN-2 sequence comparison computer program was written by Genentech, inc and the source code has been submitted with the user document to u.s.copy Office, washington d.c.,20559, where it was registered with us copyright registration number TXU 510087. The ALIGN-2 program is publicly available from Genettech, inc., south San Francisco, calif. or can be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, which includes the digital UNIX V4.0D. All sequence comparison parameters were set by the ALIGN-2 program and were unchanged.

In the case of amino acid sequence comparisons using ALIGN-2, the% amino acid sequence identity (which may alternatively be expressed as a% amino acid sequence identity for a given amino acid sequence A with or including a given amino acid sequence B) for a given amino acid sequence A with a given amino acid sequence B is calculated as follows:

100 times the fraction X/Y

Wherein X is the number of amino acid residues scored as identical matches in the alignment of program A and B by the sequence alignment program ALIGN-2, and wherein Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not be equal to the% amino acid sequence identity of B to A. Unless otherwise specifically indicated, all values of% amino acid sequence identity as used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

As used herein, "subject" or "individual" refers to 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. Patients are also subjects herein.

The term "patient" refers to a human patient. For example, the patient may be adult.

The term "diagnosis" as used herein refers to the identification or classification of a molecular or pathological state, disease or disorder (e.g., cancer). For example, "diagnosis" may refer to the identification of a particular type of cancer. "diagnosis" may also refer to the classification of a particular subtype of cancer, for example, by histopathological criteria or molecular features, e.g., a subtype characterized by the expression of one biomarker or a combination of biomarkers (e.g., a particular gene or protein encoded by the gene).

As used herein, the term "sample" refers to a composition obtained or derived from a target subject and/or individual that contains cells and/or other molecular entities to be characterized and/or identified, e.g., based on physical, biochemical, chemical, and/or physiological characteristics. For example, the phrases "tumor sample", "disease sample" and variations thereof refer to any sample obtained from a subject of interest that is expected or known to contain the cells and/or molecular entities to be characterized. Samples include, but are not limited to, 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, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, stool, tumor lysates and tissue culture media, tissue extracts such as homogenized tissue, tumor tissue, cell extracts, and combinations thereof.

A "tissue sample" or "cell sample" refers to a collection of similar cells obtained from a tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue from fresh, frozen and/or preserved organs, tissue samples, biopsies and/or aspirates; blood or any blood component, such as plasma; body fluids, such as cerebrospinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells at any time during pregnancy or development of the subject. 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. The tissue sample may comprise a mixed population of cell types (e.g., tumor cells and non-tumor cells, cancer cells and non-cancer cells). Tissue samples may contain compounds that do not naturally mix with tissue in the natural environment, such as preservatives, anticoagulants, buffers, fixatives, waxes, nutrients, antibiotics, and 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 (e.g., a bladder cancer tumor tissue sample (e.g., a MIBC tumor tissue sample)). In some aspects, the sample is a transurethral cystectomy (turbo) sample. In some aspects, the sample is a cystectomy or nephroureterectomy sample. In other aspects, the tumor tissue sample is a lung cancer tumor tissue sample (e.g., an early stage lung cancer tumor tissue sample (e.g., a NSCLC tumor tissue sample (e.g., stage II, IIIA, or IIIB NSCLC tumor tissue sample), e.g., a squamous or non-squamous NSCLC tumor tissue sample, e.g., an resectable NSCLC tumor tissue sample)). In some aspects, the sample is a locally advanced unresectable NSCLC tumor tissue sample (e.g., stage IIIB NSCLC tumor tissue sample) or a recurrent or metastatic NSCLC tumor tissue sample (e.g., stage IV NSCLC tumor tissue sample); pancreatic cancer tumor tissue samples (e.g., PDAC tumor tissue samples), e.g., metastatic PDAC tumor tissue samples; or a breast cancer tumor tissue sample (e.g., a HER2+ breast cancer tumor tissue sample or a TNBC tumor tissue sample).

For purposes herein, a "section" of a tissue sample refers to a single portion or piece of the tissue sample, e.g., a thin slice of tissue or cells cut from a tissue sample (e.g., a tumor sample). It is understood that multiple portions of a tissue sample can be obtained and analyzed, provided that it is understood that the same portion of a tissue sample can be analyzed at the morphological and molecular level, or can be analyzed for polypeptides (e.g., by immunohistochemistry) and/or polynucleotides (e.g., by in situ hybridization).

As used herein, "reference sample", "reference cell", "reference tissue", "control sample", "control cell" or "control tissue" refers to a sample, cell, tissue, standard or level for comparison purposes. In one aspect, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased site (e.g., tissue or cell) of the same subject or individual's body. For example, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue can be a healthy and/or non-diseased cell or tissue adjacent to a diseased cell or tissue (e.g., a cell or tissue adjacent to a tumor). In another aspect, the reference sample is obtained from untreated body tissue and/or cells of the same subject or individual. In yet another aspect, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased site (e.g., tissue or cell) of the body of an individual that is not the subject or individual. In yet another aspect, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the individual's body that is not the subject or individual.

The term "protein" as used herein, unless otherwise indicated, refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term includes "full-length" unprocessed protein, as well as any form of protein produced by processing in a cell. The term also encompasses naturally occurring protein variants, such as 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 may be a deoxyribonucleotide, a ribonucleotide, a modified nucleotide or base, and/or an analog thereof, or any substrate that can be incorporated into a polymer by a DNA or RNA polymerase or by a synthetic reaction. Thus, for example, polynucleotides as defined herein include, but are not limited to: single-stranded and double-stranded DNA; DNA comprising single-stranded and double-stranded regions; single-and double-stranded RNA; RNA comprising single-stranded and double-stranded regions; and hybrid molecules comprising DNA and RNA (which may be single-stranded, or more typically double-stranded, or comprise single-and double-stranded regions). In addition, the term "polynucleotide" as used herein refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The chains in such regions may be from the same molecule or from different molecules. A region may comprise all of one or more of the molecules, but typically comprises only one region of a portion of the molecule. One of the molecules having a triple-helical region is typically an oligonucleotide. The terms "polynucleotide" and "nucleic acid" specifically include mRNA and eDNA.

Polynucleotides may comprise modified nucleotides, such as methylated nucleotides and analogs thereof. If present, the nucleotide structure may be modified before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. The polynucleotide may be further modified after synthesis, for example by conjugation with a label. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as those with uncharged linkages (e.g., methyl phosphates, phosphotriesters, phosphoramidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties (pendant) such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, etc.), those containing alkylating agents, those with modified linkages (e.g., alpha anomeric nucleic acids), and unmodified forms of the polynucleotide. In addition, any hydroxyl group typically present in a sugar may be substituted (e.g., phosphate group), protected by a standard protecting group, or activated to make additional linkages to additional nucleotides, or may be conjugated to a solid or semi-solid support. The OH groups at the 5 'and 3' ends may be phosphorylated or partially substituted with an amine or organic end-capping group of 1-20 carbon atoms. Other hydroxyl groups may also be derivatized as standard protecting groups. Polynucleotides may also comprise similar forms of ribose or deoxyribose as are commonly known in the art, including, for example, 2 '-O-methyl-,' -O-allyl-, 2 '-fluoro-, or 2' -azidoribose; carbocyclic sugar analogs; an alpha-anomeric sugar; epimeric sugars such as arabinose, xylose, or lyxose; a pyranose; a furanose; sedoheptulose (sedoheptulose); acyclic analogs and abasic nucleoside analogs such as methyl ribonucleosides. One or more phosphodiester bonds may be substituted with alternative linking groups. Such alternative linking groups include, but are not limited to, aspects in which the phosphate is replaced by P (O) S ("thioester"), P (S) S ("dithioate"), "(O) NR2 (" amic ester "), P (O) R, P (O) OR ', CO, OR CH2 (" methylal "), wherein each R OR R' is independently H OR a substituted OR unsubstituted alkyl (1-20C), optionally containing an ether (-O-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, OR aralkyl (araldyl). Not all linkages in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

As used herein, "carrier" includes pharmaceutically acceptable carriers, excipients, or stabilizers which are non-toxic to the cell or mammal to which they are exposed at the dosages and concentrations employed. The physiologically acceptable carrier is typically a pH buffered aqueous solution. Examples of physiologically acceptable carriers include: buffers such as phosphates, citrates 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; an amino acid, a salt thereof,such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants, such as TWEEN ^TM Polyethylene glycol (PEG) and PLURONICS ^TM 。

The phrase "pharmaceutically acceptable" means 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.

The term "pharmaceutical formulation" or "pharmaceutical composition" refers to a formulation that is in a form that allows for the biological activity of the active ingredient contained therein to be effective, and that is free of additional components that have unacceptable toxicity to the subject to which the formulation is to be administered.

The term "package insert" is used to refer to instructions typically included in commercial packaging for a therapeutic product or pharmaceutical product that contains information regarding the indications, usage, dosage, administration, combination therapy, other therapeutic products to be used in conjunction with the packaged product, and/or contraindications and/or warnings relating to the use of such therapeutic product or pharmaceutical product.

As used herein, the term "induction phase" refers to a series of one or more dosing cycles (e.g., about 4 to 6 cycles) of one or more therapeutic agents (e.g., anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and/or chemotherapeutic agents) administered to a subject, wherein the 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 of one or more therapeutic agents (e.g., anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, and/or chemotherapeutic agent) administered to a subject after an induction phase. In some cases, the maintenance phase is initiated only when the subject has not experienced disease progression or unacceptable toxicity during the induction phase. The induction and maintenance phases may or may not include the use of the same therapeutic agent. For example, in some cases, the induction phase comprises 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 use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

In the context of bladder cancer, the term "a condition not amenable to treatment with platinum-based chemotherapy" or "unsuitability for treatment with platinum-based chemotherapy" refers to a subject that is not amenable to treatment with platinum-based chemotherapy or is unsuited for treatment with a platinum-based chemotherapeutic agent, either at the discretion of the attending clinician or according to established criteria for platinum-based chemotherapy known in the art. For example, galsky et al Lancet Oncol.12 (3): the criteria set forth in 211-4, 2011, which is incorporated by reference herein in its entirety, can be used to determine whether a subject is eligible for cisplatin-based chemotherapy. Galsky et al describe a consensus definition of patients with metastatic UC (mUC), where patients who meet at least one of the following criteria are considered inappropriate for cisplatin-based chemotherapy: (i) The World Health Organization (WHO) or Eastern Cooperative Oncology Group (ECOG) physical performance status is 2, or Karnofsky physical performance status is 60-70%; (ii) Creatinine clearance (calculated or measured) less than 1mL/s; (iii) The National Cancer Institute (NCI) adverse event general term criteria (CTCAE) v4.0 ≧ 2 for audiometric hearing loss; (iv) CTCAE v.4.0 is not less than grade 2 peripheral neuropathy; and/or New York Heart Association (NYHA) class III heart failure. In one example, patients are considered inappropriate for cisplatin-based chemotherapy if they have one or more of the following: impaired renal function (e.g., glomerular Filtration Rate (GFR) > 30 but < 60 mL/min); GFR can be assessed by direct measurement (i.e., creatinine clearance or edetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula); hearing loss (e.g., hearing loss measured at two consecutive frequencies of 25 decibels NCI CTCAE v4.0 ≧ 2); peripheral neuropathy (e.g., NCI CTCAE v4.0 ≧ grade 2 peripheral neuropathy (i.e., sensory changes or paresthesia, including stinging)); and/or an ECOG performance status assessment (see Oken et al am.j. Clin. Oncol.5:649-655, 1982, incorporated herein by reference in its entirety) (e.g., ECOG performance status of 2). In some aspects, a subject having one of the following conditions may be eligible for carboplatin-based chemotherapy: impaired renal function (e.g., GFR > 30 but < 60 mL/min); GFR can be assessed by direct measurement (i.e., creatinine clearance or edetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula); hearing loss (e.g., a 25 decibel CTCAE v4.0 ≧ 2 class audiometric hearing loss at two consecutive frequencies); peripheral neuropathy (e.g., NCI CTCAE v4.0 ≧ grade 2 peripheral neuropathy (i.e., sensory changes or paresthesia, including stinging)); and/or an ECOG performance status assessment (e.g., ECOG performance status of 2). For example, non-compliance with cisplatin treatment conditions can be defined by any of the following criteria: (i) impaired renal function (GFR < 60 mL/min); GFR can be assessed by direct measurement (i.e., creatinine clearance or edetate) and, if not, by serum/plasma creatinine calculation (Cockcroft Gault formula); (ii) Hearing loss of 25dB at two consecutive frequencies (measured by audiometry); (iii) Peripheral neuropathy at level 2 or higher (i.e., sensory changes or paresthesias, including stinging); (iv) an ECOG physical performance status of 2.

Therapeutic and diagnostic methods and uses

A. Therapeutic methods and uses related to cancer

Therapeutic methods and uses

Provided herein are methods for treating cancer (e.g., a solid tumor and/or a locally advanced or metastatic cancer, e.g., lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer), small Cell Lung Cancer (SCLC) (e.g., extensive-stage (ES) -SCLC), non-small cell lung cancer (NSCLC) (e.g., squamous NSCLC or non-squamous NSCLC, locally advanced non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC)) or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), breast cancer (e.g., triple Negative Breast Cancer (TNBC) (e.g., estrogen receptor negative (ER-), progesterone receptor negative (PR-) and HER2 negative (HER 2-) breast cancer, e.g., early TNBC (eTNBC)) or HER2 negative breast cancer), head and neck cancer (e.g., head and neck Squamous Cell Carcinoma (SCCHN), e.g., recurrent/metastatic PD-L1 scc positive), liver cancer (e.g., hepatocellular carcinoma (HCC), e.g., locally advanced or metastatic HCC and/or unresectable), bladder cancer (e.g., muscle-layer invasive bladder cancer (MIBC) or locally advanced or metastatic urothelial cancer (mcc)), esophageal cancer, pancreatic cancer (e.g., pancreatic Ductal Adenocarcinoma (PDAC), e.g., metastatic PDAC); kidney or renal cancer (e.g., renal Cell Carcinoma (RCC)); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer); or colorectal cancer (CRC; e.g., CRC with microsatellite stability (MSS) or microsatellite instability (MSI) Low (MSI-Low)), comprising administering to the subject an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody, e.g., tenellimumab), or a combination of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab, or an anti-PD-1 antagonist antibody, such as palbociclumab) for one or more dosing cycles.

The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immitumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atuzumab, or an anti-PD-1 antagonist antibody, e.g., parbolizumab) every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in Complete Remission (CR) or Partial Remission (PR). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in Progression Free Survival (PFS) or objective duration of remission (DOR). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in Overall Survival (OS). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in PFS in the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) extends OS of the subject, e.g., as compared to treatment with a PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with an anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist.

The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh) is administered every four weeks (e.g., on day 1 of each 28-day dosing cycle), and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab, or an anti-PD-1 antagonist antibody, e.g., palbocicluzumab) is administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in PFS in the subject as compared to a reference. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in DOR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) extends OS in the subject.

The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altuzumab, or an anti-PD-1 antagonist antibody, e.g., palivizumab) is administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atlizumab, or an anti-PD-1 antagonist antibody, e.g., palbociclumab) every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in PFS in the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) extends OS of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist.

The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) every three weeks (e.g., on day 1 of each 21-day dosing cycle). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered every three weeks (e.g., on day 1 of each 21-day dosing cycle), and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab, or an anti-PD-1 antagonist antibody, e.g., palboclizumab) is administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In certain instances, the invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) every three weeks (e.g., on day 1 of each 21-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in PFS in the subject as compared to a reference. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) extends OS in the subject. In some cases, the invention includes a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: a dose of about 500mg to about 700mg of an anti-TIGIT antagonist antibody every three weeks, a dose of about 900mg to about 1500mg of a PD-1 axis binding antagonist every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks. In some cases, the method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of 500 to 700mg every three weeks, a PD-1 axis binding antagonist at a dose of 900 to 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum 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 (e.g., without any chemotherapeutic agent, e.g., without administration of a chemotherapeutic agent to the subject throughout the dosing regimen).

In some embodiments, the subject has not been previously treated with a therapy directed to cancer (e.g., a cancer immunotherapy and/or a chemotherapeutic agent). In some embodiments, the subject has received a prior treatment for a therapy for cancer (e.g., a cancer immunotherapy and/or a chemotherapeutic agent). In some cases, the subject has not received prior systemic therapy (e.g., prior systemic therapy with the intent to cure, e.g., chemotherapy) for at least one month prior to administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody (e.g., two months, three months, four months, six months, one year, two years, three years, four years, five years, or ten years prior to administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody). 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 concurrently with chemotherapy. For example, a biweekly (Q2W), triweekly (Q3W), or biweekly (Q4W) dosing regimen of a PD-1 axis binding antagonist and/or anti-TIGIT antagonist antibody may be administered in conjunction with one or more chemotherapeutic agents. The one or more chemotherapeutic agents may be administered at the same frequency (Q2W, Q3W, or Q4W) or at a different frequency (e.g., a 3 week on/1 week off schedule (e.g., days 1, 8, and 15 of each 28 day cycle)) as the frequency of administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody. 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 weekly (3 weeks on/1 week off), biweekly, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every three weeks, and the one or more chemotherapeutic agents are administered weekly, biweekly, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every four weeks, and the one or more chemotherapeutic agents are administered weekly (3 weeks on/1 week off), biweekly, every three weeks, or every four weeks. In certain instances, the chemotherapeutic agent is administered multiple times per week (e.g., 2, 3, 4, 5, 6, or 7 times per week (e.g., 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 (e.g., after one, two, three, four, or more initial doses). For example, subsequent doses of a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))) can be administered at about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial dose. For example, 125mg/m may be used ² Nab-Reduction of the initial dose of paclitaxel for subsequent doses, e.g., to 100mg/m ² Or 75mg/m ² (ii) a Can be 100mg/m ² The initial dose of nab-paclitaxel is reduced for subsequent doses, e.g., to 75mg/m ² (ii) a Can be about 175mg/m ² The initial dose of paclitaxel is reduced for subsequent doses, e.g., to 150mg/m ² 、125mg/m ² 、100mg/m ² Or 75mg/m ² (ii) a Can be about 200mg/m ² The initial dose of paclitaxel is reduced for subsequent doses, e.g., to 175mg/m ² 、150mg/m ² 、125mg/m ² 、100mg/m ² Or 75mg/m ² (ii) a Can be adjusted to about 1000mg/m ² Reduction of the initial dose of gemcitabine for subsequent doses, e.g., to 900mg/m ² 、800mg/m ² 、750mg/m ² 、700mg/m ² 、600mg/m ² Or 500mg/m ² (ii) a Can be adjusted to about 75mg/m ² For subsequent doses, e.g. to 70mg/m ² 、65mg/m ² 、60mg/m ² 、55mg/m ² 、50mg/m ² Or 45mg/m ² (ii) a Can be about 500mg/m ² For subsequent doses, e.g., to 450mg/m ² 、400mg/m ² 、350mg/m ² 、300mg/m ² 、250mg/m ² Or 200mg/m ² (ii) a And/or an initial dose of carboplatin sufficient to achieve a dose of AUC =6mg/ml/min may be reduced for subsequent doses, e.g., to a dose sufficient to achieve AUC =5.5.mg/ml/min, 5.0mg/ml/min, 4.5mg/ml/min, or 4.0 mg/ml/min. In some examples, 125mg/m may be used ² The initial dose of nab-paclitaxel is reduced for subsequent doses, e.g., to 100mg/m ² Or 75mg/m ² (ii) a Can be mixed with 100mg/m ² The initial dose of nab-paclitaxel of (a) is reduced for subsequent doses, e.g., to 75mg/m ² (ii) a 175mg/m can be added ² The initial dose of paclitaxel is reduced for subsequent doses, e.g., to 150mg/m ² 、125mg/m ² 、100mg/m ² Or 75mg/m ² (ii) a Can be mixed with 200mg/m ² The initial dose of paclitaxel is reduced for subsequent doses, e.g., to 175mg/m ² 、150mg/m ² 、125mg/m ² 、100mg/m ² Or 75mg/m ² (ii) a Can be 1000mg/m ² The initial dose of gemcitabine of (1) is reduced for subsequent doses, e.g., to 900mg/m ² 、800mg/m ² 、750mg/m ² 、700mg/m ² 、600mg/m ² Or 500mg/m ² (ii) a Can be adjusted to 75mg/m ² For subsequent doses, e.g. to 70mg/m ² 、65mg/m ² 、60mg/m ² 、55mg/m ² 、50mg/m ² Or 45mg/m ² (ii) a Can be adjusted to 500mg/m ² For subsequent doses, e.g., to 450mg/m ² 、400mg/m ² 、350mg/m ² 、300mg/m ² 、250mg/m ² Or 200mg/m ² (ii) a And/or an initial dose of carboplatin sufficient to achieve a dose of AUC =6mg/ml/min may be reduced for subsequent doses, e.g., to a dose sufficient to achieve AUC =5.5.mg/ml/min, 5.0mg/ml/min, 4.5mg/ml/min, or 4.0 mg/ml/min.

The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as astuzumab, or an anti-PD-1 antagonist antibody, e.g., paribrizumab), and combination chemotherapy. In some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) are administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh) is administered every four weeks (e.g., on day 1 of each 28-day dosing cycle), and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., attrituximab) is administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, the combination chemotherapy comprises an effective amount of a first non-platinum chemotherapeutic agent and an effective amount of a second non-platinum chemotherapeutic agent. In some cases, the first non-platinum chemotherapeutic agent is an antimetabolite and the second non-platinum chemotherapeutic agent is a taxane. In some embodiments, the combination chemotherapy (e.g., an antimetabolite (e.g., gemcitabine, pemetrexed, or capecitabine) and a taxane (e.g., nab-paclitaxel and paclitaxel)) is administered once a week, once every two weeks, or three times every four weeks (e.g., on days 1, 8, and 15 of each 28-day dosing cycle).

In particular embodiments, the methods involve administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab), gemcitabine, and paclitaxel, wherein the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) are administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), and the combination chemotherapy (e.g., the antimetabolite and the taxane (e.g., gemcitabine and paclitaxel)) is administered more frequently (e.g., three times every four weeks (e.g., on days 1, 8, and 15 of each 28-day dosing cycle).

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab), an antimetabolite (e.g., gemcitabine), and a taxane (e.g., paclitaxel) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as alemtuzumab), an antimetabolite (e.g., gemcitabine), and a taxane (e.g., paclitaxel) results in an increase in PFS in the subject. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab), an antimetabolite (e.g., gemcitabine), and a taxane (e.g., paclitaxel) extends OS of the subject.

The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atuzumab, or an anti-PD-1 antagonist antibody, e.g., paribizumab), and a combination chemotherapy, wherein the combination chemotherapy comprises an effective amount of a platinum-based chemotherapeutic and an effective amount of a non-platinum-based chemotherapeutic. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab) are administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 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 (e.g., pemetrexed). In some embodiments, the combination chemotherapy (e.g., a platinum-based chemotherapeutic agent and an antimetabolite (e.g., pemetrexed)) is administered once a week, once every two weeks, once every four weeks, or three times every four weeks (e.g., on days 1, 8, and 15 of each 28-day dosing cycle).

In particular embodiments, the methods involve administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed), wherein the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altuzumab) are administered every three weeks (e.g., on day 1 of each 21-day dosing cycle), and the combination chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) are administered at the same frequency (e.g., every three weeks, e.g., on day 1 of each 21-day dosing cycle). In some cases, administration is for four to six cycles of induction dosing (e.g., four cycles of induction dosing, five cycles of induction dosing, or six cycles of induction dosing). After the induction dosing period, maintenance therapy may be administered in one or more subsequent (maintenance) dosing periods. In certain embodiments, the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent.

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as alemtuzumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) results in an increase in PFS in the subject. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as alemtuzumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) extends OS in the subject.

In some cases, a subject receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout iturin), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer can be 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., 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 (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC); bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); kidney or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC).

The invention also comprises methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attritumab, or an anti-PD-1 antagonist antibody, e.g., paribizumab), and chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab) are administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) are administered every four weeks (e.g., on day 1 of each 28 day dosing cycle). In some embodiments, chemotherapy is administered once a week, once every two weeks, once every four weeks, or three times every four weeks (e.g., on days 1, 8, and 15 of each 28-day dosing cycle). In some embodiments, chemotherapy is administered weekly.

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atuzumab, or an anti-PD-1 antagonist antibody, e.g., paribizumab), and chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumumab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attritumab, or an anti-PD-1 antagonist antibody, e.g., pabulizumab), and chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) results in an increase in PFS in the subject as compared to the reference. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attritumab, or an anti-PD-1 antagonist antibody, e.g., paribizumab), and chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) results in an increase in DOR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumumab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attritumab, or an anti-PD-1 antagonist antibody, e.g., paribizumab), and chemotherapy (e.g., a taxane (e.g., paclitaxel or nab-paclitaxel)) extends OS in the subject.

The invention also includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atuzumab, or an anti-PD-1 antagonist antibody, e.g., paribrizumab), and a combination chemotherapy, wherein the combination chemotherapy comprises an effective amount of a platinum-based chemotherapeutic and an effective amount of a non-platinum-based chemotherapeutic, wherein the non-platinum-based chemotherapeutic is a taxane (e.g., paclitaxel or nab-paclitaxel). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab) are administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some embodiments, the combination chemotherapy (e.g., a platinum-based chemotherapeutic and a taxane (e.g., paclitaxel or nab-paclitaxel)) is administered once a week, once every two weeks, once every four weeks, or three times every four weeks (e.g., on days 1, 8, and 15 of each 28-day dosing cycle).

In particular embodiments, the methods involve administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel), wherein the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., rayleigh eculizumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab) are administered every three weeks (e.g., on day 1 of each 21-day dosing cycle) and the combination chemotherapy (e.g., a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and a taxane (e.g., paclitaxel or nab-paclitaxel)) are administered at the same frequency (e.g., every three weeks, e.g., on day 1 of each 21-day dosing cycle). In some cases, administration is for four to six cycles of induction dosing (e.g., four cycles of induction dosing, five cycles of induction dosing, or six cycles of induction dosing). After the induction dosing period, maintenance therapy may be administered in one or more subsequent (maintenance) dosing periods. In certain embodiments, the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent.

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibriturin itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as attrituzumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel) results in an increase in PFS in the subject. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel) extends OS in the subject.

In some cases, a subject receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer can be 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., 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 (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC); bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); kidney or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC).

Also provided herein are methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attritumab, or an anti-PD-1 antagonist antibody, e.g., paribizumab), and a combination chemotherapy, wherein the combination chemotherapy comprises an effective amount of a platinum-based chemotherapeutic and an effective amount of a non-platinum-based chemotherapeutic, wherein the non-platinum-based chemotherapeutic is a topoisomerase II inhibitor (e.g., etoposide). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab) are administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some embodiments, the combination chemotherapy (e.g., a platinum-based chemotherapeutic agent and a topoisomerase II inhibitor (e.g., etoposide)) is administered once a week, once every two weeks, once every four weeks, or three times every four weeks (e.g., on days 1, 8, and 15 of each 28-day dosing cycle). In some embodiments, the topoisomerase II inhibitor (e.g., etoposide) is administered more frequently (e.g., three times per week, e.g., on days 1, 2, and 3 of each dosing cycle) than the platinum-based chemotherapeutic agent.

In particular embodiments, the methods involve administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide), wherein the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab) are administered every three weeks (e.g., on day 1 of each 21-day dosing cycle), and the combination chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a topoisomerase II inhibitor (e.g., etoposide)) are administered at the same frequency (e.g., every three weeks, e.g., every 21 days dosing cycle, e.g., on day 1 of each 21 days dosing cycle). In some cases, administration is for four to six cycles of induction dosing (e.g., four cycles of induction dosing, five cycles of induction dosing, or six cycles of induction dosing). After the induction dosing period, maintenance therapy may be administered in one or more subsequent (maintenance) dosing periods. In certain embodiments, the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent or a topoisomerase II inhibitor (e.g., etoposide).

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) results in (a) CR or PR. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) results in an increase in PFS in the subject. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) extends OS of the subject.

In some cases, a subject receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atlas mab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer can be 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., 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 (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC); bladder cancer (e.g., MIBC, locally advanced UC, or muuc); esophageal cancer; pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); kidney or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC).

Also provided herein are methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atlizumab, or an anti-PD-1 antagonist antibody, e.g., palboclizumab), and a VEGF antagonist (e.g., a VEGF antibody (e.g., bevacizumab)). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab), and VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered every three weeks (e.g., on day 1 of each 21 day dosing cycle).

In particular embodiments, the methods involve administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab), and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), wherein the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab), and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered every three weeks (e.g., on day 1 of each 21-day dosing cycle). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab), and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) results in an increase in OS in the subject. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as attritumab), and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) results in an increase in PFS in the subject.

In some cases, a subject receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attentizumab), and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer can be 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (e.g., TNBC (e.g., eTNBC) or HER2 positive breast cancer); head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC); bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); kidney or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC).

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

Also provided herein are methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), an anti-PD-1 antagonist antibody, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), wherein the anti-PD-1 antagonist antibody is palbociclumab. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), the anti-PD-1 antagonist antibody, and the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered every three weeks (e.g., on day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist antibody is pertuzumab.

In particular embodiments, the methods involve administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), an anti-PD-1 antagonist antibody, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), wherein the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), an anti-PD-1 antagonist antibody, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered every three weeks (e.g., on day 1 of each 21-day dosing cycle), wherein the anti-PD-1 antagonist antibody is palivizumab. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) results in an increase in OS in the subject, wherein the anti-PD-1 antagonist antibody is palbociclumab. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) results in an increase in PFS in the subject, wherein the anti-PD-1 antagonist antibody is pertuzumab.

In some cases, a subject receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) anti-PD-1 antagonist antibody and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is being treated for a solid tumor or a locally advanced or metastatic cancer, wherein the anti-PD-1 antagonist antibody is pertuzumab. Additionally or alternatively, the cancer can be 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (e.g., TNBC (e.g., eTNBC) or HER2 positive breast cancer); head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC); bladder cancer (e.g., MIBC, locally advanced UC, or muuc); esophageal cancer; pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); kidney or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC).

Also provided herein are methods and uses involving administering to a subject in need thereof an effective amount of tirayleigh immuzumab and paribizumab. In some cases, the tirayleigh mab is administered every three weeks (e.g., on days 1 and 22 of each 42-day dosing cycle) and the palbociclumab is administered every six weeks (e.g., on day 1 of each 42-day dosing cycle).

In particular embodiments, the method involves administering to a subject in need thereof an effective amount of ibritumumab tiuxetan and paribizumab, wherein ibritumumab tiuxetan is administered every three weeks (e.g., on days 1 and 22 of each 42-day dosing cycle) and paribizumab is administered every six weeks (e.g., on day 1 of each 42-day dosing cycle). In some cases, the effective amount of tirayleigh immuzumab and pertuzumab results in an increase in OS in the subject, wherein the anti-PD-1 antagonist antibody is pertuzumab. In some cases, the effective amount of ibritumomab tiuxetan and paribizumab results in an increase in PFS in the subject, wherein the anti-PD-1 antagonist antibody is paribizumab.

In some cases, a subject receiving both ibritumomab tiuxetan and paribrizumab is being treated for a solid tumor or a locally advanced or metastatic cancer, wherein the anti-PD-1 antagonist antibody is not paribrizumab. Additionally or alternatively, the cancer can be 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer); breast cancer (e.g., TNBC (e.g., eTNBC) or HER2 positive breast cancer); head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC); bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); kidney or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC).

Also provided herein are methods of treating a subject having cancer, the method 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 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum 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 include one or more dosing cycles. In some cases, the maintenance period does not include administration of a platinum-based chemotherapeutic agent. In some cases, the maintenance phase does not include administration of a non-platinum chemotherapeutic agent. In some cases, the maintenance period includes one or more of the following for the dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks.

Also provided herein are methods of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: a dose of about 500mg to about 700mg of an anti-TIGIT antagonist antibody every three weeks and a dose of about 100mg to about 300mg of an anti-PD-1 antagonist antibody every three weeks, wherein the anti-PD-1 antagonist antibody is palbociclumab.

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

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

Administration of pharmaceutical agents

Section III (K) describes the administration of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, VEGF antagonists, and chemotherapeutic agents.

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 (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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., 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 (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN); liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC); bladder cancer (e.g., MIBC, locally advanced UC, or mUC); esophageal cancer; pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC); kidney or renal cancer (e.g., RCC); melanoma; ovarian cancer; gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low 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 any of the methods, uses, or compositions for use described herein, the subject is free of Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. In some cases, in any of the methods, uses, or compositions for use described herein, the subject does not have a sensitizing EGFR gene mutation or ALK gene rearrangement. In some cases, the Eastern Cooperative Oncology Group (ECOG) physical ability status (PS) of the subject is 0 or 1.

Methods for detecting the mutant states EGFR and ALK are well known in the art and include, but are not limited to, sequencing DNA from clinical samples, e.g., tumor biopsy samples or blood samples (e.g., circulating tumor DNA in blood), using next generation sequencing methods such as the targeted gene pulldown (gene pulldown) and sequencing methods described by Frampton et al (Nature biotechnology.31 (11): 1023-1033 (2013), which is incorporated herein by reference in its entirety). Such next generation sequencing methods can be used in conjunction with any of the methods disclosed herein to detect various mutations (e.g., insertions, deletions, base substitutions, focal gene amplifications, and/or homozygous gene deletions) while enabling the use of small samples (e.g., from small core needle biopsies) Fine needle aspiration and/or cell block) or fixed samples (e.g., formalin-fixed and paraffin-embedded (FFPE) samples). Other methods of detecting the status of EGFR and ALK mutations include Fluorescence In Situ Hybridization (FISH) and Immunohistochemistry (IHC) methods. An exemplary method for detecting the status of ALK mutations is disclosed in U.S. patent No. 9,651,555, which is incorporated herein by reference in its entirety. In some cases, it is possible to use,

an anti-ALK (D5F 3) IHC assay is used to determine the mutational 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 well known in the art and are included in U.S. patent publication nos.: those described in US 2018/0235968 and Juan et al (Therapeutic Advances in Medical Oncology.9 (3): 201-216, 2017), which are incorporated herein by reference in their entirety. In some cases, the sensitizing EGFR mutation is a mutation in any one of exons 18 to 21 (e.g., a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some cases, the sensitizing EGFR mutation is a deletion of exon 19 (del 19). In other cases, the sensitizing EGFR mutation is an L858R point mutation in exon 21. In some cases, the sensitizing EGFR mutation is a G719X point mutation in exon 18, where "X" is most commonly C, a or S. In some cases, the sensitizing EGFR mutation is a G719S point mutation in 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 a T790M point mutation. In some cases, the sensitizing EGFR mutation is an E709X point mutation, where "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 well known in the art and include those described in U.S. Pat. Nos. 9,651,555 and Du et al (Thorac cancer.9:423-430, 2018), which are incorporated herein by reference in their entirety. In some cases, ALK gene rearrangement results in the production of oncogenic ALK tyrosine kinases, which activate downstream signaling pathways leading to increased cell proliferation and survival. In some cases, the ALK gene rearranges to an ALK rearrangement with 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 that results in the formation of a fused oncogene. In some cases, the ALK gene rearranges to an EML4 rearrangement with ALK, which leads to the formation of the fusion oncogene EML4-ALK.

In some cases, in any of the methods, uses, or compositions for use described herein, the subject does not have a lung lymphoepitheliomatous subtype of NSCLC. Methods for detecting subtypes of NSCLC are well known in the art and include, but are not limited to, methods determined by histopathological criteria or by molecular characteristics, e.g., a subtype characterized by the expression of one biomarker or a combination of biomarkers (e.g., a particular gene or protein encoded by the gene). 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 any of the methods of use, uses, or compositions for use described herein, the subject is free of active epstein-barr virus (EBV) infection or a known or suspected chronic active EBV infection. Indicators of active or chronic active EBV infection for use in the methods described herein can include, but are not limited to, EBV IgM, EBV IgG, epstein-barr nuclear antigen (EBNA), and epstein-barr virus particles detected in a sample (e.g., a blood or serum sample) from a subject. Methods for detecting one or more indicators of the presence or absence of active or chronic active EBV infection in a sample from a subject, including EBV IgM, EBV IgG, epstein-barr nuclear antigen (EBNA), and epstein-barr virus particles, are well known in the art, and include, but are not limited to, methods involving serodiagnosis (e.g., detecting EBV DNA (e.g., by PCR analysis of a blood sample to detect EBV virus particles) or EBV antigen or anti-EBV antibodies (e.g., detecting EBNA, EBV IgM, or EBV IgG using heterophilic antibodies)). 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 negative for detection by EBV PCR. In some cases, the subject is negative for EBV IgM and/or negative for EBV PCR detection, and positive for EBV IgG and/or positive for epstein-barr virus 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 (e.g., a tumor PD-L1 expression with a minimum PD-L1 positive tumor cell fraction or TPS ≧ 30% (e.g., ≧ 50%) as determined by IHC using the SP263 or 22C3 antibody, or a tumor area proportion occupied by PD-L1-expressing tumor-infiltrating Immune Cells (IC) in the tumor sample is greater than or equal to 1% as determined by IHC using the SP142 antibody). In some cases, a PD-L1-selected tumor is a tumor that has a PD-L1 positive tumor cell fraction of greater than or equal to 30% (e.g., greater than or equal to 50%) or PD-L1 TPS as determined by an Immunohistochemistry (IHC) assay. In some cases, the PD-L1-selected tumor is a tumor in which the proportion of tumor area occupied by Immune Cells (IC) expressing PD-L1 is greater than or equal to 1%, as determined by an Immunohistochemistry (IHC) assay. In some cases, the IHC assay uses the anti-PD-L1 antibody 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 the anti-PD-L1 antibody 22C3. In some cases, the tumor sample has been determined to have greater than or equal to 50% TPS. In some cases, the PD-L1-positive tumor cell fraction is greater than or equal to 50% (e.g., as determined by positive staining with anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), as determined by positive staining with anti-PD-L1 antibody 22C3 (e.g., using the pharmDx assay), or by positive staining with anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is greater than or equal to 30%, as determined by positive staining with anti-PD-L1 antibody SP142. In some cases, the IC has been determined to be greater than or equal to 1% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 5% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 10% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 1% and less than 50% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 1% and less than 30% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay).

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1. In some cases, a detectable protein expression level of PD-L1 has been determined by an IHC assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% and less than 5% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% and less than 50% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 50% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% of tumor-infiltrating immune cells of the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% and less than 5% of tumor-infiltrating immune cells of the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 5% and less than 10% of the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 10% of the tumor sample.

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable level of nucleic acid expression of PD-L1. In some cases, a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-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 infiltrating tumor 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 the therapy can be characterized by one or more measurements. In some embodiments, the treatment results in CR or PR. In some embodiments, treatment results in an increase in PFS or DOR.

In some cases, the treatment results in an increase in PFS in the subject, 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. For example, in embodiments in which a chemotherapeutic agent is not administered (e.g., administration of only an anti-TIGIT antagonist antibody (e.g., ibritumomab tiuxetan) in combination with a PD-1 axis binding antagonist (e.g., atelizumab)), the treatment can result in an increase in PFS in the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody, or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In embodiments in which the anti-TIGIT antagonist antibody (e.g., ibrinoiturin) and PD-1 axis binding antagonist (e.g., atelizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))), the treatment can result in an increase in PFS in the subject, e.g., (i) as compared to treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) Compared to treatment with an anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents without a PD-1 axis binding antagonist; and/or (iii) compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without the one or more chemotherapeutic agents.

In some cases, the treatment extends OS in the subject, 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. For example, in embodiments in which a chemotherapeutic agent is not administered (e.g., administration of only an anti-TIGIT antagonist antibody (e.g., ibritumomab tiuxetan) in combination with a PD-1 axis binding antagonist (e.g., atelizumab)), the treatment can result in an increase in OS in the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody, or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In embodiments in which the anti-TIGIT antagonist antibody (e.g., ibrinoitumomab) and the PD-1 axis binding antagonist (e.g., atelizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed, gemcitabine, or capecitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))), the treatment can result in an increase in OS in the subject, e.g., (i) as compared to treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) Compared to treatment with an anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents without a PD-1 axis binding antagonist; and/or (iii) compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without the one or more chemotherapeutic agents.

Progression-free survival of subjects can be measured according to RECIST v1.1 criteria, such as Eisenhauer et al, eur.j. Cancer.2009, 45: 228-47. In some embodiments, PFS is measured as the time period from the start of treatment to the first appearance of disease progression, as determined by RECIST v1.1 criteria. In some embodiments, PFS is measured as the time from the start of treatment to death.

In some embodiments, the treatment described herein extends PFS in a subject by at least about 2.4 months (e.g., 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 to 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., extending for 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 extends PFS in the subject 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, e.g., extending for 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, 33 months, 35 months, or 36 months). In some embodiments, the treatment extends PFS in the subject 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, e.g., extending for 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, 2 months, 2.3 months, 5.4 months, 5.5 months, 5.6 months, a 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 described herein extends the DOR of the subject by at least about 2.4 months (e.g., 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 to 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., extending for 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 extends DOR in the subject for at least about 4 months (e.g., 4 to 120 months, 5 to 100 months, 6 to 80 months, 7 to 60 months, 8 to 48 months, 9 to 36 months, or 10 to 24 months, e.g., extending for 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, 33 months, 35 months, or 36 months). In some embodiments, the treatment extends the DOR of the subject 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, e.g., extending for 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, 2 months, 2.3 months, 5.4 months, 5.5 months, 5.6 months, a 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 of time from the start of treatment to death. In some cases, the treatment extends OS of the subject 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 to 24 months, e.g., extending for 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, the treatment extends OS of the subject 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, e.g., a prolongation of 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, a 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 extends OS of the subject 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, e.g., 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, 34 months, 35 months, or 36 months).

B. Therapeutic methods and uses related to lung cancer

Lung cancer remains the leading cause of cancer death worldwide. It is the most common cancer in men and women in the united states, accounting for 12% -14% of all new cancer cases. In 2020, it is estimated that there will be 228,820 new cases of lung Cancer, resulting in 135,720 deaths (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 major histological types: adenocarcinoma and squamous cell carcinoma (Travis et al 2011). Adenocarcinoma histology accounts for approximately 40% -50% of all NSCLCs, while squamous cell histology accounts for approximately 20% -30% of NSCLCs (Osmani et al Semin Cancer biol.52 (Pt 1): 103-9 (2018)). The remaining NSCLC cases are represented by large cell carcinoma, neuroendocrine tumor, sarcomatoid carcinoma, and have poorly differentiated histology.

In its early stages, NSCLC is treated surgically for the purpose of healing. However, 30-70% of patients who undergo resection relapse and die as the disease progresses (Siegel et al Cancer staticistics. CA Cancer J Clin.70:7-30 (2020)). Thus, there is a high unmet need for improved medical intervention in early stage NSCLC.

For advanced disease, the overall five-year survival rate is 2% -4%. Poor prognostic factors for survival in NSCLC patients include advanced disease at first diagnosis, poor condition and a history of inadvertent weight loss. More than half of NSCLC patients are diagnosed with distant disease, which directly leads to poor survival prospects.

Despite improvements in first-line treatment of patients with advanced NSCLC, resulting in longer survival and reduced disease-related symptoms, almost all patients experience disease progression. In particular cancer immunotherapy offers the possibility of long-term disease control. In a metastatic NSCLC environment, PD-L1/PD-1 blocking antibodies (e.g., atuzumab, nivolumab, and paribizumab) provide clinically significant benefit to unselected or PD-L1-selected advanced NSCLC patients; however, a significant proportion of patients still do not respond or progress during anti-PD-L1/PD-1 therapy, and the escape mechanisms of this therapy are poorly understood.

Thus, there is an unmet need in the art for the development of effective immunotherapies and methods of using them for the treatment of lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC))) that achieve more favorable benefit-risk profiles (e.g., first line treatment).

Small cell lung cancer

Small Cell Lung Cancer (SCLC) accounts for approximately 15% of all lung cancer cases. Most (about 70%) of patients with SCLC are diagnosed with widespread disease (ES-SCLC), with poor survival prospects (median OS of about 10 to 12 months). While chemotherapy alone can alleviate symptoms and prolong survival in patients with ES-SCLC, long survival is rare. The five-year relative survival rate for stage I SCLC patients is approximately 31%. In stage IV, the five-year relative survival rate drops to approximately 2%.

Accordingly, there is a need in the art for improved treatments for lung cancer (e.g., SCLC, e.g., ES-SCLC).

i. Methods and uses for treating lung cancer

Provided herein are methods of treating a population of subjects having lung cancer, the methods comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles 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 population of subjects of at least about 6 months (e.g., between 6 months and 24 months (e.g., between about 6 months and 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)), e.g., between about 6 months and about 13 months (e.g., 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)), for example, between about 8 months to about 10 months (e.g., 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)).

Also provided herein are methods of treating a population of subjects having lung cancer, the methods comprising administering to the population of subjects a dosing regimen comprising 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 for one or more dosing cycles, wherein the treatment results in a median OS for the population of subjects of at least about 12 months (e.g., between about 12 months and about 40 months (e.g., between about 12 months and about 30 months (e.g., 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)), e.g., between about 12 months and about 20 months (e.g., 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, or 20 months)).

Methods and uses for treating small cell lung cancer

Provided herein are methods and uses for treating lung cancer (e.g., small Cell Lung Cancer (SCLC), e.g., extensive-stage SCLC (ES-SCLC)) in a subject or population of subjects, comprising administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumumab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) for one or more dosing cycles.

Dosing regimens, administration, and response to treatment

Therapeutic methods and uses of the invention described herein include, in one aspect, administering to a subject or population of subjects having lung cancer (e.g., SCLC, e.g., ES-SCLC) an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., astuzumab)), a platinum chemotherapeutic agent, and a topoisomerase II inhibitor, wherein the treatment extends Progression Free Survival (PFS) of the subject or population of subjects as compared to treatment with the PD-1 axis binding antagonist, the platinum chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody, thereby treating the subject or population of subjects. In some cases, the treatment extends OS in 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 without an anti-TIGIT antagonist antibody.

In some embodiments, the PFS of an individual is measured according to RECIST v1.1 criteria, such as Eisenhauer et al, eur.j.cancer.2009, 45: 228-47. In some embodiments, PFS is measured as the time period from the start of treatment to the first appearance of disease progression, as determined by RECIST v1.1 criteria. In some embodiments, PFS is measured as the time from the start of treatment to death.

In some embodiments, the treatment extends PFS in the subject or population of subjects by at least about 2.4 months (e.g., 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 to 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., extending for 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 extends PFS of the subject or population of subjects 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, e.g., by at least about 4.0 months, by 4.1 months, by 4.2 months, by 4.3 months, by 4.4 months, by 4.5 months, by 4.6 months, by 4.7 months, by 4.8 months, by 4.9 months, by 5.0 months, by 5.5 months, by 6.0 months, by 6.5 months, by 7.0 months, by 7.5 months, by 8.0 months, by 8.5 months, by 9.0 months, by 9.5 months, by 10 months, by 10.5 months, by 11.5 months, by 12 months, by 13 months, by 7.0 months, by 7.5 months, by 8.0 months, by 8.5 months, by 9.0 months, by 9.5 months, by 10 months, 10.5 months, by 11 months, 12 months, by 13 months, by 16 months, by 23 months, or by 35 months), as compared to a treatment with an anti-TIGIT antagonist antibody. In some embodiments, the treatment extends PFS in the subject or population of subjects 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, e.g., extending for 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 aspects, the treatment extends PFS in the 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 without an anti-TIGIT antagonist antibody.

In some cases, methods and uses of treating a subject or population of subjects having lung cancer (e.g., SCLC, e.g., ES-SCLC) comprise administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as altuzumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide), wherein the treatment prolongs 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.

In some embodiments, OS is measured as the period of time from the start of treatment to death. <xnotran> , PD-1 , II TIGIT , OS 2 (, 2 120 , 3 110 , 4 100 , 5 80 , 6 60 , 7 48 , 8 36 10 24 , , 2 , 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 , 3.0 , 3.1 , 3.2 , 3.3 , 3.4 , 3.5 , 3.6 , 3.7 , 3.8 , 3.9 , 4.0 , 4.1 , 4.2 , 4.3 , 4.4 , 4.5 , 4.6 , 4.7 , 4.8 , 4.9 , 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 , 9.5 , 10 , 10.5 , 11 , 11.5 , 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 ). </xnotran> In some cases, the treatment extends OS of the subject or population of subjects 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, e.g., extending for 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, 35 months, 36 months, or 36 months). In some cases, the treatment extends OS of the subject or population of subjects 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, e.g., 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, 33 months, or 36 months) 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.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose (e.g., a fixed dose) between about 30mg to about 1200mg (e.g., between about 30mg to about 1100mg, e.g., between about 60mg to about 1000mg, e.g., between about 100mg to about 900mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 800mg, e.g., between about 400mg to about 750mg, e.g., between about 450mg to about 750mg, e.g., between about 500mg to about 700mg, e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose (e.g., a fixed dose) of between about 30mg to about 600mg (e.g., between about 50mg to about 600mg, e.g., between about 60mg to about 600mg, e.g., between about 100mg to about 600mg, e.g., between about 200mg to about 550mg, e.g., between about 250mg to about 500mg, e.g., between about 300mg to about 450mg, e.g., between about 350mg to about 400mg, e.g., about 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of about 600mg every three weeks.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of between 30mg to 1200mg (e.g., between 30mg to 1100mg, e.g., between 60mg to 1000mg, e.g., between 100mg to 900mg, e.g., between 200mg to 800mg, e.g., between 300mg to 800mg, e.g., between 400mg to 750mg, e.g., between 450mg to 750mg, e.g., between 500mg to 700mg, e.g., between 550mg to 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose (e.g., a fixed dose) of between 30mg and 600mg (e.g., between 50mg and 600mg, e.g., between 60mg and 600mg, e.g., between 100mg and 600mg, e.g., between 200mg and 550mg, e.g., between 250mg and 500mg, e.g., between 300mg and 450mg, e.g., between 350mg and 400mg, e.g., 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of 600mg every three weeks.

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

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 80mg to about 2000mg (e.g., between about 100mg to about 1600mg, e.g., between about 200mg to about 1600mg, e.g., between about 300mg to about 1600mg, e.g., between about 400mg to about 1600mg, e.g., between about 500mg to about 1600mg, e.g., between about 600mg to about 1600mg, e.g., between about 700mg to about 1600mg, e.g., between about 800mg to about 1600mg, e.g., between about 900mg to about 1500mg, e.g., between about 1000mg to about 1400mg, e.g., between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg, e.g., between about 0mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., 1200mg, e.g., between about 1210mg to about 1200mg, e.g., 1200mg, such as a fixed dose of ± 0.g., 1200mg, such as about 1210mg, e.g., 0mg, such as ± 0.g., 1200mg, 0mg, such as ± 0mg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose (e.g., a fixed dose) of about 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose (e.g., a fixed dose) of about 1200mg every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between 80mg and 2000mg (e.g., between 100mg and 1600mg, e.g., between 200mg and 1600mg, e.g., between 300mg and 1600mg, e.g., between 400mg and 1600mg, e.g., between 500mg and 1600mg, e.g., between 600mg and 1600mg, e.g., between 700mg and 1600mg, e.g., between 800mg and 1600mg, e.g., between 900mg and 1500mg, e.g., between 1000mg and 1400mg, e.g., between 1050mg and 1350mg, e.g., between 1100mg and 1300mg, e.g., between 1150mg and 1250mg, e.g., between 1175mg and 1225mg, e.g., between 1190mg and 1210mg, e.g., 1200mg ± 5mg, e.g., 1200mg ± 2.5mg, e.g., 1200mg, e.g., 1200.g., 1200mg, 0.g., 1200mg, e.g., 1200mg, a fixed dose(s). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose (e.g., a fixed dose) of 840mg every two weeks.

In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose (e.g., a fixed dose) of about 1400mg to 2000mg every four weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose (e.g., a fixed dose) of 1400mg to 2000mg every four weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose (e.g., a fixed dose) of about 1680mg every four weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1680mg every four weeks (e.g., a fixed dose). In some cases, the dose (e.g., fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., ibrinoitumomab tiuxetan), a topoisomerase II inhibitor (e.g., etoposide), and/or a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)) can be reduced compared to a standard dose of the PD-1 axis binding antagonist administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between about 0.01mg/kg to about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., not between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, or about 15 ± 0.1mg/kg, e.g., about 15 mg/kg) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 0.01mg/kg to about 15mg/kg of the subject's body weight (e.g., between about 0.1mg/kg to about 15mg/kg, e.g., between about 0.5mg/kg to about 15mg/kg, e.g., not between about 1mg/kg to about 15mg/kg, e.g., between about 2.5mg/kg to about 15 mg/kg) every three weeks, e.g., between about 5mg/kg and about 15mg/kg, e.g., between about 7.5mg/kg and about 15mg/kg, e.g., between about 10mg/kg and about 15mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., between about 14mg/kg and about 15mg/kg, e.g., about 15 + -1 mg/kg, e.g., about 15 + -0.5 mg/kg, e.g., about 15 + -0.2 mg/kg, e.g., about 15 + -0.1 mg/kg, e.g., about 15 mg/kg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 15mg/kg administered every three weeks.

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

In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., ibrinoitumomab tiuxetan), a topoisomerase II inhibitor (e.g., etoposide), and/or a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin)) can be reduced compared to a standard dose of the PD-1 axis binding antagonist administered as a monotherapy.

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

AUC can be calculated using Calvert formula (Calvert et al, j. Clin. Oncol.1989,7:

total dose (mg) = (target AUC) x (glomerular filtration rate [ GFR ] + 25)

In some cases, for example, 1200mg of alemtuzumab is equivalent to a dose of 15m/kg based on average body weight.

In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is 200mg to 1500mg (e.g., 300mg to 1200mg, 400mg to 1100mg, or 500mg to 1000mg, e.g., 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to 750mg, 750mg to 800mg, 800mg to 900mg, 900mg to 1000mg, 1000mg to 1100mg, or 1100mg to 1200mg, e.g., about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, or about 1500 mg). In some cases, the effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is about 500mg to 1000mg (e.g., about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, or about 1000 mg).

In some cases, an effective amount of a topoisomerase II inhibitor (e.g., etoposide) is 10 to 1000mg/m ² (e.g., 20 to 800 mg/m) ² 30 to 700mg/m ² 40 to 500mg/m ² 50 to 300mg/m ² 75 to 200mg/m ² Or 80 to 150mg/m ² For example, about 20mg/m ² About 30mg/m ² About 40mg/m ² About 50mg/m ² About 60mg/m ² About 70mg/m ² About 80mg/m ² About 90mg/m ² About 100mg/m ² About 110mg/m ² About 120mg/m ² About 130mg/m ² About 140mg/m ² About 150mg/m ² About 160mg/m ² About 170mg/m ² About 180mg/m ² About 190mg/m ² About 200mg/m ² About 250mg/m ² About 300mg/m ² About 400mg/m ² About 500mg/m ² About 600mg/m ² About 700mg/m ² About 800mg/m ² About 900mg/m ² Or about 1000mg/m ² ). In some cases, topoisomerase II inhibitors (e.g.,etoposide) is about 100mg/m ² 。

In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is 200mg to 1500mg (e.g., 300mg to 1200mg, 400mg to 1100mg, or 500mg to 1000mg, e.g., 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to 750mg, 750mg to 800mg, 800mg to 900mg, 900mg to 1000mg, 1000mg to 1100mg, or 1100mg to 1200mg, e.g., 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, or 1500 mg). In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is 500mg to 1000mg (e.g., 500mg, 600mg, 700mg, 800mg, 900mg, or 1000 mg).

In some cases, an effective amount of a topoisomerase II inhibitor (e.g., etoposide) is 10 to 1000mg/m ² (e.g., 20 to 800 mg/m) ² 30 to 700mg/m ² 40 to 500mg/m ² 50 to 300mg/m ² 75 to 200mg/m ² Or 80 to 150mg/m ² For example, 20mg/m ² 、30mg/m ² 、40mg/m ² 、50mg/m ² 、60mg/m ² 、70mg/m ² 、80mg/m ² 、90mg/m ² 、100mg/m ² 、110mg/m ² 、120mg/m ² 、130mg/m ² 、140mg/m ² 、150mg/m ² 、160mg/m ² 、170mg/m ² 、180mg/m ² 、190mg/m ² 、200mg/m ² 、250mg/m ² 、300mg/m ² 、400mg/m ² 、500mg/m ² 、600mg/m ² 、700mg/m ² 、800mg/m ² 、900mg/m ² Or 1000mg/m ² ). In some cases, an effective amount of a topoisomerase II inhibitor (e.g., etoposide) is 100mg/m ² 。

In any of the methods and uses of the invention, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide)) can be 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 dosing cycle of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) (with or without a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a topoisomerase II inhibitor (e.g., etoposide)) continues until clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity) is lost. In some cases, each administration cycle is about 18 to 24 days in length (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days). In some cases, each administration cycle is about 21 days in length. In other cases, each administration cycle is about 14 days in length. In other cases, each administration cycle is about 28 days in length.

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered at about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose (e.g., a fixed dose) of about 600mg (i.e., at a dose of about 600mg every three weeks) on day 1 of each dosing cycle, e.g., each 21-day cycle. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of 600mg (e.g., a fixed dose) (i.e., at a dose of 600mg every three weeks) on day 1 of each dosing cycle, e.g., every 21 day cycle. Similarly, in some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atetrazulene)Anti)) is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, in some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is administered intravenously at a dose of about 1200mg (i.e., at a dose of about 1200mg every three weeks) on day 1 of each 21-day cycle. In other cases, for example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks). In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered intravenously at a dose of 1200mg (i.e., at a dose of 1200mg every three weeks) on day 1 of each 21-day cycle. In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) are administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. In some cases, the platinum-based chemotherapeutic agent is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. In some cases, the topoisomerase II inhibitor is administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, in some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 600mg on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) is administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered at a dose to achieve AUC =5mg/ml/min on day 1 of each of four initial dosing cycles, and a topoisomerase II inhibitor (e.g., etoposide) is administered at 100mg/m on days 1, 2, and 3 of each of the four initial dosing cycles ² The dosage of (a). In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist as disclosed herein)The anti-agent antibody, e.g., tirayleigh itumumab), is administered intravenously at a dose of 600mg on day 1 of each 21-day cycle (i.e., at a dose of 600mg per three-week) and the PD-1 axis binding antagonist, e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab), is administered intravenously at a dose of 1200mg on day 1 of each 21-day cycle (i.e., at a dose of 1200mg per three-week), the platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered at a dose of achieving =5mg/ml/min on day 1 of each of the four initial dosing cycles, and the topoisomerase II inhibitor (e.g., etoposide) is administered at a dose of 100mg/m AUC = on days 1, 2, and 3 of each of the four initial dosing cycles ² Is administered.

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

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 30mg to about 1200mg on day 1 of each of the one or more additional dosing cycles (e.g., at a dose of about 30mg to about 600mg on day 1 of each of the one or more additional dosing cycles). In some cases, the anti-TIGIT antagonist antibody is administered at a dose of about 600mg on day 1 of each of the one or more additional dosing cycles. In some cases, the PD-1 axis binding antagonist is administered at a dose of about 80mg to about 2000mg on day 1 of each of the one or more additional dosing cycles (e.g., at a dose of about 840mg, 1200mg, or 1680mg on day 1 of each of the one or more additional dosing cycles). In some cases, the additional dosing cycle comprises administering a PD-1 axis binding antagonist (e.g., atlizumab) at a dose of about 840mg every two weeks, about 1200mg every three weeks, or about 1680mg every four weeks. For example, in some cases, each of the one or more dosing cycles is about 14 days, and the PD-1 axis binding antagonist (e.g., atelizumab) is administered at a dose of about 840mg on day 1 of each of the one or more additional dosing cycles. In some cases, each of the one or more dosing cycles is about 21 days, and the PD-1 axis binding antagonist (e.g., atelizumab) is administered at a dose of about 1200mg on day 1 of each of the one or more additional dosing cycles. In some cases, each of the one or more dosing cycles is about 28 days, and the PD-1 axis binding antagonist (e.g., atlizumab) is administered at a dose of about 1680mg on day 1 of each of the one or more additional dosing cycles.

In some cases, the anti-TIGIT antagonist antibody is administered at a dose of 30-1200 mg on day 1 of each of the one or more additional dosing cycles (e.g., at a dose of 30-600 mg on day 1 of each of the one or more additional dosing cycles). In some cases, the anti-TIGIT antagonist antibody is administered at a dose of 600mg on day 1 of each of the one or more additional dosing cycles. In some cases, the PD-1 axis binding antagonist is administered at a dose of 80mg to 2000mg on day 1 of each of the one or more additional dosing cycles (e.g., at a dose of 840mg, 1200mg, or 1680mg on day 1 of each of the one or more additional dosing cycles). In some cases, the additional dosing cycle comprises administering a PD-1 axis binding antagonist (e.g., atlizumab) at a dose of 840mg every two weeks, 1200mg every three weeks, or 1680mg every four weeks. For example, in some cases, each of the one or more dosing cycles is 14 days, and the PD-1 axis binding antagonist (e.g., atlizumab) is administered at a dose of 840mg on day 1 of each of the one or more additional dosing cycles. In some cases, each of the one or more dosing cycles is 21 days, and the PD-1 axis binding antagonist (e.g., atelizumab) is administered at a dose of 1200mg on day 1 of each of the one or more additional dosing cycles. In some cases, each of the one or more dosing cycles is 28 days, and the PD-1 axis binding antagonist (e.g., atelizumab) is administered at a dose of 1680mg on day 1 of each of the one or more additional dosing cycles.

In some cases, by administering to a patient suffering from lung cancer (e.g., SCLC, for exampleE.g., ES-SCLC) is administered for one or more dosing cycles (e.g., a 21 day dosing cycle) of the following: anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., rayleigh antagonist antibody as TIGIT replacement) at a dose of about 30mg to about 1200mg (e.g., between about 30mg to about 1100mg, e.g., between about 60mg to about 1000mg, e.g., between about 100mg to about 900mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 800mg, e.g., between about 400mg to about 750mg, e.g., between about 500mg to about 700mg, e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.g., 600 mg) on day 1 of each dosing cycle, between about 80mg to about 100mg, e.g., about 1600mg, between about 200mg to about 1600mg, e.g., between about 300mg to about 1600mg, e.g., between about 400mg to about 1600mg, e.g., between about 500mg to about 1600mg, e.g., between about 600mg to about 1600mg, e.g., between about 700mg to about 1600mg, e.g., between about 800mg to about 1600mg, e.g., between about 900mg to about 1500mg, e.g., between about 1000mg to about 1400mg, e.g., between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg, e.g., between about 0mg to about 1210mg, e.g., 1200mg ± 5mg, e.g., 1200 ± 2.5mg, e.g., 1200 ± 1.0mg, e.g., 1200 ± 0.5mg, e.g., 1200mg ± 5mg, e.g., 1200 mg) of the PD-1 axis antagonist (e.g., anti-PD-1 e.g., anti-attritrin (e.g., anti-1) antibody) is administered (e.g., on a day) of about 1-day, between 30mg and 1100mg, e.g. between 60mg and 1000mg, e.g. between 100mg and 900mg, e.g. between 200mg and 800mg, e.g. between 300mg and 800mg, e.g. between 400mg and 750mg, e.g. between 450mg and 750mg E.g. between 500mg and 700mg, e.g. between 550mg and 650mg, e.g. 600mg ± 10mg, e.g. 600 ± 6mg, e.g. 600 ± 5mg, e.g. 600 ± 3mg, e.g. 600 ± 1mg, e.g. 600 ± 0.5mg, e.g. 600 mg), dose 80mg to 2000mg (e.g. between 100mg and 1600mg, e.g. between 200mg and 1600mg, e.g. between 300mg and 1600mg, e.g. between 400mg and 1600mg, e.g. between 500mg and 1600mg, e.g. between 600mg and 1600mg, e.g. between 700mg and 1600mg, e.g. between 800mg and 1600mg, e.g. between 900mg and 1500mg, e.g. between 1000mg and 1400mg, e.g. between 1050mg and 1350mg, e.g. between 1100mg and 1300mg, e.g., between 1150mg to 1250mg, e.g., between 1175mg to 1225mg, e.g., between 1190mg to 1210mg, e.g., 1200mg ± 5mg, e.g., 1200 ± 2.5mg, e.g., 1200 ± 1.0mg, e.g., 1200 ± 0.5mg, e.g., 1200 mg) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab))), sufficient to achieve a dose of 1 to 50mg/ml/min (e.g., 2 to 25mg/ml/min, 3 to 15mg/ml/min, 4 to 10mg/ml/min, or 5mg/ml/min, e.g., 2mg/ml/min, 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/min, 7mg/ml/min, 8mg/ml/min, 9mg/ml/min, 10mg/ml/min, 11mg/ml/min, 12mg/ml/min, on day 1 of each administration cycle, A dose of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) at an AUC of 13mg/ml/min, 14mg/ml/min, 15mg/ml/min, 20mg/ml/min, 25mg/ml/min, 30mg/ml/min, 35mg/ml/min, 40mg/ml/min, 45mg/ml/min, 50mg/ml/min, e.g., 5 mg/ml/min), and 100mg/m on each of days 1, 2, and 3 of each dosing cycle ² The dose of topoisomerase II inhibitor of (e.g., etoposide), wherein the treatment prolongs PFS and/or OS in the subject or population of subjects as compared to treatment with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) without an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleighumab).

In some cases, a subject or population of subjects having lung cancer (e.g., SCLC, e.g., ES-SCLC) is treated by administering to the subject or population of subjects one or more dosing cycles (e.g., 21 day dosing cycle) of: an anti-it tig antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., teneuibizumab) at a dose of 30mg to 1200mg (e.g., between 30mg to 1100mg, e.g., between 60mg to 1000mg, e.g., between 100mg to 900mg, e.g., between 200mg to 800mg, e.g., between 300mg to 800mg, e.g., between 400mg to 750mg, e.g., between 450mg to 750mg, e.g., between 500mg to 700mg, e.g., between 550mg to 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg), 80mg to 2000mg (e.g., between 100mg to 1600mg, e.g., 1600mg, between 300mg and 1600mg, e.g. between 400mg and 1600mg, e.g. between 500mg and 1600mg, e.g. between 600mg and 1600mg, e.g. between 700mg and 1600mg, e.g. between 800mg and 1600mg, e.g. between 900mg and 1500mg, e.g. between 1000mg and 1400mg, e.g. between 1050mg and 1350mg, e.g. between 1100mg and 1300mg, e.g. between 1150mg and 1250mg, e.g. between 1175mg and 1225mg, e.g. between 1190mg and 1210mg, e.g. 1200mg ± 5mg, e.g. 1200 ± 2.5mg, e.g. 1200 ± 1.0mg, e.g. 1200 ± 0.5mg, e.g. 1200 mg), a PD-1 axis binding antagonist (e.g. an anti-PD-L1 antagonist antibody (e.g. attritol), sufficient to achieve a dose of 1 to 50 mg/min (e.g. 2 mg/25 mg/min to 15 mg/15 ml/15 mg/min, e.g. 2 mg/min/15 mg/1 mg/min) on day of each administration cycle, 4 to 10mg/ml/min, or 5mg/ml/min, e.g., 2mg/ml/min, 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/min, 7mg/ml/min, 8mg/ml/min, 9mg/ml/min, 10mg/ml/min, 11mg/ml/min, 12mg/ml/min, 13mg/ml/min, 14mg/ml/min, 15mg/ml/min, 20mg/ml/min, 25mg/ml/min, 30mg/ml/min, 35mg/ml/min, 40 mg/ml/min AUC of 45mg/ml/min, 50mg/ml/min, e.g., 5 mg/ml/min) and 100mg/m on each of days 1, 2 and 3 of each dosing cycle ² The dose of topoisomerase II inhibitor of (e.g., etoposide), wherein the treatment prolongs PFS and/or OS in the subject or population of subjects compared to treatment with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) without an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan).

In some cases, the treatment extends OS of the subject or population of subjects 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, e.g., extending for 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, 35 months, 36 months, or 36 months). In some cases, the treatment extends OS of the subject or population of subjects 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, e.g., 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, 33 months, or 36 months) 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.

In some embodiments, the treatment extends PFS of the subject or population of subjects by at least about 2.4 months (e.g., 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 to 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., a prolongation of 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 extends PFS of the subject or population of subjects 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, e.g., by at least about 4.0 months, by 4.1 months, by 4.2 months, by 4.3 months, by 4.4 months, by 4.5 months, by 4.6 months, by 4.7 months, by 4.8 months, by 4.9 months, by 5.0 months, by 5.5 months, by 6.0 months, by 6.5 months, by 7.0 months, by 7.5 months, by 8.0 months, by 8.5 months, by 9.0 months, by 9.5 months, by 10 months, by 10.5 months, by 11.5 months, by 12 months, by 13 months, by 7.0 months, by 7.5 months, by 8.0 months, by 8.5 months, by 9.0 months, by 9.5 months, by 10 months, 10.5 months, by 11 months, 12 months, by 13 months, by 16 months, by 23 months, or by 35 months), as compared to a treatment with an anti-TIGIT antagonist antibody.

In some embodiments, the subject or population of subjects receives one or more additional dosing cycles (e.g., a 21 day dosing cycle) of: a dose of anti-TIGIT antagonist antibody of about 30mg to about 1200mg on day 1 of each additional dosing cycle and a dose of atelizumab of about 80mg to about 2000mg on day 1 of each additional dosing cycle, wherein carboplatin and etoposide are omitted from each additional dosing cycle of the one or more additional dosing cycles.

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to a subject or population of subjects by intravenous infusion over about 60 ± 15 minutes (e.g., 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, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) is administered to a subject or population of subjects by intravenous infusion over 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).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to the subject or population of subjects prior to the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atelizumab)). In some cases, for example, after administration of an anti-TIGIT antagonist antibody and before administration of a PD-1 axis binding antagonist, the method comprises an intermediate first observation period. In some cases, the method further comprises a second observation period after administration of the PD-1 axis binding antagonist. In some cases, the method includes both a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after 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. Where the first observation period and the second observation period are each about 60 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject during the first and second observation periods about 30 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, respectively. Where the first observation period and the second observation period are each about 30 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject for about 15 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, respectively, during the first and second observation periods.

In other instances, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atelizumab)) is administered to the subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibriturin itumumab). In some cases, for example, after administration of the PD-1 axis binding antagonist and before administration of the anti-TIGIT antagonist antibody, the method comprises an intermediate first observation period. In some cases, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some cases, the method comprises a first observation period after administration of the PD-1 axis binding antagonist and a second observation period after 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. Where the first observation period and the second observation period are each about 60 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody, respectively, over the first and second observation periods. Where the first observation period and the second observation period are each about 30 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject over the first and second observation periods about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody, respectively.

In other instances, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 (atelizumab) antagonist antibody) are administered simultaneously to the 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 (e.g., the anti-PD-L1 antagonist antibody), the method comprises an observation period. In some cases, the length of the observation period is between about 30 minutes and about 60 minutes. Where the observation period is about 60 minutes in length, the method can include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) and anti-TIGIT antagonist antibody over the observation period. Where the observation period is about 30 minutes in length, the method can include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15 ± 10 minutes after administering the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody over the observation period.

Herein, the textIn any of the methods, uses, or compositions for use described, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., alemtuzumab)), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide)) or a drug thereof can be combined with one or more additional anti-cancer therapeutic agents (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above).

In some cases, the lung cancer is Small Cell Lung Cancer (SCLC), e.g., extensive SCLC (ES-SCLC). In some cases, the subject or population of subjects is treatment naive to ES-SCLC (e.g., chemotherapy naive to ES-SCLC).

In some cases, lung cancer is not selected for PD-L1 expression. In other cases, lung cancer is selected for PD-L1 expression pair. In some cases, lung cancer is selected for PD-L1 expression by an Immunohistochemistry (IHC) assay that includes staining with an anti-PD-L1 antibody such as SP263, 22C3, SP142, or 28-8. In some cases, the anti-PD-L1 antibody is SP263 and the IHC assay is a Ventana SP263 IHC assay; the anti-PD-L1 antibody is 22C3 and the IHC assay is the pharmDx 22C3 IHC assay; the anti-PD-L1 antibody is SP142 and the IHC assay is the Ventana SP142 IHC assay, or the anti-PD-L1 antibody is 28-8 and the IHC assay is the pharmDx 28-8 IHC assay.

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable level of nucleic acid expression of PD-L1. In some cases, a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-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 infiltrating tumor 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, SCLC is extensive-stage small cell lung cancer (ES-SCLC), also known as SCLC 4 (IV) stage. In some embodiments, the SCLC is a histologically or cytologically confirmed ES-SCLC according to or as defined by the refund military authority Lung research group (VALG) staging system (see, e.g., micke et al Lung Cancer 2002, 37. In some embodiments, SCLC is classified as ES-SCLC if the individual is not operable and cannot be classified as having limited or restricted stage SCLC (L-SCLC or LS-SCLC). In some embodiments, the ES-SCLC is detectable and/or has spread beyond the initially affected lung. In some embodiments, esclc is detectable and/or has further spread to other (e.g., distant) organs such as, but not limited to, the liver, adrenal gland, lymph nodes, and/or brain. In some embodiments, esclc is difficult to treat.

In some embodiments, the prognosis for the individual subject or population of subjects is poor. In some embodiments, the subject or population of subjects is a treatment naive subject or population of subjects (e.g., a chemotherapy naive subject or population of subjects). In some embodiments, a naive subject is a subject that has not received prior treatment for, e.g., cancer, SCLC, or ES-SCLC. In some embodiments, the naive subject is a subject who has not received prior treatment for ES-SCLC. In some embodiments, the naive subject is chemotherapy naive, e.g., a subject that has not received prior chemotherapy for treatment of, e.g., cancer, SCLC, and/or ES-SCLC. In some embodiments, the subject or population of subjects has not received treatment for ES-SCLC. In some embodiments, the subject or population of subjects has not received prior systemic treatment for ES-SCLC. In some embodiments, the subject or population of subjects has received radiation therapy for limited-phase SCLC (LS-SCLC) for the purpose of cure, and has undergone a treatment-free period of at least six months since the last chemotherapy, radiation therapy, or radiation therapy treatment of ES-SCLC was diagnosed. In some embodiments, the subject or population of subjects has asymptomatic supratentorial or cerebellar Central Nervous System (CNS) metastases. In some embodiments, the subject or population of subjects does not metastasize to the midbrain, pons, medulla oblongata, or spinal cord. In some embodiments, the subject or population of subjects has a CNS disease and does not require a corticosteroid to treat the CNS disease. In some embodiments, the subject or population of subjects has a new asymptomatic metastasis and has received radiation and/or surgery for CNS metastasis. In some embodiments, the subject or population of subjects has a measurable disease according to/as defined by RECIST v1.1 criteria (see, e.g., eisenhauer et al, eur.j. Cancer 2009, 45. 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 cases, the treatment results in CR or PR. In some cases, the PFS of the subject or population of subjects is increased as compared to a reference PFS time. In some cases, wherein the reference PFS time is the median PFS time for a population of subjects who have received treatment with (e.g., an anti-PD-L1 antibody (e.g., atuzumab)), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) without an anti-TIGIT antagonist antibody (e.g., tiryleigh euzumab).

In some cases, the method further comprises an additional therapy. The additional therapy can be radiation therapy, surgery (e.g., lumpectomy and mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional therapy may be in the form of adjuvant therapy 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 administration of a side-effect limiting agent (e.g., an agent intended to reduce the incidence and/or severity of a therapeutic side-effect, such as an antiemetic, 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 therapeutic antibodies contemplated for use herein include, but are not limited to, alemtuzumab (Campath), bevacizumab (b)

Gene tack); cetuximab (cetuximab) (C)

English clone (immunolene)); panitumumab (panitumumab)

(Amgen)), (am rituximab (rituximab) (R) (R) ((R))

Genes tyk/Baijian Aidi (Biogen Idec)), pertuzumab (pertuzumab) ((pertuzumab)

2C4, gene tack), trastuzumab (trastuzumab) ((ii)

Gene tack), tositumomab (tositumomab) (Bexxar, corixia), antibody drug conjugate gemtuzumab ozogamicin (gemtuzumab ozogamicin) ((ii)

<xnotran> (Wyeth)), (apolizumab), (aselizumab), (atlizumab), (bapineuzumab), (bivatuzumab mertansine), (cantuzumab mertansine), (cedelizumab), (certolizumab pegol), cidfusituzumab, cidtuzumab, (daclizumab), (eculizumab), (efalizumab), (epratuzumab), (erlizumab), (felvizumab), (fontolizumab), , (inotuzumab ozogamicin), , (labetuzumab), (lintuzumab), (matuzumab), (mepolizumab), (motavizumab), motovizumab, (natalizumab), (nimotuzumab), nolovizumab, numavizumab, (ocrelizumab), (omalizumab), (palivizumab), (pascolizumab), pecfusituzumab, pectuzumab, (pexelizumab), ralivizumab, (ranibizumab), reslivizumab, (reslizumab), resyvizumab, (rovelizumab), (ruplizumab), (sibrotuzumab), (siplizumab), (sontuzumab), </xnotran> Tebuclizumab (tacatuzumab tetraxetan), taduzumab (tadocizumab), talilizumab (talilizumab), tellizumab (talilizumab), tefulizumab (tefibuzumab), tollizumab (toralizumab), simethiukin (tucotuzumab), tucusituzumab (tucumalizumab), umuzumab (umavuzumab), uralizumab (urotaxuzumab), ursinumab (ustikinumab), vislizumab (visilizumab), and anti-interleukin 12 (ABT-874/J695, huiweishi Research and Abbott Laboratories).

In some embodiments, the additional therapy is a therapy targeting the PI3K/AKT/mTOR pathway, an HSP90 inhibitor, tubulinA leukocyte inhibitor, an apoptosis inhibitor and/or a chemopreventive agent. In some embodiments, the additional therapy is CTLA-4 (also known as CD 152), e.g., the blocking antibody ipilimumab (also known as MDX-010, MDX-101, or MDX-101

) Tremelimumab (tremelimumab) (also known as tositumomab or CP-675,206); antagonists against B7-H3 (also known as CD 276), e.g., blocking antibody MGA271; antagonists against TGF β, for example, metelimumab (also known as CAT-192), non-hematein (also known as GC 1008), or LY2157299; a treatment comprising adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) that express a Chimeric Antigen Receptor (CAR); treatment of adoptive transfer of T cells including dominant negative TGF receptor (e.g., type II dominant negative TGF receptor); treatments including HERCREEM protocols (see, e.g., clinical trials. Gov Identifier NCT 00889954); agonists against CD137 (also known as TNFRSF9, 4-1BB or ILA), for example, the activating antibody urelumab (also known as BMS-663513); agonists against CD40, e.g., the activating antibody CP-870893; an agonist, e.g., an activating antibody, directed to OX40 (also known as CD 134) is administered in conjunction with a different anti-OX 40 antibody (e.g., agonOX); agonists against CD27, such as the activating antibodies CDX-1127, indoleamine-2, 3-dioxygenase (IDO), 1-methyl-D-tryptophan (also known as 1-D-MT); antibody-drug conjugates (in some embodiments, comprising maytansine (mertansine) or monomethyl auristatin (auristatin) E (MMAE)); anti-NaPi 2b antibody-MMAE conjugates (also known as DNIB0600A or RG 7599); trastuzumab emtansine (also known as TDM1, ado-trastuzumab emtansine or

Gene tack); DMUC5754A; antibody-drug conjugates targeting endothelin B receptor (EDNBR), e.g., antibodies against EDNBR conjugated to MMAE; an angiogenesis inhibitor; bevacizumab (also known as VEGF-Sub>A) antibody against VEGF (e.g., VEGF-Sub>A)

Gene tack); antibody MEDI3617 against angiopoietin 2 (also known as Ang 2); an antineoplastic agent; agents targeting CSF-1R (also known as M-CSFR or CD 115); anti-CSF-1R (also known as IMCCS 4); interferons, e.g., interferon alpha or interferon gamma; roferon-A; GM-CSF (also known as recombinant human granulocyte macrophage colony stimulating factor, rhu GMCSF, sargrastim or

) (ii) a IL-2 (also known as aldesleukin) or

) (ii) a IL-12; an antibody targeting CD20 (in some embodiments, the antibody targeting CD20 is obinutuzumab (also known as GA101 or GA 101)

) Or rituximab); a GITR-targeting antibody (in some embodiments, the GITR-targeting antibody is TRX 518); (iii) synergistic administration with a Cancer vaccine (in some embodiments, the Cancer vaccine is a peptide Cancer vaccine, which in some embodiments is a personalized peptide vaccine; in some embodiments, the peptide Cancer vaccine is a multivalent long peptide, polypeptide, cocktail of peptides (cocktail), hybrid peptide, or peptide-pulsed dendritic cell vaccine (see, e.g., yamada et al, cancer Sci, 104; synergy with an adjuvant; TLR agonists, e.g. Poly-ICLC (also known as

) LPS, MPL or CpG ODN; tumor Necrosis Factor (TNF) α; IL-1; HMGB1; an IL-10 antagonist; an IL-4 antagonist; an IL-13 antagonist; an HVEM antagonist; ICOS agonists, e.g., by administration of ICOS-L, or an agonist antibody to ICOS; treatment targeting CX3CL 1; treatment targeting CXCL 10; a treatment that targets CCL 5; LFA-1 or ICAM1 agonists; a selectin agonist; targeted therapy; inhibitors of B-Raf; vemurafenib (also known as vemurafenib)

) (ii) a Dabrafenib (also known as dabrafenib)

) (ii) a Erlotinib (also known as erlotinib)

) (ii) a Inhibitors of MEK such as MEK1 (also known as MAP2K 1) or MEK2 (also known as MAP2K 2); cobicistinib (cobimetinib) (also known as GDC-0973 or XL-518); trametinib (also known as trametinib)

) (ii) a Inhibitors of K-Ras; inhibitors of c-Met; onartuzumab (onartuzumab) (also known as MetMAb); inhibitors of Alk; AF802 (also known as CH5424802 or aletinib); inhibitors of phosphatidylinositol 3-kinase (PI 3K); BKM120; idelalisib (also known as GS-1101 or CAL 101); piperacillin (perifosine) (also known as KRX-0401); akt; MK2206; GSK690693; GDC-0941; an inhibitor of mTOR; sirolimus (sirolimus) (also known as rapamycin (rapamycin)); temsirolimus (temsirolimus) (also known as CCI-779 or

) (ii) a Everolimus (also known as RAD 001); ridaforolimus (ridaforolimus) (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-BEZ 235); a 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.

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

Provided herein are methods and uses for treating lung cancer (e.g., non-small cell lung cancer (NSCLC), including squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC); small Cell Lung Cancer (SCLC), including extensive-stage SCLC (ES-SCLC); and lung adenocarcinoma) in a subject or population of subjects, comprising administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumumab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as altlizumab), and first and second chemotherapeutic agents (e.g., a chemotherapeutic agent and a non-platinum chemotherapeutic agent) for one or more dosing cycles.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as astuzumab), and a combination chemotherapy. In some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) are administered every three weeks (e.g., on day 1 of each 21-day dosing cycle). In some aspects, the invention includes methods and uses involving: an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiryleigh euzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) are administered every three weeks (e.g., on day 1 of each 21-day dosing cycle) based on the Body Weight (BW) or Body Surface Area (BSA) of the subject or population of subjects.

In some aspects, the invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibriturin itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as astuzumab), and a combination chemotherapy, wherein the combination chemotherapy comprises an effective amount of a platinum-based chemotherapeutic agent and an effective amount of a non-platinum-based chemotherapeutic agent. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) are administered every three weeks (e.g., 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 (e.g., pemetrexed).

In particular embodiments, the methods involve administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altuzumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed), wherein the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altuzumab) are administered every three weeks (e.g., on day 1 of each 21-day dosing cycle), and the combination chemotherapy (e.g., a platinum-based agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) are administered at the same frequency (e.g., every three weeks, e.g., on day 1 of each 21-day dosing cycle). In some cases, administration is for four to six cycles of induction dosing (e.g., four cycles of induction dosing, five cycles of induction dosing, or six cycles of induction dosing). After the induction dosing period, maintenance therapy may be administered in one or more subsequent (maintenance) dosing periods. In certain embodiments, the one or more maintenance dosing cycles do not include a platinum-based chemotherapeutic agent.

In some cases, the invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiryleigh ewuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atuzumab) every four weeks (e.g., on day 1 of each 28-day dosing cycle).

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab) results in an increase in PFS or DOR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in OS. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in progression-free survival of the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, the effective amounts of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiglium itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) prolong OS of the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist but not the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but not the PD-1 axis binding antagonist.

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

In some embodiments, administering an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout iturin), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atlizumab), and combination chemotherapy (e.g., a combination of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) to a subject or population of subjects having lung cancer (e.g., NSCLC) according to any of the methods described herein results in a median PFS of 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 more, e.g., 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 results in a median PFS for the population of subjects of at least about 8 months (e.g., between 8 months and 36 months, e.g., between 8 months and 24 months (e.g., between 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). In some cases, the treatment results in a median PFS for the population of subjects of about 12.5 months to about 14.7 months (e.g., 12.5, 12.7, 12.9, 13.1, 13.3, 13.5, 13.7, 13.9, 14.1, 14.3, 14.5, or 14.7 months, e.g., about 12.5 to 13 months, 13 to 13.5 months, 13.5 to 14 months, or 14 to 14.7 months), in some embodiments, the administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tamulizumab tiumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as astuzumab), and combination chemotherapy (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palboceprizumab)) to a subject or population of subjects having lung cancer (e.g., NSCLC) according to any of the methods described herein results in a median PFS of at least 10 months PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies, such as atlizumab) and combination chemotherapy (e.g., a combination of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) result in a median PFS of at least 12 months.

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as altlizumab) and a combination chemotherapy (e.g., a combination of a platinum chemotherapeutic (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) to a subject or population of subjects having lung cancer results in an increase in the median OS (OS) of the subject or population of subjects, as compared to treatment with palbociclumab and the combination chemotherapy (e.g., an antimetabolite (e.g., a pemetrexed) and a platinum chemotherapeutic (e.g., carboplatin or cisplatin)). In some cases, the treatment extends OS of the subject or population of subjects for at least about 4 months (e.g., for between 4 and 12 months (e.g., 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months).

In some embodiments, administering an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout iturin), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atlizumab), and combination chemotherapy (e.g., a combination of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) to a subject or population of subjects having lung cancer (e.g., NSCLC) according to any of the methods described herein results in a median OS of greater than 22 months (e.g., at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 42, at least 48, at least 54, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, at least 180, at least 190, or at least 200 months, e.g., about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about, 33, about 34, about 35, about 36, about 40, about 42, about 48, about 54, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200 months). In some embodiments, the treatment results in a median OS for the population of subjects of at least about 24 months (e.g., between 24 months and 42 months, e.g., between 24 months and 36 months (e.g., 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 results in a median OS for the population of subjects of about 27.5 months to about 32.0 months (e.g., 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, or 32.0 months, e.g., 27.5 to 28.5, 28.5 to 29.5, 29.5 to 30.5, 30.5 to 31.5, or 31.5 to 32 months.) in some embodiments, an effective amount of an anti-tig antagonist (e.g., an it antibody (e.g., an anti-tig) is administered to the population of a subject in need thereof according to any of the methods described herein, an anti-TIGIT antagonist antibody, e.g., TIGIT itumumab), PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) as disclosed herein, and combination chemotherapy administered to a subject or population of subjects having lung cancer (e.g., NSCLC), (e.g., a combination of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., paribrizumab) results in a median OS of at least 24 months PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies, such as atlizumab) and combination chemotherapy (e.g., a combination of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) result in a median OS of at least 36 months.

In some cases, administering an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as altlizumab), and a combination chemotherapy (e.g., a combination of a platinum-based chemotherapeutic (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., pemetrexed)) to a subject or population of subjects in need thereof results in an increase in the total remission rate (ORR) of the subject or population of subjects as compared to treatment with palbociclumab and a combination chemotherapy (e.g., an antimetabolite (e.g., pemetrexed) and a platinum-based chemotherapeutic (e.g., carboplatin or cisplatin)), e.g., the ORR is increased by at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%) as compared to treatment with palbocicluzumab and a combination chemotherapy (e.g., an antimetabolite (e.g., pemetrexed (e.g., an antimetabolite and a platinum-based chemotherapeutic (e.g., carboplatin or cisplatin)).

In some embodiments, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as astuzumab), and combination chemotherapy (e.g., a combination of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) to a subject or population of subjects having lung cancer (e.g., NSCLC) according to any of the methods described herein results in an ORR greater than 47.5% (e.g., 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%, e.g., about 48%, about 49%, about 50%, about 55%, at least 90%, or 100%, about 60%, about 65%, about 75%, about 80%, about 90%, about 95%, or about 100%). In some embodiments, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout iturin), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as astuzumab), and combination chemotherapy (e.g., a combination of a platinum chemotherapeutic (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) to a subject or population of subjects having lung cancer (e.g., NSCLC) according to any of the methods described herein results in an ORR of at least 50%. In some embodiments, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout iturin), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as astuzumab), and combination chemotherapy (e.g., a combination of a platinum chemotherapeutic (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) to a subject or population of subjects having lung cancer (e.g., NSCLC) according to any of the methods described herein results in an ORR of at least 60%. In some embodiments, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout iturin), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as astuzumab), and combination chemotherapy (e.g., a combination of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and an antimetabolite (e.g., palbociclumab)) to a subject or population of subjects having lung cancer (e.g., NSCLC) according to any of the methods described herein results in an ORR of at least 70%.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tegrayleitumomab) every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in progression-free survival of the subject or population of subjects as compared to a reference. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in DOR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) extends the OS of the subject or population of subjects.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) every two weeks (e.g., on days 1 and 15 of each 28 day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tigliumiuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in progression-free survival of the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) extends the OS of the subject or population of subjects, e.g., as compared to treatment with a PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with an anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist.

In certain instances, the invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tegrayleigh immuzumab) every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in progression-free survival of the subject or population of subjects as compared to a reference. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) extends OS in the subject or population of subjects.

In some cases, a subject or population of subjects has not received prior systemic therapy (e.g., prior systemic therapy with the intent to cure, e.g., chemotherapy) within one month prior to administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody (e.g., within two months, three months, four months, six months, one year, two years, three years, four years, five years, or ten years prior to administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody). 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 concurrently with chemotherapy. For example, a biweekly (Q2W), triweekly (Q3W), or biweekly (Q4W) dosing regimen of a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody can be administered in conjunction with one or more chemotherapeutic agents. The one or more chemotherapeutic agents may be administered at the same frequency (Q2W, Q3W, or Q4W) or at a different frequency (e.g., a 3-week on/1-week off schedule) as the frequency of administration of the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody. For example, in some embodiments, the PD-1 axis binding antagonist and anti-TIGIT antagonist antibody are administered every two weeks, and the one or more chemotherapeutic agents are administered weekly (3 weeks on/1 week off), biweekly, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every three weeks, and the one or more chemotherapeutic agents are administered weekly, biweekly, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every four weeks, and the one or more chemotherapeutic agents are administered weekly (3 weeks on/1 week off), biweekly, every three weeks, or every four weeks. In certain instances, the chemotherapeutic agent is administered multiple times per week (e.g., 2, 3, 4, 5, 6, or 7 times per week (e.g., 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 (e.g., after one, two, three, four, or more initial doses). For example, subsequent doses of a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine)) can be administered at about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial dose-e.g., about 75mg/m can be administered ² For subsequent doses, e.g. to 70mg/m ² 、65mg/m ² 、60mg/m ² 、55mg/m ² 、50mg/m ² Or 45mg/m ² (ii) a Can be adjusted to about 500mg/m ² For subsequent doses, e.g., to 450mg/m ² 、400mg/m ² 、350mg/m ² 、300mg/m ² 、250mg/m ² Or 200mg/m ² (ii) a And/or an initial dose of carboplatin sufficient to achieve AUC =5mg/ml/min may be reduced for subsequent doses, e.g., to a dose sufficient to achieve AUC =4.5mg/ml/min, 4.0mg/ml/min, 3.5mg/ml/min, or 3.0 mg/ml/min.

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as alemtuzumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) results in an increase in progression-free survival of the subject or population of subjects. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as altlizumab), a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) extends OS in a subject or population of subjects.

In some cases, a subject or population of subjects receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as attrituzumab), a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) is being treated for lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC))).

Administration of pharmaceutical agents

Section III (K) describes the administration of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and chemotherapeutic agents.

Cancer characterization

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

In some cases, in any of the methods, uses, or compositions for use described herein, the subject is free of Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. In some cases, in any of the methods, uses, or compositions for use described herein, the subject does not have an EGFR gene mutation (e.g., a sensitizing EGFR gene mutation) or an ALK gene rearrangement. In some cases, the Eastern Cooperative Oncology Group (ECOG) physical Performance Status (PS) of the subject is 0 or 1.

Methods for detecting the mutant states EGFR and ALK are well known in the art and include, but are not limited to, sequencing DNA from clinical samples, e.g., tumor biopsy samples or blood samples (e.g., circulating tumor DNA in blood), using next generation sequencing methods such as the targeted gene pulldown (gene pulldown) and sequencing methods described by Frampton et al (Nature biotechnology.31 (11): 1023-1033 (2013), which is incorporated herein by reference in its entirety). Such next generation sequencing methods can be used in conjunction with any of the methods disclosed herein to detect various mutations (e.g., insertions, deletions, base substitutions, focal gene amplifications, and/or homozygous gene deletions), while enabling the use of small samples (e.g., from small core needle biopsies, fine needle aspirations, and/or cell clumps) or fixed samples (e.g., formalin-fixed and paraffin-embedded (FFPE) samples). Other methods of detecting the status of EGFR and ALK mutations include Fluorescence In Situ Hybridization (FISH) and Immunohistochemistry (IHC) methods. Assays for detecting ALK mutational statusAn exemplary method is disclosed in U.S. patent No. 9,651,555, which is incorporated by reference herein in its entirety. In some cases, it is possible to use,

an anti-ALK (D5F 3) IHC assay is used to determine the mutational 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 well known in the art and are included in U.S. patent publication nos.: those described in US 2018/0235968 and Juan et al (Therapeutic Advances in Medical Oncology.9 (3): 201-216, 2017), which are incorporated herein by reference in their entirety. In some cases, the sensitizing EGFR mutation is a mutation in any one of exons 18 to 21 (e.g., a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some cases, the sensitizing EGFR mutation is a deletion of exon 19 (del 19). In other cases, the sensitizing EGFR mutation is an L858R point mutation in exon 21. In some cases, the sensitizing EGFR mutation is a G719X point mutation in exon 18, where "X" is most commonly C, a, or S. In some cases, the sensitizing EGFR mutation is a G719S point mutation in 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 a T790M point mutation. In some cases, the sensitizing EGFR mutation is an E709X point mutation, where "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 well known in the art and include those described in U.S. Pat. Nos. 9,651,555 and Du et al (Thorac cancer.9:423-430, 2018), which are incorporated herein by reference in their entirety. In some cases, ALK gene rearrangement results in the production of oncogenic ALK tyrosine kinases, which activate downstream signaling pathways leading to increased cell proliferation and survival. In some cases, the ALK gene rearranges to an ALK rearrangement with 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 that results in the formation of a fused oncogene. In some cases, the ALK gene rearranges to an EML4 rearrangement with ALK, which leads to the formation of the fusion oncogene EML4-ALK.

In some cases, in any of the methods, uses, or compositions for use described herein, the subject does not have a lung lymphoepitheliomatous subtype of NSCLC. Methods for detecting a subtype of NSCLC are well known in the art and include, but are not limited to, methods determined by histopathological criteria or by molecular characteristics (e.g., a subtype characterized by the expression of one biomarker or a combination of biomarkers (e.g., a particular gene or protein encoded by the gene)). 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 any of the methods for use, uses, or compositions for use described herein, the subject is free of active epstein-barr virus (EBV) infection or a known or suspected chronic active EBV infection. Indicators of active or chronic active EBV infection for use in the methods described herein can include, but are not limited to, EBV IgM, EBV IgG, epstein-barr nuclear antigen (EBNA), and epstein-barr virus particles detected in a sample (e.g., a blood or serum sample) from a subject. Methods for detecting one or more indicators of the presence or absence of active or chronic active EBV infection in a sample from a subject, including EBV IgM, EBV IgG, epstein-barr nuclear antigen (EBNA), and epstein-barr virus particles, are well known in the art, and include, but are not limited to, methods involving serodiagnosis (e.g., detecting EBV DNA (e.g., by PCR analysis of a blood sample to detect EBV virus particles) or EBV antigen or anti-EBV antibodies (e.g., detecting EBNA, EBV IgM, or EBV IgG using heterophilic antibodies)). 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 negative for detection by EBV PCR. In some cases, the subject is negative for EBV IgM and/or negative for EBV PCR detection, and positive for EBV IgG and/or positive for epstein-barr virus 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 (e.g., tumor PD-L1 expression with a minimum PD-L1 positive tumor cell fraction or TPS ≧ 30% (e.g., ≧ 50%), as determined by IHC using the SP263 or 22C3 antibody, or a proportion of tumor area occupied by tumor-infiltrating Immune Cells (IC) expressing PD-L1 in the tumor sample greater than or equal to 1%, as determined by IHC with the SP142 antibody). In some cases, a PD-L1-selected tumor is a tumor that has a PD-L1 positive tumor cell fraction of greater than or equal to 30% (e.g., greater than or equal to 50%) or PD-L1TPS as determined by an Immunohistochemistry (IHC) assay. In some cases, the PD-L1-selected tumor is a tumor in which the proportion of tumor area occupied by Immune Cells (IC) expressing PD-L1 is greater than or equal to 1%, as determined by an Immunohistochemistry (IHC) assay. In some cases, the IHC assay uses the anti-PD-L1 antibody 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 the anti-PD-L1 antibody 22C3. In some cases, the tumor sample has been determined to have greater than or equal to 50% TPS. In some cases, the PD-L1-positive tumor cell fraction is greater than or equal to 50% (e.g., as determined by positive staining with anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), as determined by positive staining with anti-PD-L1 antibody 22C3 (e.g., using the pharmDx assay), or by positive staining with anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is greater than or equal to 30%, as determined by positive staining with anti-PD-L1 antibody SP142. In some cases, the IC has been determined to be greater than or equal to 1% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 5% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 10% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 1% and less than 50% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the IC has been determined to be greater than or equal to 1% and less than 30% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay).

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1. In some cases, a detectable protein expression level of PD-L1 has been determined by an IHC assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% and less than 5% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% and less than 50% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 50% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 1% of the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 1% and less than 5% of the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 5% and less than 10% of the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 10% of the tumor sample.

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

In some cases, a subject having lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC))) has been determined to have a PD-L1 positive tumor cell fraction of less than 50% (e.g., 1% to 50%, 1% to 49%, 5% to 45%, 10% to 40%, 15% to 35%, or 20% to 30%, e.g., 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%, e.g., 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%). For example, in certain instances, a subject having lung cancer has been determined to have a PD-L1 positive tumor cell fraction of 1-49% (e.g., 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%). In other cases, a subject having lung cancer has been determined to have a PD-L1 positive tumor cell fraction of less than 1% (e.g., about 0%, or undetectable PD-L1 expression).

For example, in some cases, a subject having lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC)))) has been determined to have less than 50% pd-L1 positive (e.g., 1% to 50%, 1% to 49%, 5% to 45%, 10% to 40%, 15% to 35%, or 20% to 30% pd-L1 positive, e.g., 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, e.g., 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 having lung cancer has been determined to have 1-49% pd-L1 positive (e.g., 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) TPS. In other cases, a subject having lung cancer has been determined to have less than 1% PD-L1 positive (e.g., about 0%, or undetectable PD-L1 expression) TPS.

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

In some cases, a subject having NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC))) has a PD-L1 positive tumor cell fraction of less than 50% (e.g., 1% to 50%, 1% to 49%, 5% to 45%, 10% to 40%, 15% to 35%, or 20% to 30%, e.g., 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%, e.g., 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%). For example, in certain instances, a subject having NSCLC has been determined to have a PD-L1 positive tumor cell fraction of 1-49% (e.g., 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%). In other cases, a subject having NSCLC has been determined to have a PD-L1-positive tumor cell fraction of less than 1% (e.g., about 0%, or undetectable PD-L1 expression).

For example, in some cases, a subject having NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC))) has been determined to have less than 50% pd-L1 positive (e.g., 1% to 50%, 1% to 49%, 5% to 45%, 10% to 40%, 15% to 35%, or 20% to 30% pd-L1 positive, e.g., 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, e.g., 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 having NSCLC has been determined to have 1-49% pd-L1 positive (e.g., 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) TPS. In other cases, a subject having NSCLC has been determined to have less than 1% PD-L1 positive (e.g., about 0%, or undetectable PD-L1 expression) TPS.

In some cases, a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1. In some cases, a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-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 infiltrating tumor immune cells, tumor cells, stromal cells, and any combination thereof.

In some cases, a tumor sample obtained from a subject with lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC)))) has a low or undetectable nucleic acid expression level of PD-L1. In some cases, the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-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 infiltrating tumor immune cells, tumor cells, stromal cells, and any combination thereof.

In some cases of any of the methods described herein, a subject having lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC)))) has not received prior systemic treatment for lung cancer (e.g., has not received prior systemic treatment for cure). In particular embodiments, the subject has locally advanced lung cancer and has not received prior systemic treatment for locally advanced lung cancer. In some cases, the subject has NSCLC (e.g., non-squamous NSCLC, e.g., locally advanced non-resectable or metastatic non-squamous NSCLC) and has not received prior systemic treatment for NSCLC (e.g., non-squamous NSCLC, e.g., locally advanced non-resectable or metastatic non-squamous NSCLC). Previous systemic treatments include previous neoadjuvant, adjuvant chemotherapy, radiation therapy and chemoradiotherapy for the purpose of healing non-metastatic disease.

In other cases, a subject with lung cancer (e.g., NSCLC (e.g., non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC)))) has received prior systemic treatment for lung cancer and has experienced a no-treatment interval of at least 12 months prior to treatment according to any of the methods of the present invention.

Methods and uses for treating resectable lung cancer

Provided herein are methods and uses for treating lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))) in a subject, comprising administering to the subject an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tenerriuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab, or an anti-PD-1 antagonist antibody, such as palbociclumab) for one or more dosing cycles. In some cases, at least one dosing cycle is administered as neoadjuvant therapy. In some cases, the treatment is neoadjuvant treatment. In some cases, at least one dosing cycle is administered as an adjunctive therapy. In some cases, the treatment is adjuvant treatment. In some cases, the treatment includes neoadjuvant and adjuvant treatment. In some cases, the lung cancer is resectable lung cancer. In some cases, the lung cancer is early stage lung cancer (e.g., stage II, IIIA, or IIIB lung cancer). In some cases, the lung cancer is NSCLC (e.g., squamous or non-squamous NSCLC). In some cases, lung cancer is PD-L1 positive (e.g., PD-L1 is high). In some cases, lung cancer is free of Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. In some embodiments, the subject has not been previously treated for lung cancer (e.g., prior surgery, prior immunotherapy, prior chemotherapy, or prior radiation therapy). In some cases, the subject is eligible to receive a platinum-based chemotherapy regimen. In some cases, the subject is eligible for an R0 resection for healing purposes. The subject is preferably a human.

The present invention includes methods and uses for treating a subject having resectable lung cancer (e.g., resectable squamous or non-squamous NSCLC), the method comprising administering to the subject one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., a tirayleigh immuzumab) at a dose (e.g., a fixed dose) of between about 30mg to about 1200mg every three weeks (e.g., on day 1 of each 21-day dosing cycle) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab, or an anti-PD-1 antagonist antibody, e.g., palbociclumab) at a dose (e.g., a fixed dose) of between about 80mg to about 1600mg every three weeks (e.g., on day 1 of each 21-day dosing cycle). In some aspects, the method comprises administering to the subject one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., a tirayleigh immuzumab) at a dose (e.g., a fixed dose) of between 30mg to 1200mg every three weeks (e.g., on day 1 of each 21-day dosing cycle) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab, or an anti-PD-1 antagonist antibody, e.g., palbociclumab) at a dose (e.g., a fixed dose) of between 80mg to 1600mg every three weeks (e.g., on day 1 of each 21-day dosing cycle).

The invention includes methods and uses involving: administering to a subject in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as astuzumab, or an anti-PD-1 antagonist antibody, e.g., palbociclumab) every three weeks (e.g., on day 1 of each 21-day dosing cycle). In some cases, at least one dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between about 30mg to about 1200mg every three weeks (e.g., a dose of 600mg every three weeks) and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between about 80mg to about 1600mg every three weeks (e.g., a dose of about 1200mg every three weeks) as neoadjuvant therapy. In some cases, at least one dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30mg to about 1200mg every three weeks (e.g., a dose of 600mg every three weeks) and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of between about 80mg to about 1600mg every three weeks (e.g., a dose of about 1200mg every three weeks) as adjunctive treatments. In some cases, at least one dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between 30mg and 1200mg every three weeks (e.g., a dose of 600mg every three weeks) and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between 80mg and 1600mg every three weeks (e.g., a dose of 1200mg every three weeks) as neoadjuvant therapy. In some cases, at least one dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between 30mg and 1200mg every three weeks (e.g., a dose of 600mg every three weeks) and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between 80mg and 1600mg every three weeks (e.g., a dose of 1200mg every three weeks) as adjunctive therapy.

In some cases, treatment with an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiryleigh ewolizumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) is being performed against lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))).

PD-1 axis binding antagonist anti-TIGIT antagonist antibodies can be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can be administered sequentially (on different days) or contemporaneously (on the same day or within the same treatment cycle). In some cases, the anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist is administered at about day 1 (e.g., day-3, day-2, day-1, day 2, or day 3) of the dosing cycle. In some cases, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can 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 an anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist can be administered prior to the anti-TIGIT antagonist antibody administered on the same day. In some cases, the PD-1 axis binding antagonist can be administered after the same day of administration of the anti-TIGIT antagonist antibody. In other cases, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered at the same time. In some cases, the PD-1 axis binding antagonist is in a separate composition from the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is in the same composition as the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered via an intravenous line that is separate from any other therapeutic agent administered to the patient on the same day. The PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can 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, by implantation, by inhalation, 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, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some cases, the anti-TIGIT antagonist antibody is administered intravenously. In some cases, there is a first observation period following 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 length of the observation period is between about 30 minutes and about 60 minutes. 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 over 30 ± 10 minutes and/or over 60 ± 15 minutes. In one example, the atezumab can be administered intravenously over 60 minutes; if the first infusion can be tolerated, all subsequent infusions can be delivered over 30 minutes. In some examples, the PD-1 axis binding antagonist is not administered as a bolus injection or as a bolus injection. In one example, the tenestributumab may be administered intravenously over 60 minutes; if the first infusion can be tolerated, all subsequent infusions can be delivered over 30 minutes. In some examples, the anti-TIGIT antagonist antibody is not administered as a bolus injection or bolus injection.

In any of the foregoing examples, each administration cycle can have any suitable length, such as about 7 days (about 5, 6, 7, 8, or 9 days), about 14 days (e.g., about 12, 13, 14, 15, or 16 days), about 21 days (e.g., about 18, 19, 20, 21, 22, 23, or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30, 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 a subject (e.g., a tumor sample, a blood sample (e.g., a plasma sample), or a lymph sample) has been determined. In some cases, the sample has been determined to have a detectable PD-L1 expression level (e.g., a detectable PD-L1 protein and/or nucleic acid expression level). In some cases, the detectable PD-L1 expression level is a detectable protein expression level of PD-L1. In some cases, the detectable PD-L1 expression level is a PD-L1 positive tumor cell fraction (e.g., a PD-L1 positive tumor cell fraction of greater than or equal to 50%). In some cases, a detectable protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay that includes staining with an anti-PD-L1 antibody suitable for staining (e.g., anti-PD-L1 antibody SP 263). In some cases, the IHC assay is the Ventana SP263 IHC assay. In some cases, the detectable PD-L1 expression level 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 (e.g., segmental resection, lobectomy, bilobalectomy, or total 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 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more dosing cycles) are completed prior to surgery. In some cases, 4 dosing cycles were completed prior to surgery. In some cases, 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 or more dosing cycles) are initiated post-operatively. In some cases, 16 dosing cycles are completed post-operatively. In some cases, the treatment comprises surgery. In some cases, the surgery is a segmental resection, a lobectomy, a bilobalectomy, or a total lung resection. In some cases, the treatment includes radiation therapy (e.g., post-operative radiation therapy).

In some cases, the treatment results in an increase in a Major Pathological Remission (MPR) rate as compared to the reference MPR rate. In some cases, the treatment results in complete remission of pathology (pCR) and/or an increase in pCR rate as compared to a reference pCR rate. In some cases, the treatment results in an increase in event-free survival (EFS) as compared to a reference EFS time. In some cases, the treatment results in an increase in OS compared to the reference OS time. In some cases, the reference MPR rate, reference pCR rate, and/or reference EFS time is the MPR rate, pCR rate, and/or EFS time for a population of subjects that have received a treatment comprising: (a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or (b) cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in MPR rate. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in pCR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in EFS. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in OS.

In some cases, the treatment further includes one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some cases, the neoadjuvant and/or adjuvant treatment further includes one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some cases, the one or more chemotherapeutic agents are one or more platinum-based chemotherapeutic agents and/or one or more non-platinum-based chemotherapeutic agents An alcohol; (c) cisplatin and pemetrexed; (d) carboplatin and gemcitabine; or (e) cisplatin and gemcitabine. In some cases, the one or more chemotherapeutic agents used in the treatment for non-squamous NSCLC are (a) carboplatin and pemetrexed, (b) carboplatin and paclitaxel, or (c) cisplatin and pemetrexed. In some cases, the one or more chemotherapeutic agents used in the treatment for squamous NSCLC are (a) carboplatin and gemcitabine, (b) carboplatin and paclitaxel, or (c) cisplatin and gemcitabine. In some cases, the treatment further comprises administering one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)). In some cases, the one or more chemotherapeutic agents are administered every three weeks. In some cases, the one or more chemotherapeutic agents are administered on about day 1 (e.g., day-3, day-2, day-1, day 2 or day 3) of one or more dosing cycles. In some cases, the one or more chemotherapeutic agents are administered on about day 1 (e.g., on days-3, 2, 1, 2, or 3) and about 8 (e.g., 5, 6, 7, 8, 9, 10, or 11) administration in some cases, the dosing cycle is, for example, about 7 (about 5, 6, 7, 8, or 9) days, about 14 (e.g., about 12, 13, 14, 15, or 16 days), about 21 days (e.g., about 18, 19, 20, 21, 22, 23, or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30, or 31 days), or more Intraperitoneal, intraorbital, by implantation, by inhalation, intrathecal, intraventricular, or intranasal administration. In some cases, the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist (e.g., atelizumab) and/or the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibriturin itumumab). In some cases, a non-platinum chemotherapeutic (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel)) is administered prior to a platinum chemotherapeutic (e.g., carboplatin or cisplatin).

The present invention includes methods and uses for treating a subject having resectable lung cancer (e.g., early resectable lung cancer (e.g., resectable squamous or non-squamous NSCLC))), the method comprising administering to the subject one or more dosing cycles of: a dose (e.g., fixed dose) of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) at a dose (e.g., fixed dose) between about 30mg to about 600mg every three weeks, a dose (e.g., fixed dose) of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as attritumab or an anti-PD-1 antagonist antibody, e.g., palbociclumab), a platinum chemotherapeutic (e.g., carboplatin or cisplatin), and a non-platinum chemotherapeutic (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)) at a dose between about 80mg to about 1600mg every three weeks. In some aspects, the method comprises administering to the subject one or more cycles of dosing of: a dose (e.g., fixed dose) of between 30mg to 600mg per three weeks of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a dose (e.g., fixed dose) of between 80mg to 1600mg per three weeks of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as altlizumab, or an anti-PD-1 antagonist antibody, e.g., palboclizumab), a platinum chemotherapeutic (e.g., carboplatin or cisplatin), and a non-platinum chemotherapeutic (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)).

The invention includes methods and uses for treating a subject having lung cancer (e.g., early resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC))), the methods comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as altlizumab, or an anti-PD-1 antagonist antibody, e.g., palboclizumab), a platinum chemotherapeutic (e.g., carboplatin or cisplatin), and a non-platinum chemotherapeutic (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)), wherein at least one dosing cycle comprises administering to the subject: anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30mg to about 600mg every three weeks, PD-1 axis binding antagonist at a dose (e.g., fixed dose) of between about 80mg to about 1600mg every three weeks, platinum-based chemotherapeutic agents (e.g., cisplatin or carboplatin), and non-platinum-based chemotherapeutic agents (e.g., antimetabolites (e.g., pemetrexed or gemcitabine), or taxanes (e.g., paclitaxel or nab-paclitaxel)) as neoadjuvant therapy. In some aspects, at least one dosing cycle comprises administering to the subject: anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between 30mg and 600mg every three weeks, PD-1 axis binding antagonist at a dose (e.g., fixed dose) between 80mg and 1600mg every three weeks, platinum-based chemotherapeutic agents (e.g., cisplatin or carboplatin), and non-platinum-based chemotherapeutic agents (e.g., antimetabolites (e.g., pemetrexed or gemcitabine) or taxanes (e.g., paclitaxel or nab-paclitaxel)) as neoadjuvant therapy.

The present invention includes methods and uses for treating a subject having resectable lung cancer (e.g., early resectable lung cancer (e.g., resectable NSCLC (e.g., resectable squamous or non-squamous NSCLC))), the method comprising administering to the subject one or more dosing cycles of: about 30 per three weeksA dose (e.g., fixed dose) of between mg to about 600mg of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a dose (e.g., fixed dose) of between about 80mg to about 1600mg every three weeks of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atuzumab, or an anti-PD-1 antagonist antibody, e.g., palbociclumab), and: (a) (ii) (i) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) about 75mg/m every three weeks ² The dose of platinum chemotherapeutic agent (e.g., cisplatin or carboplatin); and (b) (i) about 500mg/m every three weeks ² Or about 1000mg/m on days 1 and 8 of each administration cycle ² Or about 1250mg/m ² The dose of antimetabolite of (a); or (ii) about 100mg/m every three weeks ² About 175mg/m ² Or about 200mg/m ² The dose of taxane of (1). In some aspects, the method comprises administering to the subject one or more cycles of dosing of: a dose (e.g., fixed dose) of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) between 30mg and 600mg every three weeks, a dose (e.g., fixed dose) of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab, or an anti-PD-1 antagonist antibody, e.g., palbociclumab) between 80mg and 1600mg every three weeks, and: (a) (ii) (i) a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) 75mg/m every three weeks ² The dose of platinum chemotherapeutic agent (e.g., cisplatin or carboplatin); and (b) (i) about 500mg/m every three weeks ² Or 1000mg/m on days 1 and 8 of each administration cycle ² Or 1250mg/m ² The dose of antimetabolite of (a); or (ii) 100mg/m every three weeks ² 、175mg/m ² Or 200mg/m ² The dose of taxane.

The invention includes methods and uses for treating a subject having lung cancer (e.g., early stage lung cancer (resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))), the method comprising administering to the subject Administering one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab, or an anti-PD-1 antagonist antibody, e.g., parbolizumab), a platinum-based chemotherapeutic (e.g., cisplatin or carboplatin), and a non-platinum-based chemotherapeutic (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)), wherein at least one dosing cycle comprises administering to the subject: (a) A dose (e.g., a fixed dose) of between about 30mg to about 600mg of anti-TIGIT antagonist antibody every three weeks; (b) A dose (e.g., fixed dose) of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks; (c) platinum chemotherapeutic agents: (i) A dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) about 75mg/m every three weeks ² The dosage of (a); and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) About 500mg/m every three weeks ² Or about 1000mg/m on days 1 and 8 of each administration cycle ² Or about 1250mg/m ² The dose of antimetabolite of (a); or (ii) about 100mg/m every three weeks ² About 175mg/m ² Or about 200mg/m ² The dose of taxane of (a); wherein the treatment is neoadjuvant treatment. In some aspects, at least one dosing cycle comprises administering to the subject: (a) A dose (e.g., fixed dose) of anti-TIGIT antagonist antibody between 30mg and 600mg every three weeks; (b) A dose (e.g., fixed dose) of PD-1 axis binding antagonist between 80mg and 1600mg every three weeks; (c) platinum chemotherapeutic agents: (i) A dose to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min for a target every three weeks; or (ii) 75mg/m every three weeks ² The dosage of (a); and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) Every three weeks 500mg/m ² Or 1000mg/m on days 1 and 8 of each administration cycle ² Or 1250mg/m ² The dose of antimetabolite of (a); or (ii) 100mg/m every three weeks ² 、175mg/m ² Or 200mg/m ² The dose of taxane of (a); wherein the treatment is neoadjuvant treatment.

The invention includes methods and uses for treating a subject having lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))) comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein: (a) At least one dosing cycle comprises administering to the subject: as neoadjuvant therapy, an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between about 80mg to about 1600mg every three weeks; and (b) at least one dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between about 80mg to about 1600mg every three weeks as adjunctive therapy. In some aspects, 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: (a) At least one dosing cycle comprises administering to the subject: as neoadjuvant therapy, an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between 30mg and 1200mg every three weeks and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between 80mg and 1600mg every three weeks; and (b) at least one dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose between 30mg and 1200mg every three weeks and a PD-1 axis binding antagonist at a dose (e.g., fixed dose) between 80mg and 1600mg every three weeks as adjunctive therapy.

The invention includes methods and uses for treating a subject having lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))) comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) A dose (e.g., a fixed dose) of between about 30mg to about 1200mg of an anti-TIGIT antagonist antibody every three weeks; (b) PD-1 axis binding antagonist at a dose (e.g., fixed dose) of between about 80mg to about 1600mg every three weeksAs a neoadjuvant therapy; (c) platinum chemotherapeutic agents: (i) A dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) about 75mg/m every three weeks ² The dosage of (a); and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) About 500mg/m every three weeks ² Or about 1000mg/m on days 1 and 8 of each administration cycle ² Or about 1250mg/m ² The dose of antimetabolite of (a); or (ii) about 100mg/m every three weeks ² About 175mg/m ² Or about 200mg/m ² The dose of taxane of (a); and (II) at least one dosing cycle comprises administering to the subject: a dose (e.g., fixed dose) of between about 30mg to about 1200mg of the anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between about 80mg to about 1600mg of the PD-1 axis binding antagonist every three weeks as adjunctive therapy. In some aspects, the method comprises administering to the subject: (a) A dose (e.g., fixed dose) of between 30mg to 1200mg of an anti-TIGIT antagonist antibody every three weeks; (b) A dose (e.g., fixed dose) of PD-1 axis binding antagonist between 80mg to 1600mg every three weeks as neoadjuvant therapy; (c) platinum chemotherapeutic agents: (i) A dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) 75mg/m every three weeks ² The dosage of (a); and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) Every three weeks 500mg/m ² Or 1000mg/m on days 1 and 8 of each administration cycle ² Or 1250mg/m ² The dose of antimetabolite of (a); or (ii) 100mg/m every three weeks ² 、175mg/m ² Or 200mg/m ² The dose of taxane of (a); and (II) at least one dosing cycle comprises administering to the subject: a dose (e.g., fixed dose) of between 30mg to 1200mg of an anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between 80mg to 1600mg of a PD-1 axis binding antagonist every three weeks as adjunctive therapy.

In some cases, the treatment may further comprise additional therapies. Any suitable additional therapy known in the art or described herein may be used. The additional therapy can be radiation therapy (e.g., post-operative radiation therapy), surgery, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nano-therapy, monoclonal antibody therapy, gamma radiation, or a combination of the foregoing therapies.

In some cases, the additional therapy is administration of a side-effect limiting agent (e.g., an agent intended to reduce the occurrence and/or severity of a therapeutic side-effect, e.g., an anti-nausea agent, a corticosteroid (e.g., prednisone or an equivalent, e.g., at a dose of 1 to 2 mg/kg/day), a hormone replacement drug, etc.).

Also provided herein are methods for treating lung cancer in a subject, comprising administering to the subject a treatment regimen comprising an effective amount of a PD-1 axis binding antagonist (e.g., atelizumab) and/or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) in combination with one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) and/or a taxane (e.g., paclitaxel, e.g., nab-paclitaxel))) and/or a cancer therapy (e.g., surgery and/or radiation therapy). For example, a PD-1 axis binding antagonist can be combined with: (ii) additional chemotherapy or a combination of chemotherapeutic agents (see definition above); targeted therapies or targeted therapeutic agents; immunotherapy or immunotherapeutic agents, e.g., monoclonal antibodies; one or more cytotoxic agents (see definition above); or a combination thereof.

Administration of pharmaceutical agents

Section III (K) describes the administration of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and chemotherapeutic agents.

Cancer characterization and selection

In some cases, in any of the methods, uses, or compositions for use described herein, lung cancer (e.g., early stage lung cancer (e.g., resectable lung cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC)))) is resectable (e.g., eligible for R0 resection for healing purposes). In some cases, the lung cancer is NSCLC. In some cases, the NSCLC is squamous or non-squamous NSCLC. In some cases, lung cancer is PD-L1 positive. In some cases, lung cancer is high in PD-L1. In some cases, lung cancer is free of Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. In some cases, the lung cancer is stage II, IIIA, or IIIB lung cancer.

In some cases, in any of the methods, uses, or compositions for use described herein, the subject is eligible for platinum-based chemotherapy. In some cases, the Eastern Cooperative Oncology Group (ECOG) physical Performance Status (PS) of the subject is 0 or 1. In some cases, the subject has not received prior therapy (e.g., immunotherapy, chemotherapy, or radiation therapy) for lung cancer.

In some cases, in any of the methods, uses, or compositions for use described herein, the presence or level of circulating tumor DNA (ctDNA) can be assessed. In some cases, ctDNA is assessed in a sample (e.g., a blood sample (e.g., a plasma sample)) from the subject. In some cases, ctDNA in a sample from the subject is assessed prior to day 1 of the first dosing cycle (e.g., first dosing cycle of anti-TIGIT antagonist antibody and PD-1 axis binding antagonist). In some cases, ctDNA in a sample from a subject is assessed prior to surgery. In some cases, ctDNA in a sample from a subject is assessed post-operatively.

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

Assessment of PD-L1 expression

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

Assessment of EGFR and ALK aberrations

Methods for detecting the mutation status 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 the therapy can be characterized by one or more measurements. In some embodiments, the treatment results in an increase in the rate of Major Pathological Remission (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 results in an improvement in the results reported by the patient. In some embodiments, the treatment results in an improvement in the patient's reported physical function, character function, or GHS/QoL, as measured by EORTC-QLQ-C30. In some embodiments, the treatment results in an improvement in lung cancer symptoms such as cough, dyspnea, and chest pain reported by the patient, as measured by using EORTC-QLQ-LC 13.

In some cases, the treatment results in an increase in MPR rate in the subject, 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. In some cases, the treatment results in an increase in MPR rate in the subject, e.g., as compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without chemotherapy (e.g., platinum-based dual-agent chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)))).

In some cases, the treatment results in an increase in pCR in the subject, 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. In some cases, the treatment results in an increase in pCR in the subject, e.g., as compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without chemotherapy (e.g., platinum-based dual-agent chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel))).

In some cases, the treatment prolongs OS in the subject, 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. In some cases, the treatment extends OS in the subject, e.g., as compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without chemotherapy (e.g., platinum-based dual-agent chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)))).

In some cases, the treatment extends EFS in the subject, 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. In some cases, the treatment extends EFS in the subject, e.g., as compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody without chemotherapy (e.g., platinum-based dual-agent chemotherapy (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine) or a taxane (e.g., paclitaxel or nab-paclitaxel)))).

In some embodiments, the treatment increases MPR rate by at least 1% (e.g., 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 extends pCR of a subject for at least about 2 months (e.g., 2 to 120 months, 2.5 to 100 months, 3.0 to 80 months, 4.0 to 60 months, 5.0 to 48 months, 6.0 to 36 months, 8.0 to 24 months, or 10 to 12 months, e.g., a prolongation of 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 extends pCR of the subject for at least about 4 months (e.g., 4 to 120 months, 5 to 100 months, 6 to 80 months, 7 to 60 months, 8 to 48 months, 9 to 36 months, or 10 to 24 months, e.g., 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, 25 months, 29, months, 33, months, 35 months, or 34 months).

In some embodiments, the treatment described herein extends the EFS of the subject by at least about 2 months (e.g., 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 to 36 months, by 8.0 to 24 months, or by 1012 months, e.g., a prolongation of 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 extends EFS of the subject 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, e.g., by 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, 24 months, 25 months, 27 months, 26 months, 35 months, 31 months, 35 months, or 32 months).

In some embodiments, OS is measured as the period of time from the start of treatment to death. In some cases, the treatment extends OS of the subject 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 to 24 months, e.g., extending for 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 extends OS of the subject 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, e.g., extending for 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, 35 months, 36 months, or 36 months). In some cases, the treatment extends OS of the subject 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, e.g., 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, 34 months, 35 months, or 36 months).

C. Therapeutic and diagnostic methods and uses related to cervical cancer

Cervical cancer

Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer-related death. More than 500,000 women are diagnosed with cervical cancer each year worldwide, resulting in over 300,000 deaths. Almost 90% of cervical cancer deaths occur in developing countries. In the united states, there are 13,000 new cases of invasive cervical cancer and approximately 4000 cases of cancer-related death each year.

Treatment of early and locally advanced cervical cancer consists of surgery and radical chemoradiotherapy, respectively, and can be very effective in causing remission. However, if the cancer recurs or fails to be resolved by primary treatment, the prognosis is poor, with a 5-year survival rate of about 15%, comparable to patients with new onset metastatic disease. With few exceptions, standard of care for recurrent, persistent or new onset metastatic disease was chemotherapy plus bevacizumab based on a gynecological tumor group 240 trial that showed that bevacizumab in combination with chemotherapy improved median OS compared to chemotherapy alone (17 and 13.3 months, respectively).

Currently, there is no globally recognized standard of care after relapse or progression during chemotherapy plus bevacizumab treatment. Thus, the treatment options for these patients primarily include various cytotoxic chemotherapeutic agents, either as single agents or in combination. However, in view of historically low remission rates of about 10% to 15%, there is increasing interest in whether cytotoxic chemotherapy represents a more acceptable standard of care than optimal supportive care, given the impact and burden of such drugs on patient quality of life.

The historically low efficiency of existing therapies, coupled with the immune response due to HPV infection of cervical epithelial cells, makes cervical cancer a particularly attractive opportunity for new approaches based on immunotherapy.

Accordingly, there is a need in the art for the development of effective immunotherapies and dosing methods for treating cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer).

Methods and uses for treating cervical cancer

Provided herein are methods and uses for treating a cancer having a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) in a subject or population of subjects, 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 (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)) for one or more dosing cycles.

Dosing regimens and applications

Therapeutic methods and uses of the invention described herein include, in one aspect, administering to a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tikituyverumab) and an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab)) for one or more dosing cycles, thereby treating the subject or population of subjects.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose (e.g., a fixed dose) between about 30mg to about 1200mg (e.g., between about 30mg to about 1100mg, e.g., between about 60mg to about 1000mg, e.g., between about 100mg to about 900mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 800mg, e.g., between about 400mg to about 750mg, e.g., between about 450mg to about 750mg, e.g., between about 500mg to about 700mg, e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh uzumab) is a dose (e.g., a fixed dose) of between about 30mg to about 600mg (e.g., between about 50mg to about 600mg, e.g., between about 60mg to about 600mg, e.g., between about 100mg to about 600mg, e.g., between about 200mg to about 550mg, e.g., between about 250mg to about 500mg, e.g., between about 300mg to about 450mg, e.g., between about 350mg to about 400mg, e.g., about 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of about 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of between 30mg to 1200mg (e.g., between 30mg to 1100mg, e.g., between 60mg to 1000mg, e.g., between 100mg to 900mg, e.g., between 200mg to 800mg, e.g., between 300mg to 800mg, e.g., between 400mg to 750mg, e.g., between 450mg to 750mg, e.g., between 500mg to 700mg, e.g., between 550mg to 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh uzumab) is a dose (e.g., a fixed dose) of between 30mg to 600mg (e.g., between 50mg to 600mg, e.g., between 60mg to 600mg, e.g., between 100mg to 600mg, e.g., between 200mg to 550mg, e.g., between 250mg to 500mg, e.g., between 300mg to 450mg, e.g., between 350mg to 400mg, e.g., 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of 600mg every three weeks. In some cases, the dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., terayleigh immuzumab) administered in a combination therapy (e.g., a combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclizumab, previously referred to as pembrolizumab))) may be reduced compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is between about 80mg to about 2000mg (e.g., between about 80mg to about 1950mg, e.g., between about 80mg to about 1900mg, e.g., between about 80mg to about 1800mg, e.g., between about 100mg to about 1700mg, e.g., between about 200mg to about 1600mg, e.g., between about 300mg to about 1400mg, e.g., between about 400mg to about 1300mg, e.g., between about 500mg to about 1200mg, e.g., between about 600mg to about 1100mg, e.g., between about 700mg to about 1000mg, e.g., between about 740mg to about 940mg, e.g., between about 790mg to about 890mg, e.g., between about 815mg to about 865mg, e.g., between about 830mg to about 840mg, e.g., between about 850mg to about 840mg, e.g., a fixed dose of ± 1 mg, e.g., 0.g., 0mg ± 5mg ± 0 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 1900mg, e.g., between about 300mg to about 1700mg, e.g., between about 400mg to about 1600mg, e.g., between about 500mg to about 1600mg, e.g., between about 600mg to about 1600mg, e.g., between about 700mg to about 1600mg, e.g., between about 800mg to about 1600mg, e.g., between about 900mg to about 1500mg, e.g., between about 1000mg to about 1400mg, e.g., between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg, e.g., between about 0mg to about 1200mg, e.g., 0.g., 1200mg, e.g., 0mg, 1200mg, e.g., 0mg ± 1200mg, e.g., 1200mg, 0mg, e.g., 1200mg, about 1200mg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 2000mg, e.g., between about 300mg to about 2000mg, e.g., between about 400mg to about 2000mg, e.g., between about 500mg to about 2000mg, e.g., between about 600mg to about 1900mg, e.g., between about 700mg to about 1800mg, e.g., between about 800mg to about 1800mg, e.g., between about 900mg to about 1800 mg), e.g. between about 1000mg and about 1800mg, e.g. between about 1100mg and about 1800mg, e.g. between about 1200mg and about 1800mg, e.g. between about 1300mg and about 1800mg, e.g. between about 1400mg and about 1800mg, e.g. between about 1500mg and about 1800mg, e.g. between about 1580mg and about 1780mg, e.g. between about 1630mg and about 1730mg, e.g. between 1655mg and about 1705mg, e.g. between about 1670mg and about 1690mg, e.g. 1680mg ± 5mg, e.g. 1680 ± 2.5mg, e.g. 1680 ± 1.0mg, e.g. 1680 ± 0.5mg, e.g. 1680 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1200mg every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is between 80mg and 2000mg (e.g., between 80mg and 1950mg, e.g., between 80mg and 1900mg, e.g., between 80mg and 1800mg, e.g., between 100mg and 1700mg, e.g., between 200mg and 1600mg, e.g., between 300mg and 1400mg, e.g., between 400mg and 1300mg, e.g., between 500mg and 1200mg, e.g., between 600mg and 1100mg, e.g., between 700mg and 1000mg, e.g., between 740mg and 940mg, e.g., between 790mg and 890mg, e.g., between 815mg and 865mg, e.g., between 830mg and 850mg, e.g., 840mg ± 5mg, e.g., 840 ± 2.5mg, e.g., 840 ± 1.0mg, e.g., 840 ± 0.g., 840mg, e.g., 840mg, a fixed dose (e.g., a) of). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between 80mg to 2000mg (e.g., between 100mg to 2000mg, e.g., between 200mg to 1900mg, e.g., between 300mg to 1700mg, e.g., between 400mg to 1600mg, e.g., between 500mg to 1600mg, e.g., between 600mg to 1600mg, e.g., between 700mg to 1600mg, e.g., between 800mg to 1600mg, e.g., between 900mg to 1500mg, e.g., between 1000mg to 1400mg, e.g., between 1050mg to 1350mg, e.g., between 1100mg to 1300mg, e.g., between 1150mg to 1250mg, e.g., between 1175mg to 1225mg, e.g., between 1190mg to 1210mg, e.g., 1200mg ± 5mg, e.g., 1200mg ± 2.5, e.g., 1250mg, e.g., 0.g., 1200mg, 1200.g., 1200mg, 0.g., 1200mg, 0mg, 1200mg, e.g., 1200 mg. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is between 80mg and 2000mg every four weeks (e.g., between 100mg and 2000mg, e.g., between 200mg and 2000mg, e.g., between 300mg and 2000mg, e.g., between 400mg and 2000mg, e.g., between 500mg and 2000mg, e.g., between 600mg and 1900mg, e.g., between 700mg and 1800mg, e.g., between 800mg and 1800mg, e.g., between 900mg and 1800 mg), e.g. a dose of between 1000mg and 1800mg, e.g. between 1100mg and 1800mg, e.g. between 1200mg and 1800mg, e.g. between 1300mg and 1800mg, e.g. between 1400mg and 1800mg, e.g. between 1500mg and 1800mg, e.g. between 1580mg and 1780mg, e.g. between 1630mg and 1730mg, e.g. between 1655mg and 1705mg, e.g. between 1670mg and 1690mg, e.g. 1680mg ± 5mg, e.g. 1680 ± 2.5mg, e.g. 1680 ± 1.0mg, e.g. 1680 ± 0.5mg, e.g. 1680 mg). In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1200mg every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1200mg every three weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1680mg every four weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1680mg every four weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh itumumab) can be reduced compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose of between about 0.01mg/kg and about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg and about 45mg/kg, e.g., between about 0.1mg/kg and about 40mg/kg, e.g., not between about 1mg/kg and about 35mg/kg, e.g., between about 2.5mg/kg and about 30mg/kg, e.g., between about 5mg/kg and about 25mg/kg, e.g., between about 10mg/kg and about 20mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, or about 15 ± 0.1mg/kg, e.g., about 15mg/kg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) is between about 0.01mg/kg and about 15mg/kg of subject body weight every three weeks (e.g., between about 0.1mg/kg and about 15mg/kg, e.g., between about 0.5mg/kg and about 15mg/kg, e.g., not between about 1mg/kg and about 15mg/kg, e.g., between about 2.5mg/kg and about 15mg/kg, e.g., between about 5mg/kg and about 15mg/kg, e.g., between about 7.5mg/kg and about 15mg/kg, e.g., between about 10mg/kg and about 15mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., between about 14mg/kg and about 15mg/kg, e.g., about 15 + -1 mg/kg, e.g., about 15 + -0.5 mg/kg, e.g., about 15 + -0.2 mg/kg, e.g., about 15 + -0.1 mg/kg, e.g., about 15 mg/kg). In some cases, the effective amount of the anti-PD-L1 antagonist antibody (e.g., atuzumab) is a dose of about 15mg/kg administered every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg, or 15 ± 0.1mg/kg, e.g., 15 mg/kg) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose between 0.01mg/kg and 15mg/kg of the subject's body weight (e.g., between 0.1mg/kg and 15mg/kg, e.g., between 0.5mg/kg and 15mg/kg, e.g., between 1mg/kg and 15mg/kg, e.g., between 2.5mg/kg and 15mg/kg, e.g., between 5mg/kg and 15mg/kg, e.g., between 7.5mg/kg and 15mg/kg, e.g., between 10mg/kg and 15mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., between 14mg/kg and 15mg/kg, e.g., 15 ± 1mg/kg, e.g., 15 ± 0.5mg/kg, e.g., 15 ± 0.2mg/kg, e.g., 15mg/kg, e.g., 0.g., 15 mg/kg), e.g., 0.1mg/kg, every three weeks. In some cases, the effective amount of the anti-PD-L1 antagonist antibody (e.g., atuzumab) is a dose of 15mg/kg administered every three weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody (such as an anti-TIGIT antagonist antibody disclosed herein, e.g., teuxulizumab)) can be reduced compared to a standard dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) administered as a monotherapy or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)).

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is between about 20mg to about 1000mg (e.g., between about 40mg to about 900mg, e.g., between about 60mg to about 800mg, e.g., between about 80mg to about 700mg, e.g., between about 80mg to about 600mg, e.g., between about 100mg to about 500mg, e.g., between about 120mg to about 400mg, e.g., between about 140mg to about 300mg, e.g., between about 160mg to about 350mg, e.g., between about 180mg to about 300mg, e.g., between about 180mg to about 250mg, e.g., between about 180mg to about 220mg, e.g., between about 190mg to about 210mg, e.g., 200mg ± 5mg, e.g., 200 ± 2.5mg, e.g., 200 ± 1.0mg, e.g., 200mg, 0.5mg, e.g., a fixed dose (e.g., a dose) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is a dose (e.g., a fixed dose) of between 20mg to 1000mg (e.g., between 40mg to 900mg, e.g., between 60mg to 800mg, e.g., between 80mg to 700mg, e.g., between 80mg to 600mg, e.g., between 100mg to 500mg, e.g., between 120mg to 400mg, e.g., between 140mg to 300mg, e.g., between 160mg to 350mg, e.g., between 180mg to 300mg, e.g., between 180mg to 250mg, e.g., between 180mg to 220mg, e.g., between 190mg to 210mg, e.g., 200mg ± 5mg, e.g., 200 ± 2.5mg, e.g., 200 ± 1.0mg, e.g., 200 ± 0.5mg, e.g., 200 mg) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is a dose (e.g., a fixed dose) of 200mg every three weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palboclizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh unizumab) can be reduced compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.

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

In any of the methods and uses of the invention, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh mab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) may be 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 dosing cycle of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) continues until clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity) is lost). In some cases, each administration cycle is about 14 to 28 days in length (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). In some cases, each administration cycle is about 21 days in length. In some cases, each administration cycle is about 14 days in length. In some cases, each administration cycle is about 28 days in length. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered at about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 600mg (e.g., a fixed dose), on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks). In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is administered intravenously at a dose of 600mg (e.g., a fixed dose), at day 1 of each 21-day cycle (i.e., at a dose of 600mg every three weeks). Similarly, in some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) is administered on about day 1 (e.g., day 1 ± 3 days) of each dosing cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palivizumab)) is administered intravenously at a dose of about 200mg on day 1 of each 21-day cycle (i.e., at a dose of about 200mg every three weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 240mg on day 1 of each 14-day cycle (i.e., at a dose of about 240mg every two weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 480mg on day 1 of each 28-day cycle (i.e., at a dose of about 480mg every four weeks). In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palivizumab)) is administered intravenously at a dose of about 200mg on day 1 of each 21-day cycle (i.e., at a dose of about 200mg every three weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 240mg on day 1 of each 14-day cycle (i.e., at a dose of about 240mg every two weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is administered intravenously at a dose of about 480mg (i.e., at a dose of about 480mg every four weeks) on day 1 of each 28-day cycle.

In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or the anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) are administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose (e.g., a fixed dose) of about 600mg on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attentizumab) is administered intravenously at a dose (e.g., a fixed dose) of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks.) for example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose (i.g., a dose of about 600mg on day 1 of each 21-day cycle (i.e.g., a dose of about 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., a paulizumab) is administered intravenously at a dose (e.g., a fixed dose) on day 1 of about 200mg, e.g., an anti-TIGIT antagonist antibody as disclosed herein), fixed dose) (i.e., at a dose of 1200mg every three weeks) was administered intravenously. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of 600mg (i.e., at a dose of 600mg every three weeks) on day 1 of each 21-day cycle, and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., palbociclumab) is administered intravenously at a dose of 200mg (i.e., at a dose of 200mg every three weeks) on day 1 of each 21-day cycle.

In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or the anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) are administered about day 1 (e.g., day 1 ± 3) of the first dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose (e.g., a fixed dose) of about 600mg on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab) is administered intravenously at a dose (e.g., a fixed dose) of about 240mg on day 1 of each 14-day cycle (i.e., at a dose of about 240mg every two weeks.) for example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose (i.g., a dose of about 600mg on day 1 of each 21-day cycle (i.e.g., a dose of about 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., an anti-TIGIT-L1 axis binding antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., a fixed dose) is administered intravenously at a dose, e.g., a dose of about 600mg in about 1 mg every 28-TIGIT 1 day (e.g., a fixed dose) on day of about 480mg, e.g., a fixed dose) on day of about 1 week, e.g., an anti-TIGIT antagonist antibody, e.g., an intravenous dose of about 600mg in each 21-1 week, fixed dose) (i.e., at a dose of 240mg every two weeks) was administered intravenously. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of 600mg on day 1 of each 21-day cycle (i.e., at a dose of 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab) is administered intravenously at a dose of 480mg on day 1 of each 28-day cycle (i.e., at a dose of 480mg every four weeks).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is administered to a subject or population of subjects by intravenous infusion over about 60 ± 15 minutes (e.g., 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, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) is administered to a subject or population of subjects by intravenous infusion over 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).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is administered to a subject or population of subjects by intravenous infusion over 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). In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (parbolimab, previously referred to as pembrolizumab))) is administered to a subject or population of subjects by intravenous infusion over 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).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh mab) is administered to the subject or population of subjects prior to PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))). In some cases, for example, the method comprises an intermediate first observation period after administration of the anti-TIGIT antagonist antibody and before administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))). In some cases, the method further comprises a second observation period following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))). 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 (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))). In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. Where the length of the first observation period and the second observation period are each about 60 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 30 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), respectively). Where the length of the first observation period and the second observation period are each about 30 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 15 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), respectively).

In other instances, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))) is administered to a subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibrinout (ibritumomab) tiuxetan). In some cases, for example, after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) and before administration of the anti-TIGIT antagonist antibody, the method comprises an intermediate first observation period. In some cases, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some cases, the method includes both a first observation period after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) and a second observation period after administration of an 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. Where the length of the first observation period and the second observation period are each about 60 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)), and an anti-TIGIT antagonist antibody, respectively). Where the length of the first observation period and the second observation period are each about 30 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)), and an anti-TIGIT antagonist antibody, respectively).

In other instances, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) are administered concurrently to the subject or population of subjects. In some cases, for example, following administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), the method comprises an observation period. In some cases, the length of the observation period is between about 30 minutes and about 60 minutes. Where the length of the observation period is about 60 minutes, the method can comprise recording vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject or population of subjects over the observation period about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), and an anti-TIGIT antagonist antibody, respectively). Where the length of the observation period is about 30 minutes, the method can comprise recording vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject or population of subjects over the observation period about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), and an anti-TIGIT antagonist antibody, respectively).

In another aspect, the invention provides a method of treating a subject or population of subjects having IVB-stage, metastatic, recurrent or persistent cervical cancer by administering to the subject or population of subjects one or more cycles of dosing of: a dose (e.g., fixed dose) of 600mg every three weeks and a dose (e.g., fixed dose) of 1200mg every three weeks of alemtuzumab, wherein the anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO:17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having stage IVB, metastatic, recurrent or persistent cervical cancer by administering to the subject or population of subjects one or more cycles of dosing of: a dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 1200mg every three weeks (e.g., fixed dose) of atelizumab.

In another aspect, the invention provides a method of treating a subject or population of subjects having stage IVB, metastatic, recurrent or persistent cervical cancer by administering to the subject or population of subjects one or more cycles of dosing of: a dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 200mg every three weeks (e.g., fixed dose) of palboceprizumab.

In another aspect, the invention provides a method of treating a subject or population of subjects having stage IVB, metastatic, recurrent or persistent cervical cancer by administering to the subject or population of subjects one or more cycles of dosing of: a dose of 600mg every three weeks (e.g., fixed dose) of tenerayleigh eculizumab and a dose of 240mg every two weeks (e.g., fixed dose) of nivolumab.

In another aspect, the invention provides a method of treating a subject or population of subjects having stage IVB, metastatic, recurrent or persistent cervical cancer by administering to the subject or population of subjects one or more cycles of dosing of: a dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 480mg every four weeks (e.g., fixed dose) of nivolumab.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tenellumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects an effective amount of the anti-TIGIT antagonist antibody and an effective amount of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., PD, martuzumab) or an anti-TIGIT-1 antibody (e.g., MDX-1 axis binding antagonist antibody (e.g., MDX-1106, previously referred to as nivolumab (m mab, or previously referred to as mepiquab)).

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose (e.g., a fixed dose) between about 30mg to about 1200mg (e.g., between about 30mg to about 1100mg, e.g., between about 60mg to about 1000mg, e.g., between about 100mg to about 900mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 800mg, e.g., between about 400mg to about 750mg, e.g., between about 450mg to about 750mg, e.g., between about 500mg to about 700mg, e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of between about 30mg to about 600mg (e.g., between about 50mg to about 600mg, e.g., between about 60mg to about 600mg, e.g., between about 100mg to about 600mg, e.g., between about 200mg to about 550mg, e.g., between about 250mg to about 500mg, e.g., between about 300mg to about 450mg, e.g., between about 350mg to about 400mg, e.g., about 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a dose (e.g., a fixed dose) of between 30mg to 1200mg (e.g., between 30mg to 1100mg, e.g., between 60mg to 1000mg, e.g., between 100mg to 900mg, e.g., between 200mg to 800mg, e.g., between 300mg to 800mg, e.g., between 400mg to 750mg, e.g., between 450mg to 750mg, e.g., between 500mg to 700mg, e.g., between 550mg to 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh uzumab) is a dose of between 30mg to 600mg (e.g., between 50mg to 600mg, e.g., between 60mg to 600mg, e.g., between 100mg to 600mg, e.g., between 200mg to 550mg, e.g., between 250mg to 500mg, e.g., between 300mg to 450mg, e.g., between 350mg to 400mg, e.g., 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 600mg every three weeks. In some cases, the dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tamulizumab) to be administered in a combination therapy (e.g., a combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclizumab, previously referred to as pembrolizumab)) can be reduced compared to a standard dose of the anti-TIGIT antagonist antibody to be administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 80mg to about 2000mg (e.g., between about 80mg to about 1950mg, e.g., between about 80mg to about 1900mg, e.g., between about 80mg to about 1800mg, e.g., between about 100mg to about 1700mg, e.g., between about 200mg to about 1600mg, e.g., between about 300mg to about 1400mg, e.g., between about 400mg to about 1300 mg), e.g., a dose (e.g., a fixed dose) of between about 500mg to about 1200mg, e.g., between about 600mg to about 1100mg, e.g., between about 700mg to about 1000mg, e.g., between about 740mg to about 940mg, e.g., between about 790mg to about 890mg, e.g., between about 815mg to about 865mg, e.g., between about 830mg to about 850mg, e.g., 840mg ± 5mg, e.g., 840 ± 2.5mg, e.g., 840 ± 1.0mg, e.g., 840 ± 0.5mg, e.g., 840 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 1900mg, e.g., between about 300mg to about 1700mg, e.g., between about 400mg to about 1600mg, e.g., between about 500mg to about 1600mg, e.g., between about 600mg to about 1600mg, e.g., between about 700mg to about 1600mg, e.g., between about 800mg to about 1600mg, e.g., between about 900mg to about 1500mg, e.g., between about 1000mg to about 1400mg, e.g., between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 5mg, e.g., between about 0mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., 1200mg, e.g., between about 1175mg to about 1225mg, e.g., between about 0mg, e.g., about 1200mg, such as about 1210mg, 0mg, such as about 1200mg, 0.g., about 1200mg, 0mg, such as ± 0mg, such as about 1200mg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 2000mg, e.g., between about 300mg to about 2000mg, e.g., between about 400mg to about 2000mg, e.g., between about 500mg to about 2000mg, e.g., between about 600mg to about 1900mg, e.g., between about 700mg to about 1800mg, e.g., between about 800mg to about 1800mg, e.g., between about 900mg to about 1800 mg), e.g. between about 1000mg and about 1800mg, e.g. between about 1100mg and about 1800mg, e.g. between about 1200mg and about 1800mg, e.g. between about 1300mg and about 1800mg, e.g. between about 1400mg and about 1800mg, e.g. between about 1500mg and about 1800mg, e.g. between about 1580mg and about 1780mg, e.g. between about 1630mg and about 1730mg, e.g. between 1655mg and about 1705mg, e.g. between about 1670mg and about 1690mg, e.g. 1680mg ± 5mg, e.g. 1680 ± 2.5mg, e.g. 1680 ± 1.0mg, e.g. 1680 ± 0.5mg, e.g. 1680 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is between 80mg and 2000mg (e.g., between 80mg and 1950mg, e.g., between 80mg and 1900mg, e.g., between 80mg and 1800mg, e.g., between 100mg and 1700mg, e.g., between 200mg and 1600mg, e.g., between 300mg and 1400mg, e.g., between 400mg and 1300mg, e.g., between 500mg and 1200mg, e.g., between 600mg and 1100mg, e.g., between 700mg and 1000mg, e.g., between 740mg and 940mg, e.g., between 790mg and 890mg, e.g., between 815mg and 865mg, e.g., between 830mg and 850mg, e.g., 840mg ± 5mg, e.g., 840 ± 2.5mg, e.g., 840 ± 1.0mg, e.g., 840 ± 0.g., 840mg, e.g., 840mg, a fixed dose (e.g., a) of). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between 80mg to 2000mg (e.g., between 100mg to 2000mg, e.g., between 200mg to 1900mg, e.g., between 300mg to 1700mg, e.g., between 400mg to 1600mg, e.g., between 500mg to 1600mg, e.g., between 600mg to 1600mg, e.g., between 700mg to 1600mg, e.g., between 800mg to 1600mg, e.g., between 900mg to 1500mg, e.g., between 1000mg to 1400mg, e.g., between 1050mg to 1350mg, e.g., between 1100mg to 1300mg, e.g., between 1150mg to 1250mg, e.g., between 1175mg to 1225mg, e.g., between 1190mg to 1210mg, e.g., 1200mg ± 5mg, e.g., 1200mg ± 2.5, e.g., 1250mg, e.g., 0.g., 1200mg, 1200.g., 1200mg, 0.g., 1200mg, 0mg, 1200mg, e.g., 1200 mg. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is between 80mg and 2000mg every four weeks (e.g., between 100mg and 2000mg, e.g., between 200mg and 2000mg, e.g., between 300mg and 2000mg, e.g., between 400mg and 2000mg, e.g., between 500mg and 2000mg, e.g., between 600mg and 1900mg, e.g., between 700mg and 1800mg, e.g., between 800mg and 1800mg, e.g., between 900mg and 1800 mg), e.g. a dose of between 1000mg and 1800mg, e.g. between 1100mg and 1800mg, e.g. between 1200mg and 1800mg, e.g. between 1300mg and 1800mg, e.g. between 1400mg and 1800mg, e.g. between 1500mg and 1800mg, e.g. between 1580mg and 1780mg, e.g. between 1630mg and 1730mg, e.g. between 1655mg and 1705mg, e.g. between 1670mg and 1690mg, e.g. 1680mg ± 5mg, e.g. 1680 ± 2.5mg, e.g. 1680 ± 1.0mg, e.g. 1680 ± 0.5mg, e.g. 1680 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1200mg every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1200mg every three weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1680mg every four weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1680mg every four weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) to be administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh itumumab) can be reduced compared to a standard dose of the anti-PD-L1 antagonist antibody to be administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palivizumab)) is between about 20mg to about 1000mg (e.g., between about 40mg to about 900mg, e.g., between about 60mg to about 800mg, e.g., between about 80mg to about 700mg, e.g., between about 80mg to about 600mg, e.g., between about 100mg to about 500mg, e.g., between about 120mg to about 400mg, e.g., between about 140mg to about 300mg, e.g., between about 160mg to about 350mg, e.g., between about 180mg to about 300mg, e.g., between about 180mg to about 250mg, e.g., between about 180mg to about 220mg, e.g., between about 190mg to about 210mg, e.g., 200mg ± 5mg, e.g., 200 ± 2.5mg, e.g., 200 ± 1.0mg, e.g., 200.5 mg, e.g., 200.0.5 mg, e.g., 200 ± 2.0 mg), e.g., a fixed dose (e.g., a dose) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is a dose (e.g., a fixed dose) of between 20mg to 1000mg (e.g., between 40mg to 900mg, e.g., between 60mg to 800mg, e.g., between 80mg to 700mg, e.g., between 80mg to 600mg, e.g., between 100mg to 500mg, e.g., between 120mg to 400mg, e.g., between 140mg to 300mg, e.g., between 160mg to 350mg, e.g., between 180mg to 300mg, e.g., between 180mg to 250mg, e.g., between 180mg to 220mg, e.g., between 190mg to 210mg, e.g., 200mg ± 5mg, e.g., 200 ± 2.5mg, e.g., 200 ± 1.0mg, e.g., 200 ± 0.5mg, e.g., 200 mg) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is a dose of about 200mg every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclizumab)) is a dose of 200mg every three weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., paribizumab) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as the anti-TIGIT antagonist antibodies disclosed herein, e.g., tegraleighumab)) can be reduced compared to a standard dose of an anti-PD-L1 antagonist antibody administered as a monotherapy.

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

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose of between about 0.01mg/kg and about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg and about 45mg/kg, e.g., between about 0.1mg/kg and about 40mg/kg, e.g., not between about 1mg/kg and about 35mg/kg, e.g., between about 2.5mg/kg and about 30mg/kg, e.g., between about 5mg/kg and about 25mg/kg, e.g., between about 10mg/kg and about 20mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, or about 15 ± 0.1mg/kg, e.g., about 15mg/kg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) is between about 0.01mg/kg and about 15mg/kg of subject body weight every three weeks (e.g., between about 0.1mg/kg and about 15mg/kg, e.g., between about 0.5mg/kg and about 15mg/kg, e.g., not between about 1mg/kg and about 15mg/kg, e.g., between about 2.5mg/kg and about 15mg/kg, e.g., between about 5mg/kg and about 15mg/kg, e.g., between about 7.5mg/kg and about 15mg/kg, e.g., between about 10mg/kg and about 15mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., between about 14mg/kg and about 15mg/kg, e.g., about 15 + -1 mg/kg, e.g., about 15 + -0.5 mg/kg, e.g., about 15 + -0.2 mg/kg, e.g., about 15 + -0.1 mg/kg, e.g., about 15 mg/kg). In some cases, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atlizumab) is a dose of about 15mg/kg to be administered every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg, or 15 ± 0.1mg/kg, e.g., 15 mg/kg) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose of between 0.01mg/kg and 15mg/kg of subject body weight (e.g., between 0.1mg/kg and 15mg/kg, e.g., between 0.5mg/kg and 15mg/kg, e.g., between 1mg/kg and 15mg/kg, e.g., between 2.5mg/kg and 15mg/kg, e.g., between 5mg/kg and 15mg/kg, e.g., between 7.5mg/kg and 15mg/kg, e.g., between 10mg/kg and 15mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., between 14mg/kg and 15mg/kg, e.g., 15 ± 1mg/kg, e.g., 15 ± 0.5mg/kg, e.g., 15 ± 0.2mg/kg, e.g., 15mg/kg, e.g., 15mg/kg, every three weeks. In some cases, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atlizumab) is a dose of 15mg/kg to be administered every three weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) or an anti-PD-1 antagonist antibody (e.g., combination therapy with an anti-TIGIT antagonist antibody such as disclosed herein, e.g., tebrizumab), or an anti-PD-1 antagonist antibody (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbrizumab, previously referred to as pembrolizumab))) administered in a combination therapy (e.g., combination therapy with an anti-TIGIT antagonist antibody such as disclosed herein, e.g., tebriuzumab)) can be reduced compared to a standard dose of the PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (paluzumab, previously referred to pembrolizumab)) administered as a monotherapy.

anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., tenellizumab) and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies (e.g., atuzumab) or anti-PD-1 antagonist antibodies (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) can be 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 dosing cycle of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) continues until clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity) is lost). In some cases, each administration cycle is about 14 to 28 days in length (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). In some cases, each administration cycle is about 21 days in length. In some cases, each administration cycle is about 14 days in length. In some cases, each administration cycle is about 28 days in length. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered at about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose (e.g., a fixed dose) of about 600mg (i.e., at a dose of about 600mg every three weeks) on day 1 of each 21-day cycle. Similarly, in some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclizumab, previously referred to as pembrolizumab))) is to be administered at about day 1 (e.g., day 1 ± 3 days) of each dosing cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is to be administered intravenously at a dose (e.g., a fixed dose) of about 1200mg (i.e., at a dose of about 1200mg every three weeks) on day 1 of each 21-day cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palivizumab)) is to be administered intravenously at a dose of about 200mg on day 1 of each 21-day cycle (i.e., at a dose of about 200mg every three weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of about 240mg on day 1 of each 14-day cycle (i.e., at a dose of about 240mg every two weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of about 480mg (i.e., at a dose of about 480mg every four weeks) on day 1 of each 28-day cycle. In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or the anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) are to be administered at about day 1 (e.g., day 1 ± 3) of each dosing cycle. In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) or the anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) are to be administered at about day 1 (e.g., day 1 ± 3) of the first dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of about 600mg (i.e., at a dose of about 600mg every three weeks) on day 1 of each 21-day cycle, and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab) is to be administered intravenously at a dose of about 240mg (i.e., at a dose of about 240mg every two weeks) on day 1 of each 14-day cycle, e.g., an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of about 600mg (i.e.g., at a dose of about 600mg every three weeks) on day 1 of each 21-day cycle, and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab) is to be administered intravenously at a dose of about 480mg, e.g., an anti-TIGIT-1 axis binding antagonist antibody (e.g., an anti-1 axis binding antagonist antibody) is to be administered intravenously at a dose of about 200mg, e.g., an anti-PD antagonist antibody) is to be administered intravenously at a fixed dose of about 200mg, e.g., an anti-1 axis binding antagonist (e.g., an anti-1 axis). The PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of 240mg (i.e., at a dose of 240mg every two weeks) on day 1 of each 14-day cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of 480mg (i.e., at a dose of 480mg every four weeks) on day 1 of each 28-day cycle. In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or the anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) are to be administered on day 1 (e.g., day 1 ± 3) of each dosing cycle. In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or the anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) are to be administered on day 1 (e.g., day 1 ± 3) of the first dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of 600mg on day 1 of each 21-day cycle (i.e., at a dose of 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab) is to be administered intravenously at a dose of 240mg on day 1 of each 14-day cycle (i.e., at a dose of 240mg every two weeks.) for example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of 600mg on day 1 of each 21-day cycle (i.e., at a dose of 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., nivolumab) is to be administered intravenously at a dose of 480mg on day 1 of each 28-day cycle (i.g., at a dose of 480mg every four weeks).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered to a subject or population of subjects by intravenous infusion over about 60 ± 15 minutes (e.g., 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, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) is to be administered to a subject or population of subjects by intravenous infusion over 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).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is to be administered to a subject or population of subjects by intravenous infusion over 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). In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) is to be administered to a subject or population of subjects by intravenous infusion over 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).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is to be administered to a subject or population of subjects prior to PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (parbollizumab, previously referred to as pembrolizumab))). In some cases, for example, the method comprises an intermediate first observation period after administration of the anti-TIGIT antagonist antibody and before administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))). In some cases, the method further comprises a second observation period after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously known as pembrolizumab))). 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 (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))). In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. Where the length of the first observation period and the second observation period are each about 60 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 30 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), respectively). Where the length of the first observation period and the second observation period are each about 30 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 15 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), respectively).

In other instances, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))) is to be administered to a subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tireli euzumab). In some cases, for example, after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) and before 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 after administration of the anti-TIGIT antagonist antibody. In some cases, the method includes both a first observation period after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) and a second observation period after administration of an 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. Where the length of the first observation period and the second observation period are each about 60 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)), and an anti-TIGIT antagonist antibody, respectively). Where the length of the first observation period and the second observation period are each about 30 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject or population of subjects for the first and second observation periods about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)), and an anti-TIGIT antagonist antibody, respectively).

In other instances, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) are to be administered simultaneously to a subject or population of subjects. In some cases, for example, following administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), the method comprises an observation period. In some cases, the length of the observation period is between about 30 minutes and about 60 minutes. Where the length of the observation period is about 60 minutes, the method can include recording the vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), and the anti-TIGIT antagonist antibody, respectively). Where the length of the observation period is about 30 minutes, the method can include recording the vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), and the anti-TIGIT antagonist antibody, respectively).

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of: a dose (e.g., fixed dose) of 600mg every three weeks and a dose (e.g., fixed dose) of 1200mg every three weeks of alemtuzumab, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

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

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of: a dose (e.g., fixed dose) of 600mg every three weeks and a dose (e.g., fixed dose) of 240mg nivolumab every two weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of: a dose (e.g., fixed dose) of 600mg every three weeks and a dose (e.g., fixed dose) of 480mg every four weeks of nivolumab, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of: a dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 1200mg every three weeks (e.g., fixed dose) of atelizumab.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., MK-3475 (palbociclumab, previously referred to as pembrolizumab))) for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of: a dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 200mg every three weeks (e.g., fixed dose) of palbociclumab.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh immitumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab))) for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of: a dose of 600mg every three weeks (e.g., fixed dose) of tenerayleigh eculizumab and a dose of 240mg every two weeks (e.g., fixed dose) of nivolumab.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh immitumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab))) for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of: a dose of 600mg every three weeks (e.g., fixed dose) of tegravitumumab and a dose of 480mg every four weeks (e.g., fixed dose) of nivolumab.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh mab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering one or more dosing cycles of the medicament to the subject or population of subjects, and wherein the medicament is formulated for administration of an effective amount of the anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis binding antagonist (e.g., anti-PD-1 axis binding antibody (e.g., anti-PD-1 antibody (e.g., mmpomuzumab), e.g., mmbovisfatumab (MDX-341106, previously referred to as anti-PD-L-3475).

In another aspect, the invention provides a method of treating a subject or population of subjects having cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., alemtuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (former mab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)), and wherein the medicament is formulated for administration of an effective amount of an anti-tig antagonist antibody and an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., alemtuzumab or an anti-PD-1 antagonist antibody (e.g., martlizumab (e.g., martensix-341106) or former referred to as mklizumab)).g., anti-TIGIT-L1 antagonist antibody (e.g., mintuzumab).

In another aspect, the invention provides a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab))) for use in a method of treating a subject or population of subjects suffering from a cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) having a detectable PD-L1 expression level, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the drug and an anti-TIGIT antagonist antibody, and wherein the medicament is formulated for administering an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (martensiab) or anti-3475 (MK-L1 antagonist antibody, previously referred to as a pembrolizumab (previously referred to as tigolizumab))) and an effective amount of anti-tig.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh uzumab) is a dose (e.g., a fixed dose) of between about 30mg to about 1200mg (e.g., between about 30mg to about 1100mg, e.g., between about 60mg to about 1000mg, e.g., between about 100mg to about 900mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 800mg, e.g., between about 400mg to about 750mg, e.g., between about 450mg to about 750mg, e.g., between about 500mg to about 700mg, e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is between about 30mg to about 600mg (e.g., between about 50mg to about 600mg, e.g., between about 60mg to about 600mg, e.g., between about 100mg to about 600mg, e.g., between about 200mg to about 550mg, e.g., between about 250mg to about 500mg, e.g., between about 300mg to about 450mg, e.g., between about 350mg to about 400mg, e.g., about 375 mg) every three weeks (e.g., a dose of between 30mg and 1200mg (e.g. between 30mg and 1100mg, e.g. between 60mg and 1000mg, e.g. between 100mg and 900mg, e.g. between 200mg and 800mg, e.g. between 300mg and 800mg, e.g. between 400mg and 750mg, e.g. between 450mg and 750mg, e.g. between 500mg and 700mg, e.g. between 550mg and 650mg, e.g. 600mg ± 10mg, e.g. 600 ± 6mg, e.g. 600 ± 5mg, e.g. 600 ± 3mg, e.g. 600 ± 1mg, e.g. 600 ± 0.5mg, e.g. 600 mg)). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh uzumab) is a dose of between 30mg to 600mg (e.g., between 50mg to 600mg, e.g., between 60mg to 600mg, e.g., between 100mg to 600mg, e.g., between 200mg to 550mg, e.g., between 250mg to 500mg, e.g., between 300mg to 450mg, e.g., between 350mg to 400mg, e.g., 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 600mg every three weeks. In some cases, the dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) to be administered in a combination therapy (e.g., a combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab)) may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody to be administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is between about 80mg to about 2000mg (e.g., between about 80mg to about 1950mg, e.g., between about 80mg to about 1900mg, e.g., between about 80mg to about 1800mg, e.g., between about 100mg to about 1700mg, e.g., between about 200mg to about 1600mg, e.g., between about 300mg to about 1400mg, e.g., between about 400mg to about 1300mg, e.g., between about 500mg to about 1200mg, e.g., between about 600mg to about 1100mg, e.g., between about 700mg to about 1000mg, e.g., between about 740mg to about 940mg, e.g., between about 790mg to about 890mg, e.g., between about 815mg to about 865mg, e.g., between about 830mg to about 840mg, e.g., about 850mg, 5.g., ± 5mg, 840 + -1.0 mg, e.g., 840 + -0.5 mg, e.g., 840mg (e.g., between 80mg and 2000mg (e.g., between 80mg and 1950mg, e.g., between 80mg and 1900mg, e.g., between 80mg and 1800mg, e.g., between 100mg and 1700mg, e.g., between 200mg and 1600mg, e.g., between 300mg and 1400mg, e.g., between 400mg and 1300mg, e.g., between 500mg and 1200mg, e.g., between 600mg and 1100mg, e.g., between 700mg and 1000mg, e.g., between 740mg and 940mg, e.g., between 790mg and 890mg, e.g., between 815mg and 865mg, e.g., between 830mg and 850mg, e.g., 840mg + -5 mg, e.g., 840 + -2.5 mg, e.g., 840 + -1.0 mg, e.g., 840 + -0 mg, e.g., 840 + -0.5 mg, e.g., 840 mg) of an antagonist (e.g., such as a fixed) in some cases, e.g., 1-1L-1.g., 1-PD antagonist (e.g., PD-1-PD), attritumab)) is between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 1900mg, e.g., between about 300mg to about 1700mg, e.g., between about 400mg to about 1600mg, e.g., between about 500mg to about 1600mg, e.g., between about 600mg to about 1600mg, e.g., between about 700mg to about 1600mg, e.g., between about 800mg to about 1600mg, e.g., between about 900mg to about 1500mg, e.g., between about 1000mg to about 1400mg, e.g., between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg (e.g., a dose of between 100mg and 2000mg, such as between 200mg and 1900mg, such as between 300mg and 1700mg, such as between 400mg and 1600mg, such as between 500mg and 1600mg, such as between 600mg and 1600mg, such as between 700mg and 1600mg, such as between 800mg and 1600mg, such as between 900mg and 1500mg, such as between 1000mg and 1400mg, such as between 1050mg and 1350mg, such as between 1100mg and 1300mg, such as between 1150mg and 1250mg, such as between 1175mg and 1225 mg), such as between 1190mg and 1210mg (such as between 1190mg and 1210 mg), such as 1200mg ± 5mg, such as 1200 ± 2.5mg, such as 1200 ± 1.0mg, such as 1200 ± 0.5mg, such as 1200 mg. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 2000mg, e.g., between about 300mg to about 2000mg, e.g., between about 400mg to about 2000mg, e.g., between about 500mg to about 2000mg, e.g., between about 600mg to about 1900mg, e.g., between about 700mg to about 1800mg, e.g., between about 800mg to about 1800mg, e.g., between about 900mg to about 1800mg, e.g., between about 1000mg to about 1800mg, e.g., between about 1100mg to about 1800mg, e.g., between about 1200mg to about 1800mg, e.g., between about 1300mg to about 1800mg, e.g., between about 1400mg to about 1800mg, e.g., between about 1800mg to about 1500mg, e.g., between about 80mg to about 1580mg, e.g., between about 1780mg, between about 1630mg and about 1730mg, for example, between about 1655mg and about 1705mg, for example, between about 1670mg and about 1690mg (for example, between 100mg and 2000mg, for example, between 200mg and 2000mg, for example, between 300mg and 2000mg, for example, between 400mg and 2000mg, for example, between 500mg and 2000mg, for example, between 600mg and 1900mg, for example, between 700mg and 1800mg, for example, between 800mg and 1800mg, for example, between 900mg and 1800mg, e.g. between 1000mg and 1800mg, e.g. between 1100mg and 1800mg, e.g. between 1200mg and 1800mg, e.g. between 1300mg and 1800mg, e.g. between 1400mg and 1800mg, e.g. between 1500mg and 1800mg, e.g. between 1580mg and 1780mg, e.g. between 1630mg and 1730mg, e.g. between 1655mg and 1705mg, e.g. between 1670mg and 1690 mg), e.g. 1680mg ± 5mg, e.g. 1680 ± 2.5mg, e.g. 1680 ± 1.0mg, e.g., 1680 ± 0.5mg, e.g., 1680 mg). In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1200mg every three weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1200mg every three weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1680mg every four weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1680mg every four weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) to be administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as the anti-TIGIT antagonist antibodies disclosed herein, e.g., tirayleighab) may be reduced as compared to a standard dose of the anti-PD-L1 antagonist antibody to be administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is between about 20mg to about 1000mg (e.g., between about 40mg to about 900mg, e.g., between about 60mg to about 800mg, e.g., between about 80mg to about 700mg, e.g., between about 80mg to about 600mg, e.g., between about 100mg to about 500mg, e.g., between about 120mg to about 400mg, e.g., between about 140mg to about 300mg, e.g., between about 160mg to about 350mg, e.g., between about 180mg to about 300mg, e.g., between about 180mg to about 250mg, e.g., between about 180mg to about 220 mg), for example, a dose (e.g., a fixed dose) of between about 190mg to about 210mg (e.g., between 40mg to 900mg, e.g., between 60mg to 800mg, e.g., between 80mg to 700mg, e.g., between 80mg to 600mg, e.g., between 100mg to 500mg, e.g., between 120mg to 400mg, e.g., between 140mg to 300mg, e.g., between 160mg to 350mg, e.g., between 180mg to 300mg, e.g., between 180mg to 250mg, e.g., between 180mg to 220mg, e.g., between 190mg to 210 mg), e.g., 200mg ± 5mg, e.g., 200 ± 2.5mg, e.g., 200 ± 1.0mg, e.g., 200 ± 0.5mg, e.g., 200 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is a dose of about 200mg every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclizumab)) is a dose of 200mg every three weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palboclizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh unizumab) can be reduced compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.

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

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose of between about 0.01mg/kg and about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg and about 45mg/kg, e.g., between about 0.1mg/kg and about 40mg/kg, e.g., not between about 1mg/kg and about 35mg/kg, e.g., between about 2.5mg/kg and about 30mg/kg, e.g., between about 5mg/kg and about 25mg/kg, e.g., between about 10mg/kg and about 20mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, or about 15 ± 0.1mg/kg, e.g., about 15mg/kg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) is between about 0.01mg/kg and about 15mg/kg of subject body weight every three weeks (e.g., between about 0.1mg/kg and about 15mg/kg, e.g., between about 0.5mg/kg and about 15mg/kg, e.g., not between about 1mg/kg and about 15mg/kg, e.g., between about 2.5mg/kg and about 15mg/kg, e.g., between about 5mg/kg and about 15mg/kg, e.g., between about 7.5mg/kg and about 15mg/kg, e.g., between about 10mg/kg and about 15mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., between about 14mg/kg and about 15mg/kg, e.g., about 15 + -1 mg/kg, e.g., about 15 + -0.5 mg/kg, e.g., about 15 + -0.2 mg/kg, e.g., about 15 + -0.1 mg/kg, e.g., about 15 mg/kg). In some cases, an effective amount of an anti-PD-L1 antagonist antibody (e.g., atlizumab) is a dose of about 15mg/kg to be administered every three weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as the anti-TIGIT antagonist antibodies disclosed herein, e.g., tirayleighab) may be reduced compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.

In any use of the invention, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tenellumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) can be 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 dosing cycle of a drug comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab)) continues until clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity) is lost). In some cases, each administration cycle is about 14 to 28 days in length (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). In some cases, each administration cycle is about 21 days in length. In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered at about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of about 600mg (e.g., a fixed dose) (i.e., at a dose of about 600mg every three weeks) on day 1 of each 21-day cycle. Similarly, in some cases, a medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclizumab, previously referred to as pembrolizumab))) is to be administered at about day 1 (e.g., day 1 ± 3 days) of each dosing cycle. For example, a drug comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is to be administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks). For example, a drug comprising a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is to be administered intravenously at a dose of about 200mg on day 1 of each 21-day cycle (i.e., at a dose of about 200mg every three weeks). For example, a drug comprising a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of about 240mg on day 1 of each 14-day cycle (i.e., at a dose of about 240mg every two weeks). For example, a drug comprising a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab)) is to be administered intravenously at a dose of about 480mg (i.e., at a dose of about 480mg every four weeks) on day 1 of each 28-day cycle. In some cases, a drug comprising both an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) is to be administered on about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, a drug comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of about 600mg (i.e., at a dose of about 600mg every three weeks) on day 1 of each 21-day cycle, and a drug comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attentizumab) is to be administered intravenously at a dose of about 1200mg (i.e., at a dose of about 1200mg every three weeks) on day 1 of each 21-day cycle, e.g., a drug comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of about 600mg (i.e., at a dose of about 600mg every three weeks) on day 1 of each 21-day cycle, and a drug comprising a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., a paulimab) is to be administered at a dose of about 600mg, e.g., an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody, e.g., a drug) is to be administered intravenously at a dose of about 600mg, e.g., an anti-TIGIT antagonist antibody at a dose of about 1 week 1 to be administered at a dose of about 600mg, e.g., an intravenous dose of about 1 week, e.g., an anti-TIGIT antagonist antibody (e.g., about 600mg, e.g., about 1 antagonist antibody to be administered at a dose of about 1 antagonist antibody, e.g., a TIGIT is to be administered intravenously at a dose of about 600mg, e.g., a TIGIT antagonist antibody to be administered in every three weeks), at a dose of about 240mg every two weeks). For example, a drug comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is to be administered intravenously at a dose of about 600mg on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks), and a drug comprising a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., nivolumab) is to be administered intravenously at a dose of about 480mg on day 1 of each 28-day cycle (i.e., at a dose of about 480mg every four weeks).

In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to a subject or population of subjects by intravenous infusion over about 60 ± 15 minutes (e.g., 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, a medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (parbolimab, previously referred to as pembrolizumab)) is to be administered to a subject or population intravenously over 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).

In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to a subject or population of subjects by intravenous infusion over 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). In some cases, a medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) is to be administered to a subject or population of subjects by intravenous infusion over 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).

In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is to be administered to a subject or population of subjects prior to a medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab))). In some cases, for example, after administration of the medicament comprising the anti-TIGIT antagonist antibody and before administration of the medicament comprising the anti-PD-L1 antagonist antibody, the method comprises an intermediate first observation period. In some cases, the method further comprises a second observation period after administration of the anti-PD-L1 antagonist antibody. In some cases, the method includes a first observation period after administration of the medicament comprising the anti-TIGIT antagonist antibody and a second observation period after administration of the medicament comprising the anti-PD-L1 antagonist antibody. In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. Where the first observation period and the second observation period are each about 60 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject during the first and second observation periods about 30 ± 10 minutes after administration of the drug comprising the anti-TIGIT antagonist antibody and the drug comprising the anti-PD-L1 antagonist antibody, respectively. Where the first observation period and the second observation period are each about 30 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject for about 15 ± 10 minutes after administration of the drug comprising the anti-TIGIT antagonist antibody and the drug comprising the anti-PD-L1 antagonist antibody, respectively, during the first and second observation periods.

In other instances, a medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab))) is to be administered to a subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleighumab). In some cases, for example, after administration of the medicament comprising the anti-PD-L1 antagonist antibody and before administration of the medicament comprising the anti-TIGIT antagonist antibody, the method comprises an intermediate first observation period. In some cases, the method includes a second observation period after administration of the medicament comprising an anti-TIGIT antagonist antibody. In some cases, the method comprises a first observation period after administration of the medicament comprising the anti-PD-L1 antagonist antibody and a 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 between about 30 minutes and about 60 minutes in length. Where the first observation period and the second observation period are each about 60 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject during the first and second observation periods about 30 ± 10 minutes after administration of the medicament comprising the anti-PD-L1 antagonist antibody and the medicament comprising the anti-TIGIT antagonist antibody, respectively. Where the first observation period and the second observation period are each about 30 minutes in length, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject for about 15 ± 10 minutes after administering the drug comprising the anti-PD-L1 antagonist antibody and the drug comprising the anti-TIGIT antagonist antibody, respectively, during the first and second observation periods.

In other instances, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboceprizumab, previously referred to as pembrolizumab))) are to be administered simultaneously to a subject or population of subjects. In some cases, for example, after administration of a medicament comprising an anti-TIGIT antagonist antibody and a medicament comprising an anti-PD-L1 antagonist antibody, the method comprises an observation period. In some cases, the length of the observation period is between about 30 minutes and about 60 minutes. Where the length of the observation period is about 60 minutes, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject about 30 ± 10 minutes after administering the medicament comprising the anti-PD-L1 antagonist antibody and the medicament comprising the anti-TIGIT antagonist antibody over the observation period. Where the length of the observation period is about 30 minutes, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject about 15 ± 10 minutes after administering the medicament comprising the anti-PD-L1 antagonist antibody and the medicament comprising the anti-TIGIT antagonist antibody over the observation period.

In another aspect, the invention provides a use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as provided herein, e.g., ibrinout unumab) and an anti-PD-L1 antagonist antibody (e.g., atuzumab) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable level of PD-L1 expression, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, and wherein the medicament is formulated for administration of: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30mg to about 1200mg (e.g., between 30mg to 1200 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) at a dose (e.g., fixed dose) of between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) every three weeks.

In another aspect, the invention provides a use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as provided herein, e.g., ibrinout unumab) and an anti-PD-L1 antagonist antibody (e.g., atuzumab) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable level of PD-L1 expression, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, and wherein the medicament is formulated for administration of: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30mg to about 1200mg (e.g., between 30mg to 1200 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) at a dose (e.g., fixed dose) of between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) every two weeks.

In another aspect, the invention provides a use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as provided herein, e.g., ibrinout unumab) and an anti-PD-L1 antagonist antibody (e.g., atuzumab) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable level of PD-L1 expression, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of between about 1200mg of the anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atuzumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (parbollizumab, previously referred to as pembrolizumab)) of between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) every four weeks).

In another aspect, the invention provides a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclizumab, previously referred to as pembrolizumab))) for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the drug and an anti-TIGIT antagonist antibody, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)) between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) every three weeks and a dose (e.g., fixed dose) of anti-TIGIT antagonist antibody at about 30mg to about 1200mg (e.g., between 30mg to 1200 mg) every three weeks.

In another aspect, the invention provides a use of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable PD-L1 expression level, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles the medicament and an anti-TIGIT antagonist antibody, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atuzumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) every four weeks and a dose (e.g., fixed dose) of anti-TIGIT antagonist antibody of between about 30mg to about 1200mg (e.g., between 30mg to 1200 mg) every three weeks.

In another aspect, the invention provides a use of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable PD-L1 expression level, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles the medicament and an anti-TIGIT antagonist antibody, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) of between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) every two weeks and a dose (e.g., fixed dose) of anti-TIGIT antagonist antibody of between about 30mg to about 1200mg (e.g., between 30mg to 1200 mg) every three weeks.

In another aspect, the invention provides a use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., adnexumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (wunaclizumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of between about 30mg to about 1200mg (e.g., between 30mg to 1200 mg) of the anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) of the anti-PD-L1 antagonist antibody every three weeks.

In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable level of PD-L1 expression, wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of 600mg every three weeks and a dose (e.g., fixed dose) of 1200mg every three weeks of alemtuzumab, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

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

In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable PD-L1 expression level, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the agent, wherein the agent is formulated for administration of: a dose (e.g., fixed dose) of 600mg every three weeks of anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of 240mg every two weeks of nivolumab, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable PD-L1 expression level, wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the agent, wherein the agent is formulated for administration of: a dose (e.g., fixed dose) of 600mg per three weeks of anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of 480mg per four weeks of nivolumab, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration the medicament and attritumab, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a dose of 600mg per three weeks (e.g., a fixed dose) and attritumab is to be administered at a dose of 1200mg per three weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) in 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 and palivizumab, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a dose of 600mg every three weeks (e.g., a fixed dose) and palivizumab is to be administered at a dose of 200mg every three weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and nivolumab, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a dose of 600mg every three weeks (e.g., a fixed dose) and nivolumab is to be administered at a dose of 240mg every two weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) in 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 and nivolumab, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a dose of 600mg every three weeks (e.g., a fixed dose) and nivolumab is to be administered at a dose of 480mg every four weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration the medicament and attritumab, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a dose of 600mg every three weeks (e.g., a fixed dose) and attritumab is to be administered at a dose of 840mg every two weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) in 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 and adzuzumab, wherein the medicament is formulated for administration of the anti-TIGIT antagonist antibody at a dose of 600mg every three weeks (e.g., a fixed dose) and adzuzumab is to be administered at a dose of 1680mg every four weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides use of atuzumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated for administration of the atuzumab at a dose (e.g., fixed dose) of 1200mg every three weeks and the TIGIT antagonist antibody is to be administered at a dose (e.g., fixed dose) of 600mg every three weeks, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides use of atuzumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated for administration of the atuzumab at a dose (e.g., fixed dose) of 840mg every two weeks and the TIGIT antagonist antibody is to be administered at a dose (e.g., fixed dose) of 600mg every three weeks, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides use of palbociclizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from a cancer having a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated for administration of palbociclizumab at a dose of 200mg every three weeks (e.g., a fixed dose) and the anti-TIGIT antagonist antibody is to be administered at a dose of 600mg every three weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides for the use of nivolumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated for administration of nivolumab at a dose (e.g., fixed dose) of 240mg every two weeks and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., fixed dose) of 600mg every three weeks, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides for the use of nivolumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated for administration of nivolumab at a dose (e.g., a fixed dose) of 480mg every four weeks and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose) of 600mg every three weeks, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides use of atuzumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated for administration of atuzumab at a dose of 1680mg every four weeks (e.g., a fixed dose) and the anti-TIGIT antagonist antibody is to be administered at a dose of 600mg every three weeks (e.g., a fixed dose), and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides the use of tirayleigh immitumab and atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) having a detectable PD-L1 expression level, 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 dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 1200mg every three weeks (e.g., fixed dose) of atelizumab.

In another aspect, the invention provides the use of tirayleigh immitumab and atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) having a detectable PD-L1 expression level, 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 dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 840mg every two weeks (e.g., fixed dose) of atelizumab.

In another aspect, the invention provides the use of tirayleigh umab and atlizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) with a detectable level of PD-L1 expression, 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 dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 840mg every two weeks (e.g., fixed dose) of atelizumab.

In another aspect, the invention provides the use of tirayleigh umab and palbociclumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) having a detectable PD-L1 expression level, 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 dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 200mg every three weeks (e.g., fixed dose) of palboceprizumab.

In another aspect, the invention provides the use of tirayleigh mab and nivolumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), 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 dose of 600mg every three weeks (e.g., fixed dose) of temepruezumab and a dose of 240mg every two weeks (e.g., fixed dose) of nivolumab.

In another aspect, the invention provides the use of tirayleigh mab and nivolumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), 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 dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 480mg every four weeks (e.g., fixed dose) of nivolumab.

In another aspect, the invention provides use of tirayleigh mab in the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and atuzumab, wherein the medicament is formulated for administration of tirayleigh mab at a dose of 600mg every three weeks (e.g., a fixed dose), and atuzumab is to be administered at a dose of 1200mg every three weeks (e.g., a fixed dose).

In another aspect, the invention provides use of tirayleigh mab in the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable PD-L1 expression level (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and atuzumab, wherein the medicament is formulated for administration of tirayleigh mab at a dose of 600mg every three weeks (e.g., a fixed dose), and atuzumab is to be administered at a dose of 840mg every two weeks (e.g., a fixed dose).

In another aspect, the invention provides use of tiyuetuzumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and atuzumab, wherein the medicament is formulated for administration of tiyuetuzumab at a dose of 600mg every three weeks (e.g., a fixed dose), and atuzumab is to be administered at a dose of 840mg every two weeks (e.g., a fixed dose).

In another aspect, the invention provides use of tiplereuptamab in the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and palivizumab, wherein the medicament is formulated for administration of tiplereuptamab at a dose of 600mg every three weeks (e.g., a fixed dose), and palivizumab is to be administered at a dose of 200mg every three weeks (e.g., a fixed dose).

In another aspect, the invention provides use of tiyuetuzumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and palbociclumab, wherein the medicament is formulated for administration of tiyuetuzumab at a dose of 600mg every three weeks (e.g., a fixed dose), and nivolumab is to be administered at a dose of 240mg every two weeks (e.g., a fixed dose).

In another aspect, the invention provides use of tiyuetuzumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and palbociclumab, wherein the medicament is formulated for administration of tiyuetuzumab at a dose of 600mg every three weeks (e.g., a fixed dose), and the nabumeumab is to be administered at a dose of 480mg every four weeks (e.g., a fixed dose).

In another aspect, the invention provides use of atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and tirayleigh mab, wherein the medicament is formulated for administration of the atelizumab at a dose of 1200mg (e.g., a fixed dose) every three weeks, and the tiuxelizumab is to be administered at a dose of 600mg (e.g., a fixed dose) every three weeks.

In another aspect, the invention provides for the use of atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and tenecteuzumab, wherein the medicament is formulated for administration of atelizumab at a dose (e.g., fixed dose) of 1200mg every three weeks, and tenecteuzumab is to be administered at a dose (e.g., fixed dose) of 840mg every two weeks.

In another aspect, the invention provides use of atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a cancer with a detectable level of PD-L1 expression (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and tirayleigh mab, wherein the medicament is formulated for administration of the atelizumab at a dose of 1200mg (e.g., a fixed dose) every three weeks, and the tiuxelizumab is to be administered at a dose of 1680mg (e.g., a fixed dose) every four weeks.

In any of the methods, uses, or compositions for use described herein, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab)) or a drug thereof may be administered alone or together in concert with one or more additional anti-cancer therapeutic agents (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy/radiation therapy, and/or an anti-hormonal agent, such as those described above).

In any of the methods, uses, or compositions for use described herein, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) or a medicament thereof is used to treat a subject or population of subjects having cervical cancer. In some cases, the cervical cancer is stage IVB, metastatic, recurrent or persistent cervical cancer. In some cases, the cervical cancer is metastatic and/or relapsed PD-L1-positive cervical cancer. The cancer may be in an early or late stage.

In some cases, in any of the methods, uses, or compositions for use described herein, the detectable PD-L1 expression level is a detectable protein expression level of PD-L1. In some cases, the detectable protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay. 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 any of the methods, uses, or compositions for use described herein, the detectable PD-L1 expression level is a detectable nucleic acid expression level of PD-L1. In some cases, a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, massARRAY technology, ISH, or a combination thereof.

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, cervical cancer is stage IVB, metastatic, recurrent or persistent. In some cases, the cervical cancer is metastatic and/or relapsed 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 did not receive at least one prior therapy line. In some cases, the subject or population of subjects did not receive both prior lines of therapy. In some cases, the subject or population of subjects has received at least one but no more than two prior systemic therapies and/or there is no acceptable standard of care for them. In some cases, a subject or population of subjects has not received more than two prior treatment normals. 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, administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab)) results in a clinical response. Alemtuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously known as pembrolizumab))) without a treatment with an anti-TIGIT antagonist antibody, in some cases the clinical response is an increase in the PFS of the subject or population of subjects compared to a reference PFS time, in some cases, wherein the reference PFS time is the median of the population of subjects who have received treatment with an antibody comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., alemtuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously known as pembrolizumab))) without an anti-TIGIT antagonist antibody PFS time. In some cases, the clinical response is an increase in duration of remission (DOR) in the subject or population of subjects as compared to a reference DOR time. In some cases, wherein the reference DOR time is the median DOR time for a population of subjects who have received treatment that includes a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) but not an anti-TIGIT antagonist antibody. In some cases, the clinical response is an increase in OS.

Diagnostic methods and uses related to cervical cancer

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

Further, provided herein are methods for identifying a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) or a PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (parbolzumab, previously referred to as pembrolizumab))) that may benefit from treatment comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) wherein the identification is guided by a diagnostic method that involves determining the presence and/or expression level/amount of one or more biomarkers (e.g., PD-L1, it, activated T cells or cytokines) in a sample (e.g., a tumor sample or blood sample) obtained from the subject or population of subjects.

Further, provided herein are methods for assessing responsiveness of a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) to a therapy, wherein further, the therapy is guided by a diagnostic method that involves determining the presence and/or expression level/amount of one or more biomarkers, e.g., PD-L1, TIGIT, activated T cells, or cytokines, in a sample (e.g., tumor sample or blood sample) obtained from the subject or population of subjects.

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

Biomarkers for use in the methods described herein can include, but are not limited to, PD-L1 and/or TIGIT expression on tissue (e.g., tumor tissue) or in blood (e.g., whole blood); germline and somatic mutations (including but not limited to mutation load, MSI and MMR defects) from tissue (e.g., tumor tissue) and/or from circulating tumor DNA in the blood, identified by WGS and/or NGS, analysis of genes (e.g., CD 274) or gene signatures (e.g., TEFF) associated with tumor immunobiology; an HPV alteration; a subpopulation of lymphocytes; a bank of T cell receptors; cytokines involved in T cell activation and plasma-derived cytokines. In some cases, the biomarker is PD-L1. In some cases, the sample is a tumor sample (e.g., a Formalin Fixed Paraffin Embedded (FFPE) tumor sample).

In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., a tirayleigh monoclonal antibody) at a dose (e.g., a fixed dose) of between about 30mg to about 1200mg (e.g., between 30mg to 1200 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) at a dose (e.g., a fixed dose) of between about 80mg to about 2000mg (e.g., between 80mg to 2000 mg) every three weeks. In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) at a dose (e.g., a fixed dose) of about 600mg (e.g., 600 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) at a dose (e.g., a fixed dose) of 840mg (e.g., a fixed dose) every two weeks. In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: a dose (e.g., fixed dose) of about 600mg (e.g., 600 mg) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh itumumab) every three weeks and a dose (e.g., fixed dose) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) of 1200mg every three weeks. In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: a dose (e.g., fixed dose) of about 600mg (e.g., 600 mg) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) every three weeks and a dose (e.g., fixed dose) of 1680mg of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) every four weeks.

The presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) may be determined qualitatively and/or quantitatively based on any suitable criteria known in the art, including, but not limited to, protein fragment, DNA, mRNA, cDNA, and/or gene copy number.

In some cases, the expression level or amount of the biomarker is a detectable protein expression level of PD-L1 in a tumor sample (e.g., an FFPE tumor sample) from the subject or population of subjects. In some cases, the protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay. In some cases, the tumor sample is an FFPE tumor sample.

In some cases, a tumor sample (e.g., an FFPE tumor sample) from a subject or population of subjects has been determined to have a detectable PD-L1 expression level. In some cases, a tumor sample (e.g., an FFPE tumor sample) from a subject or population of subjects has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells. In some cases, the tumor sample is an 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 (e.g., an FFPE tumor sample) from the subject or population of subjects. In some cases, the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, serial Analysis of Gene Expression (SAGE),

Techniques, in Situ Hybridization (ISH), or a combination thereof. In some cases, the tumor sample is an FFPE tumor sample.

In some cases, the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from a subject or population of subjects selects the subject or population of subjects to be eligible for therapy with an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboceprizumab, previously referred to as pembrolizumab)), e.g., wherein a detectable PD-L1 expression level is a biomarker used to select the 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 (e.g., an FFPE tumor sample). In some cases, the tumor sample comprises infiltrating tumor immune cells, tumor cells, stromal cells, and any combination thereof. In some cases, the tumor sample is an FFPE tumor sample.

In one aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), by: from subject to testObtaining a tumor sample (e.g., biopsy) from the subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and an atuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose), wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two 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 methods of selecting a therapy for a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration The following items of (1): based on the detected PD-L1 expression in the tumor sample, tenecteuzumab was administered at a dose of 600mg every three weeks (e.g., a fixed dose) and atelizumab was administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and an atuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose), wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18 amino group A sequence, and a VL domain comprising SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, tenecteuzumab was administered at a dose of 600mg every three weeks (e.g., a fixed dose) and atelizumab was administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy may further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., an anti-CTLA-4 antagonist antibody) Yipimumab (ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and an atuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose), wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and 1680mg every four weeks The atezumab used. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, tenecteuzumab was administered at a dose of 600mg every three weeks and atelizumab was administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormone agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the present invention provides methods forA method of identifying a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and astuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose), wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for identifying compounds that may benefit from the inclusion of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attlizumab) or an anti-PD-1 antagonist antibody (e.g., A method of treating a subject or population of subjects suffering from cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) with a therapy of MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously known as pembrolizumab))) by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for identifying antibodies that may benefit from inclusion of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab)Previously referred to as pembrolizumab))) in a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlas administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for identifying a subject or subject having a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) A method of population of subjects, the method performed by the steps of: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks, and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for identifying a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), byLine: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlas administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for identifying a subject or population of subjects having cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboceprizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects To potentially benefit from therapy, the therapy includes one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for assessing responsiveness of a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboceprizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more ofThe following of each dosing cycle: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlas administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for assessing responsiveness of a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboceprizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering to the identified subject or subject The population is administered the therapy. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for assessing responsiveness of a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboceprizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlas administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlizumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for assessing responsiveness of a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent, or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboceprizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy may further include one or more additional anti-cancer therapeutic agents (e.g., an immunomodulatory agent (e.g., to reduce or inhibit one or more immune co-inhibitory receptors (e.g., one or more selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM 3) BTLA and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormone agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods of assessing responsiveness of a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlas administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: VH domain, which Has the sequence shown in SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlizumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods of assessing responsiveness of a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks, and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

)，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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for optimizing therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) in a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlas administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and attritone beads administered at a dose of 1680mg every four weeks A monoclonal antibody. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for optimizing therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) in a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) Or agents that increase or activate 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 OX-40 agonists, e.g., OX-40 agonist antibodies, chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiation therapyRadiotherapy and/or anti-hormonal agents such as those described above), or administered in conjunction therewith (alone or together).

In some cases, the invention provides methods for optimizing therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) in a subject or population of subjects having cancer (e.g., cervical cancer, e.g., IVB-stage, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlizumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for treating cancer (e.g., cervical cancer, e.g., I) A method of optimizing therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously known as pembrolizumab)) in a subject or population of subjects having VB-phase, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides for the treatment of a cancer (e.g., cervical cancer, e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastasis)A subject or population of subjects with a sexual and/or recurrent PD-L1-positive cervical cancer) that includes an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1200mg every three weeks, wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for optimizing the efficacy of a therapeutic agent comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab) or an anti-PD-1 antagonist antibody (e.g., A method of therapy of MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously known as pembrolizumab))) by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks, and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy may further include one or more additional anti-cancer therapeutic agents (e.g., an agent that is an immunomodulatory agent (e.g., that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormone agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

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

D. Therapeutic methods and uses related to breast cancer

Breast cancer

Breast cancer is the most common cancer in women, and it is estimated that 208 ten thousand new cases occur in 2018 worldwide. Breast cancer accounts for approximately 15% of all cancer deaths (approximately 626,700 cases), and is the most common cause of cancer-related deaths in women, with a five-year survival rate of approximately 15% after metastatic diagnosis. Most patients are diagnosed with localized breast cancer; however, approximately 6% of patients presenting with new onset metastatic disease and between 10% and 40% of patients with localized breast cancer will recur systemically. In the early stages of breast cancer (I to III; early breast cancer), most asymptomatic diseases are usually operable and can be treated with the aim of curing.

Breast cancer is a heterogeneous disease, encompassing about 15 different types of cancer, which are further classified for therapeutic reasons according to their Estrogen Receptor (ER), progesterone Receptor (PR), and human epidermal growth factor receptor 2 (HER 2) status. These subgroups have important implications for therapy selection, treatment outcome, relapse rate and risk of death. Triple Negative Breast Cancer (TNBC) is characterized by a lack of expression of ER, PR and HER 2. Overall, approximately 15% to 20% of breast cancers are classified as TNBC. Large-scale integrated genomic analysis has characterized the heterogeneity of TNBC and its diverse gene expression patterns and potential genomic changes, but these insights have not yet provided clear guidance for the identification of clinically effective targeted therapies currently in laboratory and clinical research.

TNBC is more likely to have aggressive characteristics, such as high proliferation rates. Patients with metastatic TNBC show particularly poor clinical outcomes, usually progress rapidly, and the median OS rate is about 16 months. Despite recent improvements in treatment, the prognosis for TNBC patients is far from optimal, and in fact, five-year survival after metastatic diagnosis is approximately 15%.

Thus, there is a high unmet need for improved medical intervention for TNBC, including early TNBC (eTNBC).

Methods and uses for treating breast cancer

In some cases, a subject or population of subjects receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab) and chemotherapy (e.g., a taxane (e.g., nab-paclitaxel or paclitaxel)) is being treated for breast cancer (e.g., HER2+ breast cancer and TNBC). In some cases, the anti-TIGIT antagonist antibody is securititumumab. 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 atelizumab. In some cases, the chemotherapy is a taxane. In some cases, the taxane is nab-paclitaxel or paclitaxel. In some cases, the taxane is nab-paclitaxel. In some cases, the breast cancer is TNBC. In some cases, the TNBC is PD-L1 positive TNBC. In some cases, TNBC is unresectable, locally advanced or metastatic. In some cases, PD-L1 positive TNBC is unresectable locally advanced or metastatic. In some cases, the subject or population of subjects has not received prior systemic therapy for breast cancer. In some cases, the subject or population of subjects has not received prior systemic therapy for metastatic breast cancer.

Methods and uses for treating eTNBC

Provided herein are methods and uses for treating early TNBC (eTNBC) in a subject or population of subjects, comprising administering to the subject or population of subjects a dosing regimen comprising an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab)) for one or more dosing cycles, thereby treating the subject or population of subjects.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezumab). In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immitumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atezumab) are administered to a subject or population of subjects in need thereof, with or without one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel) and/or a topoisomerase II inhibitor (e.g., doxorubicin))). In some cases, the method further comprises one or more procedures (e.g., mastectomy and/or axillary lymph node surgery). In some cases, surgery is performed after administration of a dosing regimen comprising an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, 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, surgery is performed between two and six weeks (e.g., 2, 3, 4, 5, and 6 weeks) after the last dose of the dosing regimen.

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

Dosing regimens and administration

The therapeutic methods and uses of the invention described herein include, in one aspect, administering to a subject or population of subjects having eTNBC a dosing regimen comprising effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., astuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)) and an anti-TIGIT antagonist antibody (e.g., tegraluzumab))Including effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (Pabolizumab, previously referred to as pembrolizumab)) and an anti-TIGIT antagonist antibody (e.g., terayleigh mab) with or without one or more chemotherapeutic agents (e.g., platinum chemotherapeutic agents (e.g., carboplatin or cisplatin) and/or non-platinum chemotherapeutic agents (e.g., alkylating agents (e.g., cyclophosphamide), taxanes (e.g., paclitaxel, e.g., nab-paclitaxel) and/or topoisomerase II inhibitors (e.g., doxorubicin)) and/or G-CSF or GM-CSF ² The dosage of (a).

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

Administration of chemotherapeutic agents

Therapeutically effective amounts of various chemotherapeutic agents are known in the art and are contemplated in the present invention. In particular instances, one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide)), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))) are administered according to the doses described in section III (K) herein.

Cancer characterization and selection

In any of the methods, uses, or compositions for use described herein, the cancer may be breast cancer. In some cases, the breast cancer is TNBC. In some cases, the TNBC is eTNBC. In some cases, eTNBC appears to be T2-4d TNBC. In some cases, the etnbcs are presented as cT2-cT4, cN0-cN3, and cM0 TNBC. In some cases, eTNBC is PD-L1 positive. In some cases, 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 been systemically treated for breast cancer (e.g., TNBC, e.g., 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 (e.g., a proportion of tumor area occupied by PD-L1-expressing tumor-infiltrating Immune Cells (ICs) in a tumor sample is greater than or equal to 1%, as determined by IHC using an SP142 antibody). In some cases, the tumor selected for PD-L1 is a tumor in which the proportion of tumor area occupied by IC expressing PD-L1 is greater than or equal to 1%, as determined by an Immunohistochemistry (IHC) assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142, SP263, 22C3, or 28-8. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, the IC has been determined to be greater than or equal to 1% (e.g., as determined using the Ventana (SP 142) PD-L1 IHC assay). In some cases, the PD-L1 expression level is detected using anti-PD-L1 antibody 22C 3. In some cases, the detectable level of PD-L1 expression is a Composite Positive Score (CPS) greater than or equal to 1 in a sample from the subject.

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable level of nucleic acid expression of PD-L1. In some cases, a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-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 infiltrating tumor immune cells, tumor cells, stromal cells, and any combination thereof.

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

Response to treatment

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

In some cases, the treatment results in an increase in event-free survival of the subject or population of subjects, 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. For example, in embodiments in which a chemotherapeutic agent is not administered (e.g., administration of only an anti-TIGIT antagonist antibody (e.g., ibritumumab) in combination with a PD-1 axis binding antagonist (e.g., atelizumab)), the treatment can result in increased event-free survival of the subject or population of subjects, 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. In embodiments in which an anti-TIGIT antagonist antibody (e.g., ibrinoitumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., atelizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel) and/or a topoisomerase II inhibitor (e.g., doxorubicin)), and/or G-CSF or GM-CSF), the treatment can result in an increase in event-free survival of the subject or population of subjects, e.g., (i) as compared to treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents and/or G-CSF or GM-CSF without the anti-TIGIT antagonist antibody; (ii) Compared to treatment with an anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents and/or G-CSF or GM-CSF without the PD-1 axis binding antagonist; and/or (iii) compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody and/or G-CSF or GM-CSF without the one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

In some cases, the treatment extends OS in the subject or population of subjects, 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. For example, in embodiments in which a chemotherapeutic agent is not administered (e.g., administration of only an anti-TIGIT antagonist antibody (e.g., tenellulomicrumab) in combination with a PD-1 axis binding antagonist (e.g., atelizumab)), the treatment can result in an increase in OS in the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody, or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In embodiments in which an anti-TIGIT antagonist antibody (e.g., ibrinoitumomab) and a PD-1 axis binding antagonist (e.g., atelizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel) and/or a topoisomerase II inhibitor (e.g., doxorubicin))) and/or G-CSF or GM-CSF), the treatment can result in an increase in OS in the subject or population of subjects, e.g., (i) as compared to treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents and/or G-CSF or GM-CSF without the anti-TIGIT antagonist antibody; (ii) Compared to treatment with an anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents and/or G-CSF or GM-CSF without the PD-1 axis binding antagonist; and/or (iii) compared to treatment with a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody and/or G-CSF or GM-CSF without the one or more chemotherapeutic agents.

Event-free survival of a subject or population of subjects can be measured according to RECIST v1.1 criteria, such as Eisenhauer et al, eur.j.cancer.2009, 45: 228-47. In some embodiments, EFS is measured as the period of time from the start of treatment to the first appearance of disease progression, as determined by RECIST v1.1 criteria. In some embodiments, EFS is measured as the time from the start of treatment to death.

In some embodiments, the treatment described herein extends EFS in a subject or population of subjects by at least about 2.4 months (e.g., 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 to 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., a prolongation of 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 extends EFS in the subject or population of subjects for at least about 4 months (e.g., 4 to 120 months, 5 to 100 months, 6 to 80 months, 7 to 60 months, 8 to 48 months, 9 to 36 months, or 10 to 24 months, e.g., 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, 29 months, 31 months, or 31 months). In some embodiments, the treatment extends EFS of the subject or population of subjects 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, e.g., extending for 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 of time from the start of treatment to death. In some cases, the treatment extends OS of the subject or population of subjects 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 to 24 months, e.g., extending for 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 extends OS of the subject or population of subjects 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, e.g., extending for 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, 35 months, 36 months, or 36 months). In some cases, the treatment extends OS of the subject or population of subjects 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, e.g., 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, 34 months, 35 months, or 36 months). In some embodiments, the treatment results in a median OS for the population of subjects of at least about 20 months (e.g., between about 20 months and about 36 months (e.g., 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 results in a median OS for the population of subjects of about 25.0 months.

In some embodiments, the treatment results in an ORR of at least about 53% (e.g., about 53% to about 100% (e.g., 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%) for the population of subjects). In some embodiments, the treatment results in an ORR of at least about 53% (e.g., about 65% to about 100% (e.g., 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%) for the population of subjects). In some embodiments, the treatment results in an ORR of 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%) for the population of subjects.

E. Therapeutic methods, diagnostics and uses related to head and neck cancer

Head and neck cancer

Head and neck cancer is a cause of high morbidity and mortality, with 890,000 new cases and 450,000 deaths in 2018 worldwide. Head and neck cancer is a heterogeneous group of cancers, including cancers that start on the mucosal surfaces of the upper aerodigestive tract and affect the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx. The major histological type is Squamous Cell Carcinoma (SCC), accounting for over 90% of all malignant diseases of the head and neck regions of the body.

Despite advances in the diagnosis and treatment of early or locally advanced squamous cell carcinoma of the head and neck (SCCHN), over 65% of these patients develop recurrent or metastatic disease. Furthermore, approximately 10% of SCCHN patients present with metastatic SCCHN at the time of initial diagnosis. For patients with locally recurrent disease, salvage surgery is curative only for selected patients with resectable locally recurrent lesions, and reissue is often limited by previous history of radiation therapy and associated toxicity and morbidity. Thus, systemic therapy is standard of care (SOC) therapy, and is also the primary means of palliative treatment for patients with recurrent or metastatic SCCHN. For these patients, the prognosis is poor, with median survival in most clinical trials ranging from 6 to 15 months, depending on the patient and disease-related factors.

Therefore, there is a high unmet need for overtaking medical interventions for head and neck cancer, particularly SCCHN.

Methods and uses for treating head and neck cancer

Provided herein are methods and uses for treating SCCHN (e.g., recurrent and/or metastatic SCCHN (e.g., PD-L1 positive and/or HPV positive recurrent and/or metastatic SCCHN)) in a subject or population of subjects, comprising administering to the subject or population of subjects a dosing regimen comprising an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX 1106 (nivolumab), MK-3475 (palboclizumab, formerly known as pembrolizumab), MEDI-0680 (AMP-514), PDR001 (sibatuzumab), REGN2810 (cimiralizumab), BGB-108, palulizumab, carpriluzumab, certralizumab, or certralizumab)) and an anti-it antagonist antibody (e.g., an anti-it antagonist as disclosed herein, e.g., tig antibody, e.g., tig), thereby treating the subject or population of subjects. Also provided herein are methods for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks. Also provided herein are methods for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg tireyueuzumab every three weeks, and a dose of about 1200mg atelizumab every three weeks.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attentizumab) and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan). In some cases, the invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as attentizumab) and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan).

In some cases, any method and use for treating SCCHN in a subject or population of subjects can result in CR or PR. In some cases, any method and use for treating SCCHN in a subject or population of subjects can result in an increase in Objective Remission Rate (ORR) specific to the subject or population of subjects. In some instances, any methods and uses for treating SCCHN in a subject or population of subjects can result in an increase in subject-or population-specific PFS, duration of remission (DOR), and/or OS.

In some cases, SCCHN is SCCHN having a detectable PD-L1 expression level. In some cases, a tumor sample obtained from a subject or population of subjects has been determined to have a detectable PD-L1 expression level (e.g., a detectable PD-L1 protein and/or nucleic acid expression level (e.g., greater than or equal to 5% tumor-associated immune cells (TICs)). In some cases, the detectable protein expression level of PD-L1 is greater than or equal to 5% (e.g., PD-L1 positive), greater than or equal to 5% and less than 20% (e.g., PD-L1 low), or greater than or equal to 20% (e.g., PD-L1 high) TIC in the tumor sample. In some cases, the detectable protein expression level of PD-L1 is greater than or equal to 10%, and less than 50% or greater than or equal to 50% 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.

Dosing regimens and administration

Therapeutic methods and uses of the invention described herein include, in one aspect, administering to a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) a treatment regimen comprising an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) for one or more dosing cycles and an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ulizumab ozogamicin).

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

Diagnostic methods and uses for head and neck cancer

The invention provides methods of selecting a therapy (e.g., a first line therapy) for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), wherein the therapy is guided by a diagnostic method that involves determining the presence and/or expression level/amount of one or more biomarkers (e.g., PD-L1 (e.g., as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (e.g., as determined by p16IHC, ISH, or PCR)) in a sample (e.g., a tumor sample or blood sample) obtained from the subject or population of subjects.

Further, provided herein are methods for identifying a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) or who may benefit from including an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX 1106 (nivolumab), MK-3475 (parbolzumab, previously known as pembrolizumab), MEDI-0680 (AMP-514), PDR001 (sibatuzumab), REGN2810 (cimiralizumab), BGB-108, palonolizumab, carpricizumab, certralizumab, or terlizumab)), wherein the identification is guided by a diagnostic method that involves determining the presence of one or more biomarkers (e.g., PD-L1 (e.g., as determined by ihpd-L1 protein and/or blood sample) in a sample obtained from the subject or population of subjects (e.g., a tumor sample or blood sample), or the level of nucleic acid (e), e.g., as determined by IHC expression or PCR) or by PCR.

Further, provided herein are methods of assessing responsiveness of a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) to a therapy, wherein further, the therapy is guided by a diagnostic method that involves determining the presence and/or expression level/amount of one or more biomarkers (e.g., PD-L1 (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 sample (e.g., a tumor sample or blood sample) obtained from the subject or population of subjects.

Further, provided herein are methods of optimizing therapy for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), wherein further, the therapy is guided by a diagnostic method that involves determining the presence and/or expression level/amount of one or more biomarkers (e.g., PD-L1 (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 sample (e.g., a tumor sample or blood sample) obtained from the subject or population of subjects.

Biomarkers for the methods described herein can include, but are not limited to, PD-L1 expression on a tissue (e.g., tumor tissue) or in blood (e.g., whole blood); germline and somatic mutations (including but not limited to mutation load, MSI and MMR defects) from tissue (e.g., tumor tissue) and/or from circulating tumor DNA in the blood, identified by WGS and/or NGS, analysis of genes or gene signatures associated with tumor immunobiology; an HPV alteration; a subpopulation of lymphocytes; a bank of T cell receptors; cytokines involved in T cell activation and plasma-derived cytokines. In some cases, the biomarker is PD-L1. In some cases, a tumor sample obtained from a subject or population of subjects has been determined to have a detectable PD-L1 expression level (e.g., a detectable PD-L1 protein and/or nucleic acid expression level (e.g., greater than or equal to 5% tumor-associated immune cells (TICs)). In some cases, the detectable protein expression level of PD-L1 is greater than or equal to 5% (e.g., PD-L1 positive), greater than or equal to 5% and less than 20% (e.g., PD-L1 low), or greater than or equal to 20% (e.g., PD-L1 high) tumor-associated immune cells (TICs) in the tumor sample. In some cases, the detectable protein expression level of PD-L1 is greater than or equal to 10%, and less than 50% or greater than or equal to 50% TIC in the tumor sample. In some cases, the sample is a tumor sample (e.g., 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 determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1 (e.g., as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (e.g., as determined by p16IHC, ISH, or PCR)) in a sample (e.g., a tumor sample or blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., a tirayleigh unimumab) at a dose (e.g., a fixed dose) of between about 30mg to about 1200mg (e.g., 30mg to 1200 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., an attrituximab)) at a dose (e.g., a fixed dose) of between about 80mg to about 2000mg (e.g., 80mg to 2000 mg) every three weeks. In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1 (e.g., as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (e.g., as determined by p16IHC, ISH, or PCR)) in a sample (e.g., a tumor sample or blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) at a dose of about 600mg (e.g., 600 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) at a dose of about 840mg every two weeks. In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1 (e.g., as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (e.g., as determined by p16IHC, ISH, or PCR)) in a sample (e.g., a tumor sample or blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., securityluzumab) at a dose of about 600mg (e.g., 600 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) at a dose of about 1200mg every three weeks. In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1 (e.g., as determined by PD-L1 protein and/or nucleic acid expression) or HPV status (e.g., as determined by p16IHC, ISH, or PCR)) in a sample (e.g., a tumor sample or a blood sample) from the subject or population of subjects, and administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) at a dose of about 600mg (e.g., 600 mg) every three weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) at a dose of about 1680mg every four weeks.

The presence and/or expression level/amount of a biomarker (e.g., PD-L1 (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)) may be determined qualitatively and/or quantitatively based on any suitable criteria 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 the biomarker is a detectable protein expression level of PD-L1 in a tumor sample (e.g., an FFPE tumor sample) from the subject or population of subjects. In some cases, the protein expression level of PD-L1 has been determined by an IHC assay. In some cases, the tumor sample is an FFPE tumor sample.

In some cases, a tumor sample (e.g., an FFPE tumor sample) from a subject or population of subjects has been determined to have a detectable PD-L1 expression level. In some cases, a tumor sample (e.g., an FFPE tumor sample) from a subject or population of subjects has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells. In some cases, the tumor sample is an 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 (e.g., an FFPE tumor sample) from the subject or population of subjects. In some cases, the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, serial Analysis of Gene Expression (SAGE),

Techniques, in Situ Hybridization (ISH), or a combination thereof. In some cases, the tumor sample is an FFPE tumor sample.

In some cases, the presence and/or expression level/amount in a sample (e.g., a tumor sample or a blood sample) from a subject or population of subjects (e.g., PD-L1 (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)) selects the subject or population of subjects as being eligible for therapy with an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), e.g., wherein a detectable PD-L1 expression level is a biomarker for selecting individuals. 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 (e.g., an FFPE tumor sample). In some cases, the tumor sample comprises infiltrating tumor immune cells, tumor cells, stromal cells, and any combination thereof. In some cases, the tumor sample is an FFPE tumor sample.

In one aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, the anti-TIGIT antagonist antibody was administered at a dose of 600mg every three weeks (e.g., fixed dose) and the atlizumab was administered at a dose of 1200mg every three weeks (e.g., fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two 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 methods of selecting a therapy for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), the method by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: administration of Tirayleigh Euzumab at a dose of 600mg every three weeks and based on detected PD-L1 expression in tumor samples Attrituximab administered at a dose of 1200mg every three weeks. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), the method by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, the anti-TIGIT antagonist antibody was administered at a dose of 600mg every three weeks (e.g., fixed dose) and the alemtuzumab was administered at a dose of 1200mg every three weeks (e.g., fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and 840mg every two weeks The atezumab used. In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, tenecteuzumab was administered at a dose of 600mg every three weeks and atelizumab was administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein of PD-L1 in the tumor sample by IHC assay using anti-PD-L1 suitable for stainingExpression levels, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, the anti-TIGIT antagonist antibody was administered at a dose of 600mg every three weeks (e.g., fixed dose) and the alemtuzumab was administered at a dose of 1200mg every three weeks (e.g., fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In another aspect, the invention provides methods of selecting a therapy for a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression in the tumor sample, tenecteuzumab was administered at a dose of 600mg every three weeks and atelizumab was administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) Or increasing or activating one or more immune co-stimulatory receptorsAn agent of the body (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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation therapy/radiotherapy, and/or an anti-hormonal agent, such as those described above), or administered in conjunction therewith (alone or together).

In some cases, the invention provides methods for identifying a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), the method performed by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and alemtuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for identifying a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), The method is carried out by the following steps: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for identifying a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), the method performed by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, and assaying by IHC using anti-PD-L1 suitable for stainingThe method detects the protein expression level of PD-L1 in a tumor sample and identifies a subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and alemtuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for identifying a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks (e.g., a fixed dose) and atelizumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist CTLA-4 antagonist antibodies (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for identifying a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) who may benefit from therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and astuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for identifying antibodies that may benefit from inclusion of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., a c/d antagonist antibody) A method of treating a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) with atuzumab) or anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormone agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for assessing SCCHN-related disease in a subject or population of subjects suffering from SCCHN (e.g., recurrent and/or metastatic SCCHN) comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., astuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or M)K-3475 (palivizumab, previously known as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and astuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for assessing responsiveness of a subject or population of subjects suffering from SCCHN (e.g., recurrent and/or metastatic SCCHN) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an immunomodulatory agent (e.g., to reduce or inhibit one or more of the above) An agent of an immune co-inhibitory receptor (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for assessing responsiveness of a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and astuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and an agent of 840mg every two weeks Amount of alemtuzumab administered. In some cases, the invention provides methods for assessing responsiveness of a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides for assessing a subject or population of subjects afflicted with SCCHN (e.g., recurrent and/or metastatic SCCHN)A method of responsiveness to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))), the method performed by the steps of: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and astuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods of assessing responsiveness of a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) to a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks, and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering to the identified subject or subject The subject population is administered the therapy. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for optimizing a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)) in a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and astuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlizumab administered at a dose of 1680mg every four weeks . In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for optimizing a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabolizumab, previously referred to as pembrolizumab))) in a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormone agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods for optimizing a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabolizumab, previously referred to as pembrolizumab))) in a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and alemtuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlizumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods for optimizing a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabolizumab, previously referred to as pembrolizumab))) in a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN), by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: replacement administered at a dose of 600mg every three weeks Rayleauuzumab and atlizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormone agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the invention provides methods of optimizing a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)) in a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks (e.g., a fixed dose) and astuzumab administered at a dose of 1200mg every three weeks (e.g., a fixed dose). In some cases, the therapy comprises one or more of The following of the multiple dosing cycles: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atlizumab administered at a dose of 1680mg every four weeks. In some cases, the therapy includes the following for one or more cycles of administration: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 840mg every two weeks. In some cases, the invention provides methods of optimizing a therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab)) in a subject or population of subjects having SCCHN (e.g., recurrent and/or metastatic SCCHN) by: obtaining a tumor sample (e.g., biopsy) from a subject or population of subjects, detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using anti-PD-L1 suitable for staining, and identifying the subject or population of subjects as likely to benefit from a therapy comprising one or more cycles of administration of: tenecteuzumab administered at a dose of 600mg every three weeks and atelizumab administered at a dose of 1200mg every three weeks. In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) Or agents that increase or activate 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 OX-40 agonists, e.g., OX-40 agonist antibodies, chemotherapeutic agents, cytotoxic agentsGrowth inhibitory agents, radiation therapy/radiotherapy and/or anti-hormonal agents such as those described above), or administered in conjunction therewith (alone or together).

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that reduces or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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., an OX-40 agonist antibody, a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, radiation/radiation therapy, and/or an anti-hormonal agent, such as those described above), or is administered in conjunction (alone or together) therewith.

In some cases, the method further comprises administering the therapy to the identified subject or population of subjects. In some cases, the therapy can further include one or more additional anti-cancer therapeutic agents (e.g., an agent that decreases or inhibits one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab)

) 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 the group consisting of CD226, OX-40, CD28, CD27, CD137, HVEM and/or GITR), such as OX-40Agonists, e.g., OX-40 agonist antibodies), chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiation/radiation therapy, and/or anti-hormonal agents, such as those described above), or administered in conjunction therewith (alone or together).

In some cases, in any of the diagnostic methods or uses described herein, the SCCHN is a recurrent and/or metastatic SCCHN. The cancer may be in an early or late stage. In some cases, the therapy is first line therapy. In some cases, the subject or population of subjects has not received prior therapy. In some cases, the prior therapy is a 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 (e.g., recurrent and/or metastatic SCCHN). In some cases, the SCCHN is a recurrent and/or metastatic SCCHN. In some cases, SCCHN is PD-L1 positive. In some cases, SCCHN is HPV positive. In some cases, SCCHN is HPV negative. In some cases, SCCHN is PD-L1 positive and HPV positive. In some cases, 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 a prior systemic therapy for recurrent and/or metastatic disease.

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 (e.g., a tumor that has a detectable PD-L1 expression level (e.g., a detectable protein expression level of PD-L1 (e.g., a tumor-associated immune cell (TIC)) of greater than or equal to 5%)). Detectable protein expression level of PD-L1 (e.g., TIC greater than or equal to 5%)). In some cases, detectable protein expression level of PD-L1 is detectable protein expression level of PD-L1 (e.g., TIC greater than or equal to 5%). In some cases, detectable protein expression level of PD-L1 is TIC greater than or equal to about 5% (e.g., 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 more). In some cases, detectable protein expression level of PD-L1 is TIC greater than or equal to 5% and less than 20% (e.g., 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%). In some cases, a TIC greater than or equal to 5% and less than 20% is defined as PD-L1 low. In some cases, the detectable protein expression level of PD-L1 is greater than or equal to 20% (e.g., 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%) TIC. In some cases, a TIC greater than or equal to 20% is defined as a PD-L1 high. In some cases, the detectable protein expression level of PD-L1 is greater than or equal to about 10% (e.g., 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, or more) TIC. In some cases, the detectable protein expression level of PD-L1 is greater than or equal to 10% and less than 50% TIC (e.g., 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 is greater than or equal to 50% TIC (e.g., 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 the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some cases, the IHC assay uses the anti-PD-L1 antibody SP263. In some cases, TIC (e.g., using the Ventana (SP 263) PD-L1 IHC assay) has been determined to be greater than or equal to 5%. In some cases, TIC (e.g., using the Ventana (SP 263) PD-L1 IHC assay) has been determined to be greater than or equal to 5% and less than 20%. In some cases, TIC (e.g., using the Ventana (SP 263) PD-L1 IHC assay) has been determined to be greater than or equal to 20%. In some cases, TIC (e.g., using the Ventana (SP 263) PD-L1 IHC assay) has been determined to be greater than or equal to 10%. In some cases, TIC (e.g., using the Ventana (SP 263) PD-L1 IHC assay) has been determined to be greater than or equal to 10% and less than 50%. In some cases, TIC (e.g., using the Ventana (SP 263) PD-L1 IHC assay) has been determined to be greater than or equal to 50%.

In some cases, in a composition for use, or for any of the methods, uses, or for use described herein, a sample obtained from a subject or population of subjects (e.g., a tumor sample) has a detectable level of nucleic acid expression of PD-L1. In some cases, a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-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 infiltrating tumor 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 that is free of detectable HPV. In some cases, HPV is detected directly or indirectly. In some cases, HPV is detected by protein expression levels (e.g., p16 or HPV viral proteins). In some cases, HPV is detected by the level of nucleic acid expression. In some cases, HPV status is determined by p16IHC, in situ hybridization, 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 the subject or population of subjects to the therapy can be characterized by one or more measurements. In some embodiments, the treatment results in CR or PR. In some instances, any method and use for treating SCCHN in a subject or population of subjects can result in an increase in the Objective Remission Rate (ORR) specific to the subject or population of subjects. In some instances, any methods and uses for treating SCCHN in a subject or population of subjects can result in an increase in subject-or population-specific PFS, duration of remission (DOR), and/or OS.

In some cases, in any of the methods, uses, or compositions for use described herein, administration of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attlizumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab)) results in a clinical response. MDX-1106 (nivolumab) or MK-3475 (palivizumab, previously referred to as pembrolizumab))) without treatment with an anti-TIGIT antagonist antibody, the median ORR of a population of subjects not including treatment with an anti-TIGIT antagonist antibody, in some cases, the reference ORR is at least about 19% (e.g., between about 19% and about 80%, e.g., between about 19% and about 60% (e.g., 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%)), in some cases, the reference ORR is at least about 36% (e.g., between about 36% and about 80%, e.g., between about 36% and about 60% (e.g., 36%, 37%, 38%, 39%, 40%, 45%, 50%, 55%, or 60%), (in some cases, the reference ORR is at least about 19% to about 36%. In some cases, the clinical response is an increase in PFS of the subject or population of subjects compared to a reference PFS time. In some cases, wherein the reference PFS time is the median PFS time for a population of subjects who have received treatment that includes a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (pabulizumab, previously referred to as pembrolizumab))) but not an anti-TIGIT antagonist antibody. In some cases, the clinical response is an increase in DOR for the subject or population of subjects as compared to a reference DOR time. In some cases, wherein the reference DOR time is the median DOR time for a population of subjects that have received treatment that includes a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab)) but not an anti-TIGIT antagonist antibody. In some cases, the reference DOR time is at least about 4 months (e.g., between about 4 months and about 42 months) (e.g., between about 6 months and 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 reference DOR time is at least about 6.7 months (e.g., 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 (e.g., 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 was OS-once-added.

In some cases, the treatment results in an ORR greater than 15% (e.g., 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 that is greater than the reference ORR. In some cases, the reference ORR is 19%. In some cases, the reference ORR is 24.4%. In some cases, the reference ORR is 28.8%. In some cases, the reference ORR is 35%.

In some cases, the treatment results in an increase in PFS, DOR, or OS in the subject or population of subjects, 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.

In some embodiments, OS is measured as the period of time from the start of treatment to death. In some cases, the treatment extends OS of the subject or population of subjects 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 to 24 months, e.g., extending for 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 extends OS of the subject or population of subjects 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, e.g., extending for 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, 35 months, 36 months, or 36 months). In some cases, the treatment extends OS of the subject or population of subjects 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, e.g., 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, 34 months, 35 months, or 36 months). In some cases, the treatment results in an increase in OS compared to the reference OS time. In some cases, the reference OS time is at least about 8 months (e.g., 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months). In some cases, the reference OS time is at least about 14.9 months (e.g., 15 months, 16 months, 17 months, 18 months, 19 months, or 20 months). In some cases, the reference OS time is at least about 11.6 months to about 14.9 months.

In some embodiments, the treatment described herein extends the PF S of a subject or population of subjects by at least about 2.4 months (e.g., 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 to 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., a prolongation of 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 extends PFS in a subject or population of subjects 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, e.g., extending for at least about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 10.5, 11, 11.5, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 months). In some embodiments, the treatment extends PFS in a subject or population of subjects 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, e.g., extending for 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 extends DOR of a subject or population of subjects by at least about 2.4 months (e.g., 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 to 48 months, by 6.0 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., a prolongation of 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 extends DOR of the subject or population of subjects for at least about 4 months (e.g., 4 to 120 months, 5 to 100 months, 6 to 80 months, 7 to 60 months, 8 to 48 months, 9 to 36 months, or 10 to 24 months, e.g., 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, 24 months, 25 months, 29 months, 26 months, 31 months, 35 months, 31 months). In some embodiments, the treatment extends the DOR of the subject or population of subjects 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, e.g., extending for 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 results in a time to confirmation worsening (TTCD) improvement in patient-reported physical function, as measured by patient-reported outcome

Project library v 2.0-body function-measured by profile 10 b. In some cases, the treatment results in an improvement in physical function and/or pain relative to baseline, by

Project library v 2.0-physical function-profile 10b,

Project library v 1.0-fatigue-Profile 4a,

Project library v 1.0-pain disturbance profiles 4a and

number rating scale v 1.0-pain intensity 1a rating.

F. Therapeutic methods and uses related to liver cancer

Liver cancer

Liver cancer is the fifth most common cancer worldwide and the second most common cause of cancer-related death, with 854,000 new cases and 810,000 deaths per year. After diagnosis, most patients with primary liver cancer present with advanced disease, a stage where curative therapy is not recommended. The world health organization estimates that over 100 million people will die of liver cancer in 2030, which highlights a significant global public health problem.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting for approximately 90% of all primary hepatic malignant tumors. HCC is the most lethal disease, with a mortality to morbidity ratio of 0.98, being the highest of all solid tumors. As a result of the late appearance of symptoms, up to 80% of patients presenting HCC for the first time suffer from advanced unresectable or metastatic disease. In the united states, the 5-year OS rate for patients with HCC is 17%, and drops dramatically to only 3% if distant metastases are present.

Thus, there is an unmet need in the art to develop effective immunotherapies for treating liver cancer, such as HCC, e.g., locally advanced HCC, metastatic HCC, or unresectable HCC.

Methods and uses for treating liver cancer

Provided herein are methods and uses for treating or delaying progression of liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects, comprising administering to the subject or population of subjects a dosing regimen comprising effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) and an anti-TIGIT antagonist antibody (e.g., tirayleigh itumumab), wherein the subject or population of subjects has not previously received systemic treatment for liver cancer (e.g., HCC). Also provided herein are methods and uses for treating or delaying progression of liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects, comprising administering to the subject or population of subjects a treatment regimen comprising effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., ibritumomab tiuxelin). In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) and an anti-TIGIT antagonist antibody (e.g., tirayleigh immuzumab) for one or more dosing cycles. In other embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., terayleigh immuzumab)) for one or more dosing cycles.

Also provided herein are methods of enhancing immune function in a subject or population of subjects having liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC), the method comprising administering to the subject or population of subjects a treatment regimen comprising effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) and an anti-TIGIT antagonist antibody (e.g., tirylyouitumumab). In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) and an anti-TIGIT antagonist antibody (e.g., tirayleigh immuzumab) for one or more dosing cycles.

For example, provided herein are methods and uses for treating or delaying progression of liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects, comprising administering to the subject or population of subjects a treatment regimen comprising effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) and an anti-TIGIT antagonist antibody (e.g., ibritumomab tiuxetan). In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) and an anti-TIGIT antagonist antibody (e.g., tegraleigh immuzumab) for one or more dosing cycles.

Also provided herein are pharmaceutical compositions comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) for treating liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects, wherein the treatment comprises a treatment regimen comprising administering the PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody (e.g., ibritumomab tiuxetan). In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) and an anti-TIGIT antagonist antibody (e.g., tirayleigh immuzumab) for one or more dosing cycles.

Also provided herein are pharmaceutical compositions comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) for treating liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects, wherein the treatment comprises a treatment regimen comprising administering the PD-1 axis binding antagonist in combination with a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., ibriturin). In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., ibritumomab tiuxetan) for one or more cycles of administration.

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

In another example, provided herein is a pharmaceutical composition comprising an anti-TIGIT antagonist antibody (e.g., ibrinout iturin) for use in treating liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC) in a subject or population of subjects, wherein the treatment comprises a treatment regimen comprising administering the anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). In some embodiments, the treatment regimen comprises an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., terayleigh immuzumab)) for one or more dosing cycles.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the liver cancer may be in an early or late stage. In some embodiments, the liver cancer is HCC (e.g., locally advanced or metastatic and/or unresectable HCC). In some cases, liver cancer is locally advanced or metastatic and/or unresectable HCC. In some embodiments, the liver cancer is high risk liver cancer (e.g., 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 invasion and/or a tumor occupancy of the liver of greater than or equal to 50%.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the treatment results in remission 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 has objective remission, extends PFS in the subject or population of subjects, extends OS in the subject or population of subjects, extends Time To Radiological Progression (TTRP) in the subject or population of subjects, extends duration of remission (DOR) in the subject or population of subjects, and/or reduces the risk of mortality, e.g., as compared to a reference treatment. In some embodiments, the treatment results in a median PFS of at least about 5.6 months (e.g., between 5.6 months and 14 months (e.g., 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)) for the population of subjects. In some embodiments, the treatment results in a median PFS of at least about 6.83 months (e.g., 6.9 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, or 14 months) for the population of subjects. In some embodiments, the treatment results in a median PFS for the population of subjects of at least about 5.6 months to at least about 6.83 months (e.g., at least about 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, or 6.83 months). In some embodiments, the reference treatment comprises current standard of care. In some embodiments, the reference treatment comprises a PD-1 axis binding antagonist (e.g., atelizumab) and a VEGF antagonist (e.g., bevacizumab) without the use of an anti-TIGIT antagonist antibody. In some embodiments, the reference treatment comprises a PD-1 axis binding antagonist and a VEGF antagonist. In some embodiments, the reference treatment comprises a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody, without a VEGF antagonist. In some embodiments, the reference treatment comprises a VEGF antagonist and an anti-TIGIT antagonist antibody, without the use of a PD-1 axis binding antagonist. In some embodiments, the reference treatment comprises a PD-1 axis binding antagonist without a VEGF antagonist and an anti-TIGIT antagonist antibody. In some embodiments, the reference treatment comprises a VEGF antagonist without the use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist. In some embodiments, the reference therapy 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 response of the treatment may be improved as compared to any suitable standard of care cancer therapy. In some embodiments, the standard-of-care cancer therapy is standard-of-care liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC) therapy. In some embodiments, a standard of care liver cancer (e.g., HCC) therapy comprises a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is a multi-kinase inhibitor. In some embodiments, the multi-kinase inhibitor is sorafenib or lenvatinib. In some embodiments, the multi-kinase inhibitor is sorafenib.

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), or a medicament thereof, can be administered for manufacture of a medicament, or formulated for synergistic (alone or together) administration with one or more additional anti-cancer therapeutic agents (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, radiation/radiation therapy, and/or anti-hormonal agents, e.g., those described above).

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the subject or population of subjects has not been previously treated for liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC). In some cases, the subject or population of subjects has not received prior therapy. In some cases, the subject or population of subjects did not receive at least one prior therapy line. In some cases, the subject or population of subjects did not receive both prior lines of therapy. In some cases, the subject or population of subjects has received at least one but no more than two prior systemic therapies and/or there is no acceptable standard of care for them. In some cases, a subject or population of subjects has not received more than two prior treatment normals. 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 been previously treated for liver cancer, e.g., HCC (e.g., locally advanced or metastatic and/or unresectable HCC). In some embodiments, the subject or population of subjects has not been previously treated for HCC. In some embodiments, the subject or population of subjects has not been previously treated 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 has not received prior systemic therapy for liver cancer (e.g., HCC, including locally advanced or metastatic and/or unresectable HCC). In some embodiments, the subject or population of subjects has not received prior systemic therapy for liver cancer (e.g., HCC).

In some embodiments of any of the methods, uses, or pharmaceutical compositions for use described herein, the subject or population of subjects has not received prior treatment with a PD-1 axis binding antagonist, a VEGF antagonist, or an anti-TIGIT antagonist antibody.

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-Pugh liver function. For example, in some embodiments, a subject or population of subjects has Child-Pugh grade 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 the methods, uses, or pharmaceutical compositions 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 atelizumab. 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 securititumumab.

Exemplary method

In one aspect, the invention provides a method of treating a subject or population of subjects having HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of administration of: a dose (e.g., fixed dose) of 600mg every three weeks of anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of 1200mg every three weeks of atlizumab, wherein the anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO:17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19. In some cases, the subject or population of subjects has not been previously treated for HCC (e.g., locally advanced or metastatic and/or unresectable HCC).

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of dosing of: a dose (e.g., fixed dose) of 600mg every three weeks of anti-TIGIT antagonist antibody, a dose (e.g., fixed dose) of 1200mg every three weeks of atuzumab, and a dose of 15mg/kg every three weeks of bevacizumab, wherein the anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO:17 or 18, and a VL domain having the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides a method of treating a subject or population of subjects having HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of administration of: a dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab and a dose of 1200mg every three weeks (e.g., fixed dose) of atelizumab.

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of dosing of: a dose of 600mg every three weeks (e.g., fixed dose) of tenecteuzumab, a dose of 1200mg every three weeks (e.g., fixed dose) of atelizumab, and a dose of 15mg/kg every three weeks of bevacizumab.

In another aspect, the invention provides a method of treating a subject or population of subjects having HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of administration of: a dose of 420mg (e.g., fixed dose) of tenecteuzumab every two weeks, and a dose of 840mg (e.g., fixed dose) of atelizumab every two weeks.

In another aspect, the invention provides a method of treating a subject or population of subjects having HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of administration of: a dose of 420mg (e.g., fixed dose) of tenecteuzumab every two weeks, a dose of 840mg (e.g., fixed dose) of atelizumab every two weeks, and a dose of 5mg/kg, 7.5mg/kg, or 10mg/kg of bevacizumab every two weeks.

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of dosing of: a dose of 840mg every four weeks (e.g., a fixed dose) of tenecteuzumab and a dose of 1680mg every four weeks (e.g., a fixed dose) of atelizumab.

In another aspect, the invention provides a method of treating a subject or population of subjects suffering from HCC (e.g., locally advanced or metastatic and/or unresectable HCC) by administering to the subject or population of subjects one or more cycles of dosing of: a dose of 840mg (e.g., fixed dose) of tiregumab every four weeks, a dose of 1680mg (e.g., fixed dose) of atuzumab every four weeks, and a dose of 5mg/kg, 7.5mg/kg, or 10mg/kg of bevacizumab every two weeks.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects an effective amount of the anti-TIGIT antagonist antibody and an effective amount of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) for one or more dosing cycles.

In another aspect, the invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects an effective amount of a TIGIT antagonist antibody, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) and an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for one or more cycles of administration.

Exemplary drugs and uses thereof

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of between about 30mg to about 1200mg of an anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between about 80mg to about 2000mg of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) every three weeks. In some aspects, the medicament is formulated for administration of: a dose (e.g., fixed dose) of between 30mg to 1200mg of an anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between 80mg to 2000mg of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) every three weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of between about 30mg to about 1200mg per three weeks of anti-TIGIT antagonist antibody, a dose (e.g., fixed dose) of between about 80mg to about 2000mg per three weeks of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., attritumab)) and a dose of between about 0.1mg/kg and 50mg/kg per three weeks of VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)). In some aspects, the medicament is formulated for administration of: a dose (e.g., fixed dose) of anti-TIGIT antagonist antibody between 30 and 1200mg every three weeks, a dose (e.g., fixed dose) of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., attlizumab)) between 80 and 2000mg every three weeks, and a dose of VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)) between about 0.1 and 50mg/kg every three weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, and wherein the medicament is formulated for administration of: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 30mg to about 600mg every two weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) at a dose (e.g., fixed dose) of between about 80mg to about 1200mg every two weeks. In some aspects, the medicament is formulated for administration of: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) between 30mg and 600mg every two weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) at a dose (e.g., fixed dose) between 80mg and 1200mg every two weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody between about 30mg and about 600mg every two weeks, a dose (e.g., fixed dose) of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) between about 80mg and about 1200mg every two weeks, and a dose of the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) between about 0.1mg/kg and 50mg/kg every two weeks. In some aspects, the medicament is formulated for administration of: a dose (e.g., fixed dose) of between 30mg to 600mg per two weeks of anti-TIGIT antagonist antibody, a dose (e.g., fixed dose) of between 80mg to 1200mg per two weeks of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., attritumab)) and a dose of between 0.1mg/kg and 50mg/kg per two weeks of VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)).

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, and wherein the medicament is formulated for administration of: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of between about 600mg to about 1200mg every four weeks and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) at a dose (e.g., fixed dose) of between about 1200mg to about 2000mg every four weeks. In some aspects, the medicament is formulated for administration of: a dose (e.g., fixed dose) of between 600mg and 1200mg of an anti-TIGIT antagonist antibody every four weeks and a dose (e.g., fixed dose) of between 1200mg and 2000mg of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) every four weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for the manufacture or preparation of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, and wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of between about 600mg to about 1200mg per four weeks of an anti-TIGIT antagonist antibody, a dose (e.g., fixed dose) of between about 1200mg to about 2000mg per four weeks of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)), and a dose of between about 0.1mg/kg and 50mg/kg per two weeks of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). In some aspects, the medicament is formulated for administration of: a dose (e.g., fixed dose) of between 600mg and 1200mg per four weeks of an anti-TIGIT antagonist antibody, a dose (e.g., fixed dose) of between 1200mg and 2000mg per four weeks of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)), and a dose of between 0.1mg/kg and 50mg/kg per two weeks of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)).

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

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects the medicament and the anti-TIGIT antagonist antibody for one or more dosing cycles, and wherein the medicament is formulated for administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) at a dose (e.g., a fixed dose) of between about 30mg to about 2000mg per three weeks, and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose of between about 1200mg, e.g., 0mg per three weeks). In some aspects, the medicament is formulated for administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) at a dose (e.g., a fixed dose) of between 80mg to 2000mg every three weeks, an anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose) of between 30mg to 1200mg every three weeks, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered at a dose of between 0.1mg/kg and 50mg/kg every three weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab)) for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects the drug and the anti-TIGIT antagonist antibody for one or more dosing cycles, and wherein the medicament is formulated for administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab) at a dose (e.g., fixed dose)) of between about 80mg to about 1200mg every two weeks and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., fixed dose) of between about 30mg to about 600mg every two weeks. In some aspects, the medicament is formulated for administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) at a dose (e.g., a fixed dose) of between 80mg to 1200mg every two weeks, and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose) of between about 30mg to about 600mg every two weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects the medicament and the anti-TIGIT antagonist antibody for one or more dosing cycles, and wherein the medicament is formulated for administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) at a dose (e.g., a fixed dose) of between about 30mg to about 600mg per two weeks (e.g., a fixed dose), and the anti-VEGF antagonist antibody is to be administered at a dose (e.g., 0mg/kg per two weeks). In some aspects, the medicament is formulated for administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) at a dose (e.g., a fixed dose) of between 80mg to 1200mg every two weeks, an anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose) of between 30mg to 600mg every two weeks, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered at a dose of between 0.1mg/kg and 50mg/kg every two weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., aduzumab)) for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects the drug and the anti-TIGIT antagonist antibody for one or more dosing cycles, and wherein the medicament is formulated for administration of the PD-1 axis binding antagonist (e.g., the anti-PD-L1 antagonist antibody (e.g., aduzumab) at a dose (e.g., fixed dose) of between about 1200mg to about 2000mg every four weeks and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., fixed dose) of between about 600mg to about 1200mg every four weeks. In some aspects, the medicament is formulated for administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) at a dose (e.g., a fixed dose) of between 1200mg to 2000mg every four weeks, and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose) of between about 600mg to about 1200mg every four weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more dosing cycles of the medicament and the anti-TIGIT antagonist antibody, and wherein the medicament is formulated for administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) at a dose (e.g., a fixed dose) of between about 1200mg to about 2000mg per four weeks, and the anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose of the anti-TIGIT antagonist antibody (e.g., a fixed dose) between about 1200mg to about 1200mg per four weeks, and about 50mg per about 0 kg of anti-VEGF (e.g., anti-VEGF). In some aspects, the medicament is formulated for administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab)) at a dose (e.g., a fixed dose) of between 1200mg to 2000mg every four weeks, an anti-TIGIT antagonist antibody is to be administered at a dose (e.g., a fixed dose) of between 600mg to 1200mg every four weeks, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered at a dose of between 0.1mg/kg and 50mg/kg every two weeks.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody and atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of 600mg every three weeks and a dose (e.g., fixed dose) of 1200mg every three weeks of alemtuzumab, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody, atuzumab, and bevacizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of 600mg every three weeks of anti-TIGIT antagonist antibody, a dose (e.g., fixed dose) of 1200mg every three weeks of atuzumab, and a dose of 15mg/kg every three weeks of bevacizumab, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody and atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, wherein the medicament is formulated for administration of: a dose (e.g., fixed dose) of 420mg per two weeks of anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of 840mg per two weeks of atuzumab, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

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

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody and atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, wherein the medicament is formulated for administration of: a dose of 840mg (e.g., fixed dose) every four weeks of an anti-TIGIT antagonist antibody and a dose of 1680mg (e.g., fixed dose) of alemtuzumab every four weeks, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

In another aspect, the invention provides use of an anti-TIGIT antagonist antibody, atelizumab and bevacizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC), wherein the method comprises administering to the subject or population of subjects one or more cycles of administration of the medicament, wherein the medicament is formulated for administration of: a dose of 840mg (e.g., fixed dose) of anti-TIGIT antagonist antibody every four weeks, a dose of 1680mg (e.g., fixed dose) of atuzumab every four weeks, and a dose of 5mg/kg, 7.5.mg/kg, or 10mg/kg bevacizumab every two weeks, and wherein the anti-TIGIT antagonist antibody comprises: a VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO:19, as described in further detail below. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 17; and a VL domain having SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain having SEQ ID NO: 18; and a VL domain having SEQ ID NO: 19.

Dosing regimens and administration

Therapeutic methods and uses of the invention described herein include, in one aspect, administering to a subject or population of subjects having liver cancer (e.g., hepatocellular carcinoma (HCC), including locally advanced or metastatic and/or unresectable HCC) a treatment regimen comprising effective amounts of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., ewolimumab tiuxetan).

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

Effective dose

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is administered at a dose as described in section III (K) in a combination therapy (e.g., a combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., adzuzumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), and the dose can be reduced compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy. Section III (K) describes the administration of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, and VEGF antagonists.

Administration cycle

In any of the methods and uses of the invention, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh mab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attuzumab)) or a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) can be 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 dosing cycle of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) and/or VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) continues until clinical benefit (e.g., confirmed disease progression, drug resistance, death or unacceptable toxicity) is lost. In some cases, each administration cycle is about 14 to 28 days in length (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). In some cases, each administration cycle is about 21 days in length. In some cases, each administration cycle is about 14 days in length. In some cases, each administration cycle is about 28 days in length. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered at about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose (e.g., a fixed dose) of about 600mg on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks). In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered about day 1 (e.g., day 1 ± 3) of each dosing cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) is administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks). In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered at about day 1 (e.g., day 1 ± 3 days) of each dosing cycle. For example, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered intravenously at a dose of about 15mg/kg on day 1 of each 21-day cycle (i.e., at a dose of about 15mg/kg every three weeks). In some examples, for example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of 600mg (e.g., a fixed dose) (i.e., at a dose of 600mg every three weeks) on day 1 of each 21-day cycle. In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered on day 1 (e.g., day 1 ± 3 days) of each dosing cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) is administered intravenously at a dose of 1200mg (i.e., at a dose of 1200mg every three weeks) on day 1 of each 21-day cycle. In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered on day 1 (e.g., day 1 ± 3 days) of each dosing cycle. For example, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered intravenously at a dose of 15mg/kg on day 1 of each 21-day cycle (i.e., at a dose of 15mg/kg every three weeks).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab), and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered at about day 1 (e.g., day 1 ± 3) of each dosing cycle.

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 600mg (i.e., at a dose of about 600mg every three weeks) on day 1 of each 21-day cycle, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab) is administered intravenously at a dose of about 1200mg (i.e., at a dose of about 1200mg every three weeks) on day 1 of each 21-day cycle, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered intravenously at a dose of about 15mg/kg (i.e., at a dose of about 15mg/kg every three weeks) on day 1 of each 21-day dosing cycle.

In other cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 420mg (i.e., at a dose of about 420mg every two weeks) on day 1 of each 14-day cycle, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab) is administered intravenously at a dose of about 840mg (i.e., at a dose of about 840mg every two weeks) on day 1 of each 14-day cycle, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered intravenously at a dose of about 5mg/kg, 7.5mg/kg, or 10mg/kg (i.e., at a dose of about 5mg/kg, 7.5mg/kg, or 10mg/kg every two weeks) on day 1 of each 14-day dosing cycle, hi other cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., an anti-TIGIT antibody, e.g., an altuzumab) is administered intravenously at a dose of about 1 mg/kg, e.g., about 840 mg/kg, 14-1 mg, 14-L14-day (i.g., at a dose of about 14-day) and 14-day administration dose of each 14-day) A dose of 7.5mg/kg or 10 mg/kg).

In other cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 840mg (i.e., at a dose of about 840mg every four weeks) on day 1 of each 28-day cycle, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab) is administered intravenously at a dose of about 1680mg (i.e., at a dose of about 1680mg every four weeks) on day 1 of each 28-day cycle, and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered intravenously at a dose of about 5mg/kg, 7.5mg/kg, or 10mg/kg (i.e., at a dose of about 5mg/kg, 7.5mg/kg, or 10mg/kg every two weeks) on days 1 and 15 of each 28-day dosing cycle, hi other cases, an anti-it antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., an anti-TIGIT antibody, e.g., an anti-1 mg/kg (e.g., an anti-VEGF antagonist antibody) is administered intravenously at a dose of about 1680 mg/kg) administered at a dose of about 1, e.g., about 1680 mg/kg, e.g., about 1 mg/kg, e.g., about 0mg/kg every four days, e.g., about 0 mg/kg) on days, i.g., about 0mg/kg every 28-28 days, i.g., about 0 mg/kg) on days of each 28 days, and four days of each 28 days, at a dose of 5mg/kg, 7.5mg/kg or 10mg/kg every two weeks).

Order of administration and observation period

In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., altlizumab)) is administered to the subject or population of subjects prior to a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and/or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomuzumab). In some cases, for example, after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab)) and before administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), the method comprises a first observation period in the middle. In some cases, for example, following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered to the subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan). In other instances, following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to the subject or population of subjects prior to a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab)) is first administered to a subject or population of subjects, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered to the subject or population of subjects after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab)) and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., bevacizumab)) is administered to the subject or population of subjects after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) antagonist. In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., tenellituzumab)) is first administered to a subject or population of subjects followed by administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered to the subject or population of subjects followed by administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., tenellituzumab)).

In some cases, the method further comprises a second observation period following administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan). In some cases, the method further comprises a third observation period following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab).

In some cases, the method comprises both a first observation period after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab)) and a second observation period after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleighumab). In some cases, the method comprises a first observation period after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab)), a second observation period after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), and a third observation period after administration of a TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a 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 (e.g., between about 30 minutes and 60 minutes in length, between 60 and 90 minutes in length, and/or between 90 and 120 minutes in length). Where the length of each of the first, second, and third observation periods is about 60 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject for the first, second, or third observation period about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attuzumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh mab), or a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). Where the length of each of the first, second, and third observation periods is about 30 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject for the first, second, or third observation period about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attuzumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh mab), or a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to the subject or population of subjects prior to the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., attrituzumab)) or VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)).

In some cases, for example, after administration of the anti-TIGIT antagonist antibody and prior to administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) or VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), the method includes an intermediate first observation period. In some cases, for example, following administration of the anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) is administered to the subject or population of subjects prior to a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). In other cases, for example, following administration of the anti-TIGIT antagonist antibody, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered to the subject or population of subjects prior to PD-1 axis binding of the antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)). In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., tataurillulinumab)), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., adzuzumab)) is first administered to the subject or population of subjects after administration of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., tataurilinukuzumab)), and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered to the subject or population of subjects after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., adzuzumab)). In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., ibritumomab tiuxetan)) is first administered to a subject or population of subjects, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered to the subject or population of subjects after administration of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., ibritumomab tiuxetan)) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atzezumab)) is administered to the subject or population of subjects after administration of the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)).

In some cases, the method further comprises a second observation period following administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) or a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). In some cases, the method further comprises a third observation period following administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)).

In some cases, the method includes both a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attlizumab)) or VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), in some cases, the method includes a first observation period after administration of the anti-TIGIT antagonist antibody, a second observation period after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attlizumab)) or VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), and a third observation period after administration of the TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the VEGF antagonist, where the length of each of the first, second, and third observation periods is about 60 minutes, the method can comprise recording vital signs (e.g., pulse rate, respiration rate, blood pressure, and body temperature) of the subject or population of subjects for the first, second, and third observation periods about 30 ± 10 minutes after administration of the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atuzumab)), or VEGF antagonist (e.g., anti-VEGF antibody (e.g., bevacizumab)), the method can comprise, where the length of each of the first, second, and third observation periods is about 30 minutes, administering the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, or the VEGF antagonist, about 15 ± 10 minutes after the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) or VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject or population of subjects are recorded over the first, second, and third observation periods.

In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered to the subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)). In some cases, for example, after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and prior to administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atzezumab)), the method comprises an intermediate first observation period. In some cases, for example, after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to the subject or population of subjects prior to PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)). In other cases, for example, after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered to the subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., teneligylornizumab). In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., ibritumomab tiuxetan)) is first administered to a subject or population of subjects after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is administered to a subject or population of subjects after administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., ibritumomab tiuxetan)). In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is first administered to a subject or population of subjects after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein (e.g., terayleighumab)) is administered to a subject or population of subjects after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)).

In some cases, the method further comprises a second observation period following administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)). In some cases, the method further comprises a third observation period following administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)).

In some cases, the method includes both a first observation period after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) and a second observation period after administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezumab)). In some cases, the method comprises a first observation period after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), a second observation period after administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)), and a third observation period after administration of a TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist. In some cases, the first, second, and third observation periods are each between about 30 minutes and about 60 minutes in length. Where the length of each of the first, second, and third observation periods is about 60 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject about 30 ± 10 minutes after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) over the first, second, or third observation periods. Where the length of each of the first, second, and third observation periods is about 30 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject about 15 ± 10 minutes after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan), or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) over the first, second, or third observation periods.

In other instances, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) are administered concurrently to the subject or population of subjects. In some cases, for example, after administration of the anti-TIGIT antagonist antibody and prior to administration of the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), the method comprises an observation period.

In other instances, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) are administered to the subject or population of subjects simultaneously. In some cases, for example, after administration of the anti-TIGIT antagonist antibody and prior to administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), the method comprises an observation period.

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

In some cases, the length of the observation period is between about 30 minutes and about 60 minutes. Where the observation period is about 60 minutes, the method can include recording vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject or population of subjects about 30 ± 10 minutes after administration. Where the observation period is about 30 minutes, the method can include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15 ± 10 minutes after administration.

In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is administered after simultaneous administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibriturin itumumab) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)).

In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered after simultaneous administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered after simultaneous administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atlizumab)) and a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)).

In some cases, for example, after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), the method comprises a second observation period. In some cases, for example, after administration of a VEGF antagonist, e.g., an anti-VEGF antibody (e.g., bevacizumab)) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), the method comprises a second observation period. In some cases, the length of the second observation period is between about 30 minutes and about 60 minutes. Where the second observation period is about 60 minutes, the method can include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 30 ± 10 minutes after administration. Where the second observation period is about 30 minutes, the method can include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15 ± 10 minutes after administration.

G. Therapeutic methods and uses associated with urothelial cancer

Urothelial cancer

Urothelial Cancer (UC) is the most common cancer of the urinary system worldwide. Most cases originate in the bladder. UC can be diagnosed as non-muscle-invasive, muscle-invasive or metastatic disease, with one-third of the new cases diagnosed as muscle-invasive disease (classified according to tumor, lymph node and metastasis (TNM), cT2-T4a Nx M0). Muscle Invasive UC (MIUC) refers collectively to Muscle Invasive Bladder Cancer (MIBC) and muscle invasive Urinary Tract Urothelial Cancer (UTUC). In 2018, 549,393 new cases of bladder cancer and 199,922 deaths were estimated globally. In europe, 197,110 new cases of bladder cancer and 64,970 deaths were estimated, including 164,450 new cases and 52,930 deaths in 28 member countries of the european union. In the united states, 81,400 new cases of bladder cancer and 17,980 deaths are expected in 2020. The median age of patients diagnosed with UC in the united states is 73 years, the highest diagnosed age among all tumor types.

There is a particular pressing need for therapeutic methods for treating MIBC. MIBC accounts for approximately 30% of new cases of urothelial cancer. MIBC has a 5-year survival rate of 25-50% (european urological institute EAU guideline 2013), with little improvement over the last 30 years due to the lack of effective new therapies in this disease area (surveillance, epidemiology and end result (SEER) program. Statistical fact of cancer: bladder cancer, 2020). Thus, there is a high unmet need for improved medical interventions.

Methods and uses for treating urothelial cancer

Provided herein are methods and uses for treating lung cancer UC (e.g., bladder cancer (e.g., MIBC)) in a subject or population of subjects, comprising administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tamarind), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atuzumab, or an anti-PD-1 antagonist antibody, such as palbociclumab) for one or more dosing cycles. The subject is preferably a human. In some embodiments, the subject or population of subjects has not been previously treated with cancer immunotherapy.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atuzumab, or an anti-PD-1 antagonist antibody, e.g., paribizumab) every three weeks (e.g., on day 1 of each 21-day dosing cycle).

The invention includes methods and uses for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose (e.g., fixed dose) of between about 30mg to about 1200mg of an anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between about 80mg to about 1600mg of a PD-1 axis binding antagonist every three weeks, wherein the subject or population of subjects is not eligible to be treated with a platinum-based chemotherapeutic agent (e.g., cisplatin). In some aspects, the method comprises administering to the subject or population of subjects one or more cycles of administration of: a dose (e.g., fixed dose) of between 30mg to 1200mg per three weeks of an anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of between 80mg to 1600mg per three weeks of a PD-1 axis binding antagonist, wherein the subject or population of subjects is not eligible for treatment with a platinum-based chemotherapeutic agent (e.g., cisplatin).

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

The invention includes methods and uses for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose (e.g., fixed dose) of between about 30mg to about 1200mg of the anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between about 80mg to about 1600mg of the PD-1 axis binding antagonist every three weeks, wherein the treatment is a perioperative treatment. In some aspects, the method comprises administering to the subject or population of subjects one or more cycles of administration of: a dose (e.g., fixed dose) of between 30mg to 1200mg of an anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between 80mg to 1600mg of a PD-1 axis binding antagonist every three weeks, wherein the treatment is a perioperative treatment.

The invention includes methods and uses for treating a subject or population of subjects having surgically operable MIBC, the method comprising administering to the subject or population of subjects one or more cycles of administration of: a dose (e.g., fixed dose) of between about 30mg to about 1200mg of the anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between about 80mg to about 1600mg of the PD-1 axis binding antagonist every three weeks. In some aspects, the method comprises administering to the subject or population of subjects one or more cycles of administration of: a dose (e.g., fixed dose) of between 30mg to 1200mg of an anti-TIGIT antagonist antibody every three weeks and a dose (e.g., fixed dose) of between 80mg to 1600mg of a PD-1 axis binding antagonist every three weeks.

The PD-1 axis binding antagonist anti-TIGIT antagonist antibody can be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can be administered sequentially (on different days) or contemporaneously (on the same day or within the same treatment cycle). In some cases, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can 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 an anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist can be administered prior to the anti-TIGIT antagonist antibody administered on the same day. In some cases, the PD-1 axis binding antagonist can be administered after the same day of administration of the anti-TIGIT antagonist antibody. In other cases, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered at the same time. In some cases, the PD-1 axis binding antagonist is in a separate composition from the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is in the same composition as the anti-TIGIT antagonist antibody. In some cases, the PD-1 axis binding antagonist is administered via an intravenous line that is separate from any other therapeutic agent administered to the patient on the same day. The PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can 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, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some cases, the anti-TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some cases, the anti-TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some cases, the anti-TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some cases, there is a first observation period following 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 length of the observation period is between about 30 minutes and about 60 minutes. 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 over 30 ± 10 minutes and/or over 60 ± 15 minutes. In one example, the atezumab can be administered intravenously over 60 minutes; if the first infusion can be tolerated, all subsequent infusions can be delivered over 30 minutes. In some examples, the PD-1 axis binding antagonist is not administered as a bolus injection or a bolus injection. In one example, the ibritumomab tiuxetan may be administered intravenously over 60 minutes; if the first infusion can be tolerated, all subsequent infusions can be delivered over 30 minutes. In some examples, the anti-TIGIT antagonist antibody is not administered as a bolus injection or bolus injection.

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

In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in pCR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab) results in relapse-free survival (RFS), e.g., a landmark RFS (e.g., a landmark RFS at 12, 18, or 24 months). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab) results in event-free survival (EFS), e.g., landmark EFS (e.g., landmark EFS at 12, 18, or 24 months). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab) results in OS, e.g., landmark OS (e.g., landmark OS at 12, 18, or 24 months). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab) results in an increase in the rate of pathological degradation. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tigliu itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in pCR in the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) extends the EFS (e.g., the landmark EFS) of the subject or population of subjects, e.g., as compared to treatment with a PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with an anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atlas) extends RFS (e.g., landmark RFS) in the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) extends the OS (e.g., landmark OS) of the subject or population of subjects, e.g., as compared to treatment with a PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with an anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tegrayleitumomab) every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered every four weeks (e.g., on day 1 of each 28-day dosing cycle), and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altlizumab, or an anti-PD-1 antagonist antibody, e.g., palboclizumab) is administered every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on day 1 of each 21-day dosing cycle), or every four weeks (e.g., on day 1 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in CR or PR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in pCR of the subject or population of subjects as compared to a reference. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) results in an increase in EFS and/or RFS. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) extends the OS of the subject or population of subjects.

The invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atlizumab, or an anti-PD-1 antagonist antibody, e.g., palbociclumab) every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in pCR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) results in an increase in EFS and/or RFS in the subject or population of subjects, e.g., as compared to treatment with the PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) extends the OS of the subject or population of subjects, e.g., as compared to treatment with a PD-1 axis binding antagonist but without the anti-TIGIT antagonist antibody or as compared to treatment with an anti-TIGIT antagonist antibody but without the PD-1 axis binding antagonist.

In certain instances, the invention includes methods and uses involving: administering to a subject or population of subjects in need thereof an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tegrayleigh immuzumab) every two weeks (e.g., on days 1 and 15 of each 28-day dosing cycle). In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in pCR. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) results in an increase in EFS and/or RFS in a subject or population of subjects as compared to a reference. In some cases, administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) extends OS in the subject or population of subjects.

In some cases, a subject or population of subjects receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) is being treated for MIBC.

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

In some cases, the additional therapy is administration of a side-effect limiting agent (e.g., an agent intended to reduce the occurrence and/or severity of a therapeutic side-effect, e.g., an anti-nausea agent, a corticosteroid (e.g., prednisone or an equivalent, e.g., at a dose of 1 to 2 mg/kg/day), a hormone replacement drug, etc.).

In any of the foregoing examples, each administration cycle can be of any suitable length, e.g., about 7 days, about 14 days, about 21 days, about 28 days, or longer. In some cases, each dosing cycle is about 21 days.

Also provided herein are methods for treating MIBC in a subject or population of subjects, the method comprising administering to the subject or population of subjects a dosing regimen comprising an effective amount of a PD-1 axis binding antagonist (e.g., atelizumab) and/or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tegraleighumab) in combination with another anti-cancer agent or cancer therapy. For example, a PD-1 axis binding antagonist can be combined with: (ii) additional chemotherapy or a combination of chemotherapeutic agents (see definition above); targeted therapies or targeted therapeutic agents; immunotherapy or immunotherapeutic agents, e.g., monoclonal antibodies; one or more cytotoxic agents (see definition above); or a combination thereof.

In some cases where the patient has metastatic urothelial cancer (mecc) and the mecc progresses during or after platinum-containing therapy, the methods provided herein further comprise 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. 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) vildagliptin-enfratuzumab or (b) govitegam-shaxituzumab.

Also provided herein are methods for treating a subject or population of subjects having a uc, the method comprising administering a first dosing regimen to the subject or population of subjects followed by a second dosing regimen, wherein (a) the first dosing regimen comprises one or more cycles of dosing of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atelizumab (e.g., a fixed dose) every three weeks; and (b) the second dosing regimen comprises one or more of the following for the dosing cycle: about 1200mg dose (e.g., fixed dose) of attritumab every three weeks and (i) wettin-enritumumab administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (ii) govitegam-shacetotuzumab administered at a dose of 10mg/kg per week (e.g., fixed dose), administered for 2 weeks/off for 1 week, wherein the second dosing cycle is administered to the subject or population of subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity during the first dosing regimen. In some aspects, provided herein are methods for treating a subject or population of subjects having a uc, the method comprising administering to the subject or population of subjects a first dosing regimen, followed by a second dosing regimen, wherein (a) the first dosing regimen comprises one or more cycles of dosing of: a dose of 600mg every three weeks and a dose of 1200mg every three weeks (e.g., a fixed dose) of atelizumab; and (b) the second dosing regimen comprises one or more of the following for the dosing cycle: a dose (e.g., fixed dose) of 1200mg of alemtuzumab every three weeks and (i) vildagliptin-enfratuzumab administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (ii) govittazin-shacetuzumab administered at a dose (e.g., fixed dose) of 10mg/kg per week for 2 weeks/off for 1 week, wherein the second dosing cycle is administered to the subject or population of subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity during the first dosing regimen.

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

In some cases, the treatment results in a median OS for the population of subjects of at least about 7.9 months (e.g., 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, 10 months, 11 months, 12 months, 13 months, or 14 months). In some cases, the treatment results in a median OS for the population of subjects of at least about 8.6 months (e.g., 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). In some cases, the treatment results in a median OS for the population of subjects of about 7.9 months to about 8.6 months (e.g., 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 results in an ORR of the population of subjects of at least about 13.4% to at least about 31% (e.g., at least about 13.5%, 14%, 15%, 18%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, or 31%). In some cases, the treatment results in an ORR of at least about 31% (e.g., between about 31% and about 100%, e.g., between about 31% and about 60% (e.g., 35%, 40%, 45%, 50%, 55%, or 60%) for the population of subjects.

In some cases, the treatment results in a median OS for the population of subjects of at least about 7.9 (e.g., between about 7.9 and about 36 months (e.g., between about 7.9 and about 24 months (e.g., 8 months, 10 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months, or 24 months))). In some cases, the treatment results in a median OS for the population of subjects of at least about 16.3 months (e.g., between about 16.3 months and 36 months (e.g., between about 16.3 months and about 24 months (e.g., 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months))). In some cases, the treatment results in a median OS for the population of subjects of about 7.9 months to about 16.3 months (e.g., 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, e.g., 7.9 to 9 months, 9 to 10 months, 10 to 11 months, 11 to 12 months, 12 to 13 months, 13 to 14 months, 14 to 15 months, 15 to 16 months, or more than 16 months).

Administration of anti-TIGIT antagonist antibodies

Administration of anti-TIGIT antagonist antibodies is described in section III (K).

Administration of PD-1 axis binding antagonists

Administration of PD-1 axis binding antagonists is described in section III (K).

Cancer characterization and selection

In some cases, in any of the methods, uses, or compositions for use described herein, UC (e.g., bladder cancer (e.g., MIBC)) is surgically manipulatable (e.g., UC suitable for cystectomy (e.g., bladder cancer (e.g., MIBC))). In some cases, in any of the methods, uses, or compositions for use described herein, the MIBC is surgically operable (e.g., MIBC suitable for cystectomy).

In some cases, in any of the methods, uses, or compositions for use described herein, the subject is not eligible for platinum-based chemotherapy (e.g., is not eligible for use of cisplatin). In some cases, the subject is not eligible for cisplatin. In some cases, the subject has a creatinine clearance < 60 mL/min. In some cases, the subject has a creatinine clearance ≧ 30 mL/min. In some cases, the subject has a hearing loss greater than or equal to grade 2. In some cases, the subject has a grade 2 or greater neuropathy. In some cases, subjects with creatinine clearance < 60mL/min, hearing loss greater than or equal to grade 2, and/or neuropathy greater than or equal to grade 2 are not eligible for cisplatin. In some cases, subjects with creatinine clearance < 60mL/min did not meet the conditions for cisplatin. In some cases, subjects with hearing loss greater than or equal to grade 2 are not eligible for cisplatin. In some cases, subjects with neuropathy greater than or equal to grade 2 are not eligible to use cisplatin. In some cases, subjects who reject cisplatin-based chemotherapy are not eligible to use cisplatin. In some cases, the Eastern Cooperative Oncology Group (ECOG) physical Performance Status (PS) of the subject is 0 or 1.

In some cases, in any of the methods, uses, or compositions for use described herein, the presence or level of circulating tumor DNA (ctDNA) can be assessed. In some cases, ctDNA is assessed in a sample (e.g., a blood sample) from the subject. In some cases, ctDNA in a sample from the subject is assessed prior to day 1 of the first dosing cycle (e.g., the first dosing cycle of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist). In some cases, ctDNA in a sample from a subject is assessed prior to surgery (e.g., cystectomy). In some cases, ctDNA in a sample from a subject is assessed following surgery (e.g., cystectomy). In some cases, ctDNA in a sample from a subject is assessed 4 to 6 weeks (e.g., 4 weeks, 5 weeks, or 6 weeks) after surgery (e.g., cystectomy). In some cases, ctDNA of a sample from a subject is assessed 6 months after surgery (e.g., 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 the therapy can be characterized by one or more measurements. 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 landmark RFS, landmark EFS, or landmark OS. In some embodiments, the treatment results in an increase in the rate of pathological degradation.

In some cases, the treatment results in an increase in pCR in the subject, 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.

In some cases, the treatment prolongs OS in the subject, 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. In some cases, the treatment extends EFS in the subject, 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. In some cases, treatment prolongs RFS in the subject, 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. In some cases, treatment increases the rate of pathological degradation in the subject, 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.

In some embodiments, the treatment described herein extends pCR of a subject for at least about 2 months (e.g., 2 to 120 months, 2.5 to 100 months, 3.0 to 80 months, 4.0 to 60 months, 5.0 to 48 months, 6.0 to 36 months, 8.0 to 24 months, or 10 to 12 months, e.g., extending for 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 extends pCR of the subject for at least about 4 months (e.g., 4 to 120 months, 5 to 100 months, 6 to 80 months, 7 to 60 months, 8 to 48 months, 9 to 36 months, or 10 to 24 months, e.g., extending for 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, 33 months, 35 months, or 36 months).

In some embodiments, the treatment described herein extends the EFS of the subject by at least about 2 months (e.g., 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 to 36 months, by 8.0 to 24 months, or by 10 to 12 months, e.g., extending for 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 extends the EFS of the subject 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, e.g., extending for 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, 33 months, 35 months, or 36 months).

In some embodiments, the treatment described herein extends RFS in a subject for at least about 2 months (e.g., 2 to 120 months, 2.5 to 100 months, 3.0 to 80 months, 4.0 to 60 months, 5.0 to 48 months, 6.0 to 36 months, 8.0 to 24 months, or 10 to 12 months, e.g., extending for 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 extends RFS in the subject for at least about 4 months (e.g., 4 to 120 months, 5 to 100 months, 6 to 80 months, 7 to 60 months, 8 to 48 months, 9 to 36 months, or 10 to 24 months, e.g., extending for 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, 33 months, 35 months, or 36 months).

In some embodiments, OS is measured as the period of time from the start of treatment to death. <xnotran> , OS 2 (, 2 120 , 3 110 , 4 100 , 5 80 , 6 60 , 7 48 , 8 36 10 24 , , 2 , 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 , 3.0 , 3.1 , 3.2 , 3.3 , 3.4 , 3.5 , 3.6 , 3.7 , 3.8 , 3.9 , 4.0 , 4.1 , 4.2 , 4.3 , 4.4 , 4.5 , 4.6 , 4.7 , 4.8 , 4.9 , 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 , 9.5 , 10 , 10.5 , 11 , 11.5 , 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 ). </xnotran> In some cases, the treatment extends OS of the subject 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, e.g., a prolongation of 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, a 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 extends OS of the subject 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, e.g., 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, 34 months, 35 months, or 36 months).

H. Therapeutic methods and uses associated with pancreatic cancer

Pancreatic cancer

Of the pancreatic cancer patients, 80% present with advanced disease at the time of initial diagnosis. Disease recurrence occurs even in patients undergoing radical surgery, resulting in 5-year survival rates of 25% to 30% and 10% in pancreaticoduodenectomy lymph node-negative and lymph node-positive patients, respectively. Patients with locally advanced and unresectable disease often receive chemotherapy, resulting in a median OS of 9 to 13 months, but rarely provide long-term survival.

Thus, there is a high unmet need for improved medical interventions.

Methods and uses for treating pancreatic cancer

In some cases, a subject or population of subjects receiving an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody such as atelizumab), an antimetabolite (e.g., gemcitabine), and a taxane (e.g., paclitaxel) is being treated for pancreatic cancer (e.g., pancreatic Ductal Adenocarcinoma (PDAC), e.g., metastatic PDAC (mPDAC)).

The invention includes a method of treating a subject or population of subjects having pancreatic cancer, the method comprising administering to the subject or subject A dosing regimen comprising one or more of the following for a 28 day dosing cycle: a dose of about 420mg of tegraluretuzumab on days 1 and 15 of each 28-day dosing cycle, a dose of about 840mg of atelizumab on days 1 and 15 of each 28-day dosing cycle, about 1000mg/m on days 1, 8, and 15 of each 28-day dosing cycle ² And about 125mg/m on days 1, 8 and 15 of each 28-day dosing cycle ² Nab-paclitaxel at the dosage of (a). In some cases, the method comprises administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 28-day dosing cycle: a dose of 420mg of tegaserod on days 1 and 15 of each 28-day dosing cycle, a dose of 840mg of atelizumab on days 1 and 15 of each 28-day dosing cycle, 1000mg/m on days 1, 8, and 15 of each 28-day dosing cycle ² And 125mg/m on days 1, 8 and 15 of each 28-day dosing cycle ² Nab-paclitaxel at the dosage of (a). In some cases, the pancreatic cancer is PDAC, e.g., mPDAC. In some aspects, the subject or subjects have not received prior systemic therapy for metastatic PDAC.

In some cases, the treatment results in an ORR of at least about 41.7% to about 46.7% (e.g., 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, or 46.7% (e.g., 41.7% to 43%, 43% to 45%, or 45% to 46.7%) for the population of subjects, in some cases the treatment results in an ORR increase of at least about 20% as compared to treatment comprising gemcitabine and nab-paclitaxel without the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, in some cases the treatment results in a median PFS of the population of subjects of at least about 5.5 months (e.g., between about 5.5 months and 14 months (e.g., between about 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, or 14 months)). In some cases, the treatment results in a median PFS for the population of subjects of at least about 7 months (e.g., between about 7 months and 14 months (e.g., 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, or 14 months)). In some cases, the treatment results in a median PFS for the population of subjects of 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 more than 7 months). In some cases, the treatment results in a median OS for the population of subjects of at least about 8.5 months (e.g., between about 8.5 months and about 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)). In some cases, the treatment results in a median OS for the population of subjects of at least about 10.6 months (e.g., between about 10.6 months and about 16 months (10.6 months, 11 months, 12 months, 13 months, 14 months, 15 months, or 16 months)). In some cases, the treatment results in a median OS for the population of subjects of at least about 8.5 months to about 10.6 months (e.g., 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, or more than 10.6 months).

Administration of pharmaceutical agents

Section III (K) describes the administration of anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, antimetabolites, and taxanes.

I. Therapeutic methods and uses associated with esophageal cancer

The invention includes a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody on day 1 of each dosing cycle of between about 30mg to about 1200mg (e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) and a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody on day 1 of each dosing cycle of between about 80mg to about 1600mg (e.g., between about 1000mg to about 1400mg, for example, a dose (e.g., a fixed dose) of PD-1 axis binding antagonist of between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg, e.g., between about 1190mg to about 1210mg, e.g., 1200mg ± 5mg, e.g., 1200 ± 2.5mg, e.g., 1200 ± 1.0mg, e.g., 1200 ± 0.5mg, e.g., 1200 mg). In some cases, the method comprises administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody of between about 500mg to about 700mg (e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) on day 1 of each dosing cycle and a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody of between about 900mg to about 1500mg (e.g., between about 1000mg to about 1400mg, for example, a dose (e.g., a fixed dose) of PD-1 axis binding antagonist of between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg, e.g., between about 1190mg to about 1210mg, e.g., 1200mg ± 5mg, e.g., 1200 ± 2.5mg, e.g., 1200 ± 1.0mg, e.g., 1200 ± 0.5mg, e.g., 1200 mg). In some aspects, the method comprises administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21 day dosing cycle: a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody between 500mg and 700mg (e.g., between 550mg and 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) on day 1 of each dosing cycle and a dose (e.g., fixed dose) of the antagonist antibody between 900mg and 1500mg (e.g., between 1000mg and 1400mg, e.g., 1050mg to 1350mg, e.g., 1100mg to 1300mg, e.g., 1150mg to 1250mg, e.g., 1175mg to 1225mg, e.g., 1190mg to 1210mg, e.g., 1200mg ± 5mg, e.g., 1200 ± 2.5mg, e.g., 1200 ± 1.0mg, e.g., 1200 ± 0.g., 1200 mg) on day 1 of each dosing cycle.

The invention includes a method for treating a subject or population of subjects suffering from esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody on day 1 of each dosing cycle of between about 500mg to about 700mg (e.g., between about 550mg to about 650mg, e.g., 600mg + -10 mg, e.g., 600 + -6 mg, e.g., 600 + -5 mg, e.g., 600 + -3 mg, e.g., 600 + -1 mg, e.g., 600 + -0.5 mg, e.g., 600 mg) and a dose (e.g., fixed dose) of the anti-TIGIT antagonist antibody on day 1 of each dosing cycle of between about 900mg to about 1500mg (e.g., between about 1000mg to about 1400mg, e.g., between about 1050mg to about 1350mg, for example, a dose (e.g., fixed dose) of PD-1 axis binding antagonist between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg, e.g., between about 1190mg to about 1210mg, e.g., 1200mg ± 5mg, e.g., 1200 ± 2.5mg, e.g., 1200 ± 1.0mg, e.g., 1200 ± 0.5mg, e.g., 1200 mg), wherein the subject or population of subjects has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. In some aspects, the method comprises administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose (e.g., a fixed dose) of the anti-TIGIT antagonist antibody at a dose (e.g., a fixed dose) of between 500mg and 700mg (e.g., between 550mg and 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) on day 1 of each dosing cycle and a dose (e.g., a fixed dose) of the antagonist at a dose (e.g., a PD-1 axis) of between 900mg and 1500mg (e.g., between 1000mg and 1400mg, e.g., 1050mg and 1350mg, e.g., 1100mg to 1300mg, e.g., 1150mg to 1250mg, e.g., 1175mg to 1225mg, e.g., 1190mg to 1210mg, e.g., 1200mg ± 5mg, e.g., 1200 ± 2.g., 1200 ± 1.0mg, e.g., 1200 mg) on day 1 of each dosing cycle, wherein the subject has been treated with a non-platinum chemotherapeutic agent.

In some cases, the subject or population of subjects has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent. In some cases, the subject or population of subjects has 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 chemotherapeutic agent is omitted from the dosing regimen after six administrations.

In some cases, the platinum chemotherapeutic agent is cisplatin. In some cases, cisplatin is at about 80mg/m on day 1 of each dosing cycle ² The dosage of (a). In some cases, cisplatin is administered at 80mg/m on day 1 of each dosing cycle ² Is administered.

In some cases, the non-platinum chemotherapeutic agent is an antimetabolite. In some cases, the antimetabolite is 5-fluorouracil. In some cases, 5-fluorouracil is administered at 800mg/m on days 1 to 5 of each 21-day dosing cycle ² Dose administration per 24 hours.

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

In some cases, the subject or subjects have not previously been treated for metastatic esophageal cancer.

The invention includes a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more 21-day cycles of: a dose (e.g., fixed dose) of about 600mg of tirucaleu on day 1 of each dosing cycle, a dose (e.g., fixed dose) of about 1200mg of atuzumab on day 1 of each dosing cycle, about 80mg/m on day 1 of each dosing cycle ² And 800mg/m on days 1 to 5 of each 21-day dosing cycle ² 5-fluorouracil at a dose of 24 hours, in which cisplatin was omitted from the dosing regimen after six doses. In some aspects, the method comprises administering to the subject or population of subjects a dosing regimen comprising one or more 21 day cycles ofThe following items: a dose (e.g., fixed dose) of 600mg of tiryleiguzumab on day 1 of each dosing cycle, a dose (e.g., fixed dose) of 1200mg of altlizumab on day 1 of each dosing cycle, 80mg/m on day 1 of each dosing cycle ² And 800mg/m on days 1 to 5 of each 21-day dosing cycle ² 5-fluorouracil at a dose of 24 hours, in which cisplatin was omitted from the dosing regimen after six doses.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh uzumab) is a dose (e.g., a fixed dose) of between about 10mg to about 1000mg (e.g., between about 20mg to about 1000mg, e.g., between about 50mg to about 900mg, e.g., between about 100mg to about 850mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 600mg, e.g., between about 400mg to about 500mg, e.g., between about 405mg to about 450mg, e.g., between about 410mg to about 430mg, e.g., about 420 mg) once every two weeks (Q2W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose (e.g., a fixed dose) of between about 10mg to 1000mg (e.g., between 20mg to 1000mg, e.g., between 50mg to 900mg, e.g., between 00mg to 850mg, e.g., between 200mg to 800mg, e.g., between 300mg to 600mg, e.g., between 400mg to 500mg, e.g., between 405mg to 450mg, e.g., between 410mg to 430mg, e.g., 420 mg) once every two weeks (Q2W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose of about 420mg every two weeks (e.g., 420mg ± 10mg, e.g., 420 ± 6mg, e.g., 420 ± 5mg, e.g., 420 ± 3mg, e.g., 420 ± 1mg, e.g., 420 ± 0.5mg, e.g., 420 mg) every two weeks.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a dose between about 200mg to about 2000mg (e.g., between about 200mg to about 1600mg, e.g., between about 250mg to about 1600mg, e.g., between about 300mg to about 1600mg, e.g., between about 400mg to about 1500mg, e.g., between about 500mg to about 1400mg, e.g., between about 600mg to about 1200mg, e.g., between about 700mg to about 1100mg, e.g., between about 800mg to about 1000mg, e.g., between about 800mg to about 900mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every four weeks (Q4W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a dose of between 200mg and 2000mg (e.g., between 200mg and 1600mg, e.g., between 250mg and 1600mg, e.g., between 300mg and 1600mg, e.g., between 400mg and 1500mg, e.g., between 500mg and 1400mg, e.g., between 600mg and 1200mg, e.g., between 700mg and 1100mg, e.g., between 800mg and 1000mg, e.g., between 800mg and 900mg, e.g., 800, 810, 820, 830, 840, 850, 860, 870, 880, 890 to 900 mg) every four weeks (Q4W).

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 80mg to about 2000mg (e.g., between about 80mg to about 1950mg, e.g., between about 80mg to about 1900mg, e.g., between about 80mg to about 1800mg, e.g., between about 100mg to about 1700mg, e.g., between about 200mg to about 1600mg, e.g., between about 300mg to about 1400mg, e.g., a dose of between about 400mg to about 1300mg, such as between about 500mg to about 1200mg, such as between about 600mg to about 1100mg, such as between about 700mg to about 1000mg, such as between about 740mg to about 940mg, such as between about 790mg to about 890mg, such as between about 815mg to about 865mg, such as between about 830mg to about 850mg, such as 840mg ± 5mg, such as 840 ± 2.5mg, such as 840 ± 1.0mg, such as 840 ± 0.5mg, such as 840 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 2000mg, e.g., between about 300mg to about 2000mg, e.g., between about 400mg to about 2000mg, e.g., between about 500mg to about 2000mg, e.g., between about 600mg to about 1900mg, e.g., between about 700mg to about 1800mg, e.g., between about 800mg to about 1800mg, e.g., between about 900mg to about 1800 mg), e.g. between about 1000mg and about 1800mg, e.g. between about 1100mg and about 1800mg, e.g. between about 1200mg and about 1800mg, e.g. between about 1300mg and about 1800mg, e.g. between about 1400mg and about 1800mg, e.g. between about 1500mg and about 1800mg, e.g. between about 1580mg and about 1780mg, e.g. between about 1630mg and about 1730mg, e.g. between 1655mg and about 1705mg, e.g. between about 1670mg and about 1690mg, e.g. 1680mg ± 5mg, e.g. 1680 ± 2.5mg, e.g. 1680 ± 1.0mg, e.g. 1680 ± 0.5mg, e.g. 1680 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between 80mg to 2000mg (e.g., between 80mg to 1950mg, e.g., between 80mg to 1900mg, e.g., between 80mg to 1800mg, e.g., between 100mg to 1700mg, e.g., between 200mg to 1600mg, e.g., between 300mg to 1400mg, e.g., between 400mg to 1300mg, e.g., between 500mg to 1200mg, e.g., between 600mg to 1100mg, e.g., between 700mg to 1000mg, e.g., between 740mg to 940mg, e.g., between 790mg to 890mg, e.g., between 815mg to 865mg, e.g., between 830mg to 850mg, e.g., 840mg ± 5mg, e.g., 840 ± 2.5mg, e.g., 840 ± 1.0mg, e.g., 840mg, e.g., 840mg, 0.g., 840 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose of between 80mg to 2000mg (e.g., between 100mg to 2000mg, e.g., between 200mg to 2000mg, e.g., between 300mg to 2000mg, e.g., between 400mg to 2000mg, e.g., between 500mg to 2000mg, e.g., between 600mg to 1900mg, e.g., between 700mg to 1800mg, e.g., between 800mg to 1800mg, e.g., between 900mg to 1800mg, e.g., between 1000mg to 1800mg, e.g., between 1100mg to 1800mg, e.g., between 1200mg to 1800mg, e.g., between 1300mg to 1800mg, e.g., between 1400mg to 1800mg, e.g., between 1500mg to 1800mg, e.g., between 1580mg to 1780mg, e.g., between 1630mg to 1730mg, e.g., between 1700mg to 1655mg, e.g., between 1680mg to 1680mg, such as 1680mg to 1680mg, such as 16905 mg. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 840mg every two weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 840mg every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1680mg every four weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1680mg every four weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh itumumab) can be reduced compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy.

The invention includes a method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosing regimen and a second dosing regimen, wherein (a) the first dosing regimen comprises one or more of the following for a 21-day dosing cycle: about 80mg/m on day 1 of each dosing cycle ² And 800mg/m on days 1 to 5 of each 21-day cycle ² 5-Fluorouracil at a dose of 24 hours, in which cisplatin is in hexaOmitted from the dosing regimen after the second administration; (b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 600mg of tirayleigh immuzumab on day 1 of each dosing cycle and a dose of about 1200mg of atuzumab on day 1 of each dosing cycle.

In some aspects of any of the above methods, the treatment results in an ORR of at least about 14% in the population of subjects (e.g., results in an ORR of 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% to 16%, 16% to 18%, 18% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100%).

J. Diagnostic methods and uses related to cancer

The invention provides methods for treating cancer (e.g., 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))))); a method of selecting a therapy for a subject with cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), breast cancer (e.g., TNBC (e.g., eTNBC) or HER2 positive breast cancer), head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN), liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC), bladder cancer (e.g., MIBC, locally advanced UC or mcc), esophageal cancer, pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC), kidney or renal cancer (e.g., RCC), melanoma, ovarian cancer, gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low)), wherein the therapy is guided by a diagnostic method that involves determining one or more biomarkers (e.g., in a sample (e.g., a tumor sample or blood sample) obtained from the subject, PD-L1, TIGIT, activated T cells, or cytokines).

Further, provided herein are methods for identifying a patient with cancer (e.g., lung cancer (e.g., early 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, recurrent or metastatic NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC) or stage IV NSCLC (e.g., wherein the subject has not been previously treated for stage IV NSCLC)) that would benefit from treatment comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiyleigh uniuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atuzumab); cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1-positive cervical cancer), breast cancer (e.g., TNBC (e.g., eTNBC) or HER 2-positive breast cancer), head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1-positive SCCHN), liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC), bladder cancer (e.g., MIBC, locally advanced UC or mcc), esophageal cancer, pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC), kidney or renal cancer (e.g., RCC), melanoma, ovarian cancer, gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low CRC)), wherein the identification is guided by a diagnostic method that involves determining the presence and/or expression level/amount of one or more biomarkers (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., a tumor sample or a blood sample) obtained from the subject.

Further, provided herein are methods for assessing a patient having cancer (e.g., 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))))); a method of determining responsiveness to therapy in a subject having cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), breast cancer (e.g., TNBC (e.g., eTNBC) or HER2 positive breast cancer), head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN), liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC), bladder cancer (e.g., MIBC, locally advanced UC or mcc), esophageal cancer, pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC), kidney or renal cancer (e.g., RCC), melanoma, ovarian cancer, gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low)), wherein further therapy is guided by a diagnostic method involving determining one or more biomarkers (e.g., a tumor sample or a blood sample) obtained from the subject, PD-L1, TIGIT, activated T cells or cytokines) in a cell.

Further, provided herein are methods for treating cancer (e.g., 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 non-resectable NSCLC, stage IIIB NSCLC, recurrent or metastatic NSCLC (e.g., locally advanced non-resectable or metastatic non-squamous NSCLC (e.g., stage IV non-squamous NSCLC), or stage IV NSCLC (e.g., where the subject has not previously been treated for stage IV NSCLC))))); a method of optimizing therapy in a subject for cervical cancer (e.g., stage IVB, metastatic, recurrent or persistent cervical cancer, e.g., metastatic and/or recurrent PD-L1 positive cervical cancer), breast cancer (e.g., TNBC (e.g., eTNBC) or HER2 positive breast cancer), head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 positive SCCHN), liver cancer (e.g., HCC, e.g., locally advanced or metastatic HCC and or unresectable HCC), bladder cancer (e.g., MIBC, locally advanced UC or mcc), esophageal cancer, pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC), kidney or renal cancer (e.g., RCC), melanoma, ovarian cancer, gastric cancer (e.g., gastroesophageal junction cancer) or CRC (e.g., MSS or MSI-Low)), wherein further therapy is guided by a diagnostic method that involves determining one or more biomarkers (e.g., a tumor sample or blood sample) in a sample obtained from the subject, PD-L1, TIGIT, activated T cells or cytokines) in a cell.

Biomarkers for use in the methods described herein can include, but are not limited to, PD-L1 and/or TIGIT expression on tissue (e.g., tumor tissue) or in blood (e.g., whole blood); germline and somatic mutations (including but not limited to mutation load, MSI and MMR defects) from tissue (e.g., tumor tissue) and/or from circulating tumor DNA in the blood, identified by WGS and/or NGS, analysis of genes (e.g., CD 274) or gene signatures (e.g., TEFF) associated with tumor immunobiology; a subpopulation of lymphocytes; a pool of T cell receptors; cytokines involved in T cell activation and plasma-derived cytokines. In some cases, the biomarker is PD-L1. In some cases, the sample is a tumor sample (e.g., a formalin-fixed paraffin-embedded (FFPE) tumor sample).

In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., a tumor sample or a blood sample) from the subject, and administering to the subject an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., teuxuuzumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., altuzumab, or an anti-PD-1 antagonist antibody, e.g., palivizumab) for one or more cycles of administration according to any of the methods or uses described in section III (a).

In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject, and administering to the subject a dosing regimen comprising one or more cycles of dosing of: a dose (e.g., fixed dose) of about 700mg to about 1000mg of anti-TIGIT antagonist antibody every four weeks and a dose (e.g., fixed dose) of about 1400mg to 2000mg of PD-1 axis binding antagonist every four weeks. In some cases, the dosing regimen comprises the following for one or more cycles of administration: a dose (e.g., fixed dose) of 700mg to 1000mg per four weeks of an anti-TIGIT antagonist antibody and a dose (e.g., fixed dose) of 1400mg to 2000mg per four weeks of a PD-1 axis binding antagonist.

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

In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject, and administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose (e.g., fixed dose) of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose (e.g., fixed dose) of about 80mg and 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent for non-three weeks. In some cases, the method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: a dose (e.g., fixed dose) of 30mg to 1200mg of an anti-TIGIT antagonist antibody every three weeks, a dose (e.g., fixed dose) of 80mg and 1600mg of PD-1 axis binding antagonist every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject, and administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of about 200mg every three weeks, wherein the anti-PD-1 antagonist antibody is palbociclumab. In some cases, the method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of 30 to 1200mg every three weeks and an anti-PD-1 antagonist antibody at a dose of 200mg every three weeks, wherein the anti-PD-1 antagonist antibody is palbociclumab.

In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., a tumor sample or a blood sample) from the subject, and administering to the subject a dosing regimen comprising one or more dosing cycles of ibritumomab tirayleigh and palbociclumab, wherein palbociclumab is administered at a dose of between about 100mg to about 1000mg every six weeks. In some cases, the palbociclizumab is administered at a dose of about 400mg every six weeks.

In some cases, the method comprises determining the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., tumor sample or blood sample) from the subject, and administering to the subject a dosing regimen comprising one or more cycles of dosing of the followingItem (1): a dose (e.g., a fixed dose) of between about 30mg to about 1200mg of an anti-TIGIT antagonist antibody every three weeks; a dose (e.g., fixed dose) of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks; at about 10mg/m ² To about 10000mg/m ² An intermediate dose (e.g., a fixed dose) of an antimetabolite administered twice daily for 2 weeks per three weeks/off for 1 week. In some cases, the method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: a dose (e.g., fixed dose) of between 30mg to 1200mg of an anti-TIGIT antagonist antibody every three weeks; a dose (e.g., fixed dose) of PD-1 axis binding antagonist between 80mg to 1600mg every three weeks; at 10mg/m ² To 10000mg/m ² In between doses (e.g., fixed doses) twice daily oral antimetabolite administered 2 weeks per three weeks/off for 1 week.

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

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

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

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

The presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) may be determined qualitatively and/or quantitatively based on any suitable criteria known in the art, including, but not limited to, protein fragment, DNA, mRNA, cDNA, and/or gene copy number. In some cases, the biomarker is PD-L1.PD-L1 expression can be assessed as described in section III (L). In some cases, the biomarker is TIGIT. TIGIT expression can be assessed as described in section III (M). In some cases, the biomarker is EGFR and/or ALK aberration. EGFR and/or ALK aberration 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 (e.g., an FFPE tumor sample) from the subject. In some cases, the protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay. In some cases, the tumor sample is an FFPE tumor sample.

In some cases, a tumor sample from a subject (e.g., an FFPE tumor sample) has been determined to have a detectable PD-L1 expression level. In some cases, a tumor sample (e.g., an FFPE tumor sample) from a subject has been determined to have a detectable PD-L1 expression level in tumor-infiltrating immune cells. In some cases, the tumor sample is an 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 (e.g., an FFPE tumor sample) from the subject. In some cases, the nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, serial Analysis of Gene Expression (SAGE),

Techniques, in Situ Hybridization (ISH), or a combination thereof. In some cases, the tumor sample is an FFPE tumor sample.

In some cases, the presence and/or expression level/amount of a biomarker (e.g., PD-L1, TIGIT, activated T cells, or cytokines) in a sample (e.g., a tumor sample or a blood sample) from the subject selects the subject as eligible for therapy with an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (such as altlizumab) or an anti-PD-1 antagonist antibody such as parbolizumab), e.g., wherein a detectable PD-L1 expression level is the biomarker used to select the 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 (e.g., an FFPE tumor sample). In some cases, the tumor sample comprises infiltrating tumor immune cells, tumor cells, stromal cells, and any combination thereof. In some cases, the tumor sample is an FFPE tumor sample.

In some cases, the method further comprises administering the therapy to the identified subject. In some cases, the therapy may further include or be administered in conjunction (alone or together) with one or more additional therapeutic agents (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), a VEGF antagonist, a chemotherapeutic (e.g., a platinum-based chemotherapeutic or a non-platinum-based chemotherapeutic), an ADC (e.g., viltin-endrotumab or govittakang-shacetuzumab), or a CSF (e.g., pegylated filgrastim, filgrastim or sargrastim).

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.

K. Administration of drugs

i. Administration of anti-TIGIT antagonist antibodies

As a general proposition, a therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) administered to a human will be in the range of about 0.01 to about 50mg/kg of patient body weight, whether by one or more administrations. In some embodiments, a therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) administered to a human is in the range of 0.01 to 50mg/kg of patient body weight, whether by one or more administrations.

In some exemplary embodiments, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered at a dose of about 0.01 to about 45mg/kg, about 0.01 to about 40mg/kg, about 0.01 to about 35mg/kg, about 0.01 to about 30mg/kg, about 0.01 to about 25mg/kg, about 0.01 to about 20mg/kg, about 0.01 to about 15mg/kg, about 0.01 to about 10mg/kg, about 0.01 to about 5mg/kg, or about 0.01 to about 1mg/kg, e.g., daily, weekly, biweekly, every three weeks, or every four weeks. In exemplary embodiments, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered at a dose of 0.01 to 45mg/kg, 0.01 to 40mg/kg, 0.01 to 35mg/kg, 0.01 to 30mg/kg, 0.01 to 25mg/kg, 0.01 to 20mg/kg, 0.01 to 15mg/kg, 0.01 to 10mg/kg, 0.01 to 5mg/kg, or 0.01 to 1mg/kg, e.g., daily, weekly, biweekly, every three weeks, or every four weeks.

In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered at about day 1 (e.g., day-3, day-2, day-1, day 2, day 3) of each dosing cycle.

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered in a stepwise dosing regimen (e.g., based on the Body Weight (BW) or Body Surface Area (BSA) of the subject) (e.g., every three weeks). Such dosing regimens may be useful for treating subjects of relatively low body weight (e.g., 40kg or less (e.g., 5kg to 40kg, 15kg to 40kg, or 5kg to 15 kg)) and have been developed through biomimetic studies based on extrapolation of pharmacokinetic parameters estimated based on adult data.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) to treat a subject having cancer is a stepped dose based on the weight of the subject. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 30mg to about 1200mg every three weeks (e.g., about 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of between about 250mg to about 350mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 350mg to about 450mg every three weeks (e.g., about 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 550mg to about 650mg every three weeks (e.g., about 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of about 300mg every three weeks; (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of about 400mg every three weeks; or (c) greater than 40kg and the anti-TIGIT antagonist antibody is administered at a dose of about 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose between 10mg to 1000mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between 30mg and 1200mg every three weeks (e.g., 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose between 250mg and 350mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between 350mg and 450mg every three weeks (e.g., 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between 550mg to 650mg every three weeks (e.g., 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of 300mg every three weeks; (b) Greater than 15kg and less than or equal to 40kg and the anti-TIGIT antagonist antibody is administered at a dose of 400mg every three weeks; or (c) greater than 40kg and the anti-TIGIT antagonist antibody is administered at a dose of 600mg every three weeks.

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

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh umab) is a dose of between about 10mg to about 1000mg (e.g., between about 20mg to about 1000mg, e.g., between about 50mg to about 900mg, e.g., between about 100mg to about 850mg, e.g., between about 200mg to about 700mg, e.g., between about 250mg to about 600mg, e.g., between about 300mg to about 500mg, e.g., between about 350mg to about 450mg, e.g., between about 390mg to about 410mg, e.g., about 400 mg) once every three weeks (Q3W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 400mg every three weeks (e.g., 400mg ± 10mg, e.g., 400 ± 6mg, e.g., 400 ± 5mg, e.g., 400 ± 3mg, e.g., 400 ± 1mg, e.g., 400 ± 0.5mg, e.g., 400 mg) for a subject weighing greater than 15kg and less than or equal to 40 kg. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., between 10mg and 1000mg (e.g., between 20mg and 1000mg, e.g., between 50mg and 900mg, e.g., between 100mg and 850mg, e.g., between 200mg and 700mg, e.g., between 250mg and 600mg, e.g., between 300mg and 300mg, e.g., between 400mg and 400mg, e.g., between 400mg and 450mg, e.g., between 390mg, 400mg, e.g., between 400mg and 410mg, e.g., between 400mg and 390mg, for a subject weighing greater than 15kg and less than or equal to 40kg (e.g., 15.g., 15.2kg, 28kg, 29kg, 30kg, 31kg, 32kg, 33kg, 34kg, 35kg, 36kg, 37kg, 38kg, 39kg, or 39.5 kg) three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh unuzumab) is a dose of 400mg every three weeks (e.g., 400mg ± 10mg, e.g., 400 ± 6mg, e.g., 400 ± 5mg, e.g., 400 ± 3mg, e.g., 400 ± 1mg, e.g., 400 ± 0.5mg, e.g., 400 mg) for a subject weighing greater than 15kg and less than or equal to 40 kg.

In some cases, an anti-it TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh umab) is a dose of between about 10mg to about 1000mg (e.g., between about 10mg to about 900mg, e.g., between about 50mg to about 900mg, e.g., between about 100mg to about 750mg, e.g., between about 100mg to about 600mg, e.g., between about 150mg to about 500mg, e.g., between about 200mg to about 400mg, e.g., between about 250mg to about 350mg, e.g., between about 290mg to about 310mg, e.g., about 300 mg) once every three weeks (Q3W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 300mg every three weeks (e.g., 300mg ± 10mg, e.g., 300 ± 6mg, e.g., 300 ± 5mg, e.g., 300 ± 3mg, e.g., 300 ± 1mg, e.g., 300 ± 0.5mg, e.g., 300 mg) for a subject weighing less than or equal to 15 kg. In some cases, an anti-TIGIT antagonist antibody (e.g., a c-terminal inhibitory antibody) for a subject that weighs less than or equal to 15kg (e.g., 0.5kg, 1kg, 1.5kg, 2.0kg, 2.5kg, 3.0kg, 3.5kg, 4.0kg, 4.5kg, 5.0kg, 5.5kg, 6.0kg, 6.5kg, 7.0kg, 7.5kg, 8.0kg, 8.5kg, 9.0kg, 9.5kg, 10.0kg, 10.5kg, 11.0kg, 11.5kg, 12.0kg, 12.5kg, 13.0kg, 13.5kg, 14.0kg, 14.5kg, or 15.0 kg), an effective amount of an anti-TIGIT antagonist antibody, e.g., ibritumomab tiuxetan, as disclosed herein is a dose between 10mg to 1000mg (e.g., between 10mg to 900mg, e.g., between 50mg to 900mg, e.g., between 100mg to 750mg, e.g., between 100mg to 600mg, e.g., between 150mg to 500mg, e.g., between 200mg to 400mg, e.g., between 250mg to 350mg, e.g., between 290mg to 310mg, e.g., 300 mg) once every three weeks (Q3W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 300mg every three weeks (e.g., 300mg ± 10mg, e.g., 300 ± 6mg, e.g., 300 ± 5mg, e.g., 300 ± 3mg, e.g., 300 ± 1mg, e.g., 300 ± 0.5mg, e.g., 300 mg) for a subject weighing less than or equal to 15 kg.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) to treat a subject having cancer is a stepped dose based on the body surface area of the subject. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a stepped dose based on the body surface area of a subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 350mg every three weeks); (c) Greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 30mg to about 1200mg every three weeks (e.g., about 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a stepped dose based on the body surface area of a subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 250mg to about 350mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 300mg to about 400mg every three weeks (e.g., about 350mg every three weeks); or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And anti-TIGIT antagonist antibody is administered at a dose of between about 400mg to about 500mg every three weeks (e.g., about 450mg every three weeks)(ii) administration of an amount; or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 550mg to about 650mg every three weeks (e.g., about 600 every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body surface area of the subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of about 300mg every three weeks; (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of about 400mg every three weeks; or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of 450mg every three weeks; or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of about 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) to treat a subject having cancer is a stepped dose based on the body surface area of the subject. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body surface area of the subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 350mg every three weeks); (c) Greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 30mg and 1200mg every three weeks (e.g., 600mg every three weeks). In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab)) Is a stepped dose based on the body surface area of the subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 250mg and 350mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 300mg and 400mg every three weeks (e.g., 350mg every three weeks); or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 400mg to 500mg every three weeks (e.g., 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 550mg to 650mg every three weeks (e.g., 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a stepped dose based on the body surface area of a subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of 300mg every three weeks; (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of 400mg every three weeks; or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of 450mg every three weeks; or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of 600mg every three weeks.

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

In some cases, greater than 0.75m for body surface area ² And is less than or equal to 1.25m ² (e.g., 0.76 m) ² 、0.77m ² 、0.78m ² 、0.79m ² 、0.80m ² 、0.82m ² 、0.84m ² 、0.86m ² 、0.88m ² 、0.90m ² 、0.95m ² 、1.0m ² 、1.05m ² 、1.10m ² 、1.15m ² 、1.20m ² Or 1.25m ² ) An effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is between about 10mg to about 1000mg (e.g., between about 20mg to about 1000mg, e.g., between about 50mg to about 900mg, e.g., between about 100mg to about 850mg, e.g., between about 200mg to about 700mg, e.g., between about 250mg to about 600mg, e.g., between about 300mg to about 500mg, e.g., between about 400mg to about 500mg, e.g., between about 440mg to about 460mg, e.g., about 450 mg) once every three weeks (Q3W). In some cases, greater than 0.75m for body surface area ² And is less than or equal to 1.25m ² An effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 450mg every three weeks (e.g., 450mg ± 10mg, e.g., 450 ± 6mg, e.g., 450 ± 5mg, e.g., 450 ± 3mg, e.g., 450 ± 1mg, e.g., 450 ± 0.5mg, e.g., 450 mg) every three weeks.

In some cases, greater than 0.5m for body surface area ² And less than or equal to 0.75m ² (e.g., 0.51 m) ² 、0.52m ² 、0.53m ² 、0.54m ² 、0.55m ² 、0.56m ² 、0.57m ² 、0.58m ² 、0.59m ² 、0.60m ² 、0.61m ² 、0.62m ² 、0.63m ² 、0.64m ² 、0.65m ² 、0.66m ² 、0.67m ² 、0.68m ² 、0.69m ² 、0.70m ² 、0.71m ² 、0.72m ² 、0.73m ² 、0.74m ² Or 0.75m ² ) An effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is between about 10mg to about 1000mg (e.g., between about 20mg to about 1000mg, e.g., between about 50mg to about 900mg, e.g., between about 100mg to about 850mg, e.g., between about 200mg to about 700mg, e.g., between about 250mg to about 600mg, e.g., between about 300mg to about 500mg, e.g., between about 300mg to about 400mg, e.g., between about 340mg to about 360mg, e.g., about 350 mg) once every three weeks (Q3W). In some cases, greater than 0.5m for body surface area ² And less than or equal to 0.75m ² An effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 350mg every three weeks (e.g., 350mg ± 10mg, e.g., 350 ± 6mg, e.g., 350 ± 5mg, e.g., 350 ± 3mg, e.g., 350 ± 1mg, e.g., 350 ± 0.5mg, e.g., 350mg every three weeks).

In some cases, less than or equal to 0.5m for body surface area ² (e.g., 0.02 m) ² 、0.04m ² 、0.06m ² 、0.08m ² 、0.1m ² 、0.15m ² 、0.20m ² 、0.25m ² 、0.30m ² 、0.35m ² 、0.40m ² 、0.45m ² Or 0.50m ² ) An effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is between about 10mg to about 1000mg (e.g., between about 10mg to about 900mg, e.g., between about 50mg to about 900mg, e.g., between about 100mg to about 750mg, e.g., between about 100mg to about 600mg, e.g., between about 150mg to about 500mg, e.g., between about 200mg to about 40 mg) once every three weeks (Q3W)0mg, e.g., between about 250mg to about 350mg, e.g., between about 290mg to about 310mg, e.g., about 300 mg). In some cases, less than or equal to 0.5m for body surface area ² An effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 300mg every three weeks (e.g., 300mg ± 10mg, e.g., 300 ± 6mg, e.g., 300 ± 5mg, e.g., 300 ± 3mg, e.g., 300 ± 1mg, e.g., 300 ± 0.5mg, e.g., 300 mg) every three weeks.

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

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a dose of between about 30mg to about 1200mg (e.g., between about 30mg to about 1100mg, e.g., between about 60mg to about 1000mg, e.g., between about 100mg to about 900mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 800mg, e.g., between about 400mg to about 750mg, e.g., between about 450mg to about 750mg, e.g., between about 500mg to about 700mg, e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 ± 0.g., 600 mg) once every three weeks (Q3W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is between about 200mg to about 2000mg (e.g., between about 200mg to about 2000mg, e.g., between about 400mg to about 1900mg, e.g., between about 500mg to about 1800mg, e.g., between about 600mg to about 1700mg, e.g., between about 700mg to about 1400mg, e.g., between about 800mg to about 1600mg, e.g., a dose of between about 900mg to about 1500mg, such as between about 1000mg to about 1400mg, such as between about 1050mg to about 1350mg, such as between about 1100mg to about 1300mg, such as between about 1150mg to about 1250mg, such as between about 1175mg to about 1225mg, such as between about 1190mg to about 1210mg, such as about 1200mg, such as 1200mg ± 10mg, such as 1200 ± 6mg, such as 1200 ± 5mg, such as 1200 ± 3mg, such as 1200 ± 1mg, such as 1200 ± 0.5mg, such as 1200 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose of about 1200mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 1200mg every three weeks.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tegraleigh itumumab) is between about 200mg to about 2000mg (e.g., between about 200 to 300mg, between about 300 to 400mg, between about 400 to 500mg, between about 500 to 600mg, between about 600 to 700mg, between about 700 to 800mg, between about 800 to 900mg, between about 900 to 1000mg, between about 1000 to 1100mg, between about 1100 to 1200mg, between about 1200 to 1300mg, between about 1300 to 1400mg, between about 1500 to 1500mg, between about 1500 to 1600mg, between about 1600 to 1700mg, between about 1700 to 1700mg, between about 1800 to 1900mg, or between about 1900 to 2000mg, e.g., between about 200mg to about 1600mg, e.g., between about 250mg to 1600mg, e.g., between about 1600mg, between about 300mg to about 1600mg, such as between about 400mg to about 1500mg, such as between about 500mg to about 1400mg, such as between about 600mg to about 1200mg, such as between about 700mg to about 1100mg, such as between about 800mg to about 1000mg, such as between about 800mg to about 900mg, such as, for example, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 880, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, about 1500, about 1550, about 1600mg, about 1650mg, about 1700mg, about 1750mg, about 1800mg, about 1900mg, about 0mg or about 2000mg, such as, about 800, about 810, about 840, about 870, about 830, about 860, about 830, about 900mg, or about 800, about 880, about 700 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 700mg to about 1000mg every four weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 700mg to 1000mg every four weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 840mg every four weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 840mg every four weeks. This 840mg Q4W dosing regimen was supported by PK modeling and simulation as well as exposure-safety analysis results. In short, the mean concentration after this 840mg Q4W dosing regimen was similar to the mean concentration for the 600mg dosing regimen every 3 weeks, which was evaluated in previous studies. The Cmax for this 840mg Q4W dosing regimen was simulated at steady state to be 28% higher than the Cmax for the 600mg every 3 weeks dosing regimen, but to fall within the clinically observed exposure range for the highest administered dose (1200 mg every 3 weeks). Preliminary analysis of the tiryleigh itumumab exposure-safety relationship based on previous observations (tiryleigh itumumab dose ranging from 2 to 1200mg every 3 weeks, administered as monotherapy or in combination with 1200mg atuzumab every 3 weeks) showed that tiryleigh itumumab exhibited a flat exposure-safety relationship. In summary, given that the predicted exposure is within the range of effective exposures observed, and that tiryleigh itumumab exhibits a flat exposure-safety relationship, this 840mg Q4W dosing regimen can provide safety and efficacy comparable to a 600mg dosing regimen every 3 weeks.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 840mg every four weeks (e.g., 840mg ± 10mg, e.g., 840 ± 6mg, e.g., 840 ± 5mg, e.g., 840 ± 3mg, e.g., 840 ± 1mg, e.g., 840 ± 0.5mg, e.g., 840 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is between about 200mg to about 2000mg (e.g., between about 200mg to about 2000mg, e.g., between about 400mg to about 1900mg, e.g., between about 500mg to about 1800mg, e.g., between about 600mg to about 1700mg, e.g., between about 700mg to about 1400mg, e.g., between about 800mg to about 1600mg, e.g., between about 900mg to about 1500mg, e.g., between about 1000mg to about 1400mg, e.g., between about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1050mg, e.g., between about 1175mg to about 1225mg per four weeks (Q4W), for example, a dose of between about 1190mg and about 1210mg (e.g. between 200mg and 2000mg, e.g. between 400mg and 1900mg, e.g. between 500mg and 1800mg, e.g. between 600mg and 1700mg, e.g. between 700mg and 1400mg, e.g. between 800mg and 1600mg, e.g. between 900mg and 1500mg, e.g. between 1000mg and 1400mg, e.g. between 1050mg and 1350mg, e.g. between 1100mg and 1300mg, e.g. between 1150mg and 1250mg, e.g. between 1175mg and 1225mg, e.g. between 1190mg and 1210 mg), e.g. about 1200mg, e.g. 1200mg ± 10mg, e.g. 1200 ± 6mg, e.g. 1200 ± 5mg, e.g. 1200 ± 3mg, e.g. 1200 ± 1mg, e.g. 1200 ± 0.5mg, e.g. 1200 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose of about 1200mg every four weeks.

In some cases, the dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) administered in a combination therapy (e.g., a combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., palbociclumab)) can be reduced compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously. Alternatively, in some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered subcutaneously. In some cases, the tirucaleuzumab is administered intravenously to the patient at a dose of about 420mg every 2 weeks, at a dose of about 1200mg every 3 weeks, or at a dose of about 1200mg every 4 weeks. In some cases, the tirayleigh antibody is administered intravenously to the patient at a dose of 420mg every 2 weeks, at a dose of 1200mg every 3 weeks, or at a dose of 1200mg every 4 weeks.

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

Administration of PD-1 Axis binding antagonists

As a general proposition, a therapeutically effective amount of a PD-1 axis binding antagonist (e.g., atlizumab) administered to a human will be in the range of about 0.01 to about 50mg/kg of patient body weight, whether by one or more administrations.

In some exemplary embodiments, the PD-1 axis binding antagonist is administered at a dose of about 0.01 to about 45mg/kg, about 0.01 to about 40mg/kg, about 0.01 to about 35mg/kg, about 0.01 to about 30mg/kg, about 0.01 to about 25mg/kg, about 0.01 to about 20mg/kg, about 0.01 to about 15mg/kg, about 0.01 to about 10mg/kg, about 0.01 to about 5mg/kg, or about 0.01 to about 1mg/kg, e.g., daily, weekly, biweekly, every three weeks, or every four weeks. In some exemplary embodiments, the PD-1 axis binding antagonist is administered at a dose of 0.01 to 45mg/kg, 0.01 to 40mg/kg, 0.01 to 35mg/kg, 0.01 to 30mg/kg, 0.01 to 25mg/kg, 0.01 to 20mg/kg, 0.01 to 15mg/kg, 0.01 to 10mg/kg, 0.01 to 5mg/kg, or 0.01 to 1mg/kg, e.g., daily, weekly, biweekly, every three weeks, or every four weeks.

In some cases, the PD-1 axis binding antagonist is administered at about day 1 (e.g., day-3, day-2, day-1, day 2, or day 3) of the dosing cycle.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab), or an anti-PD-1 antagonist antibody (e.g., palivizumab) is a dose (e.g., a dose) between about 20mg to about 1600mg (e.g., between about 40mg to about 1500mg, e.g., between about 200mg to about 1400mg, e.g., between about 300mg to about 1400mg, e.g., between about 400mg to about 1400mg, e.g., between about 500mg to about 1300mg, e.g., between about 600mg to about 1200mg, e.g., between about 700mg to about 1100mg, e.g., between about 800mg to about 1000mg, e.g., between about 800mg to about 900mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) once every two weeks (Q2W), a fixed dose) in some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab) or an anti-PD-1 antagonist antibody (e.g., paribizumab)) is a dose (e.g., a fixed dose) of between 20mg to 1600mg (e.g., between 40mg to 1500mg, e.g., between 200mg to 1400mg, e.g., between 300mg to 1400mg, e.g., between 400mg to 1400mg, e.g., between 500mg to 1300mg, e.g., between 600mg to 1200mg, e.g., between 700mg to 1100mg, e.g., between 800mg to 1000mg, e.g., between 800mg to 900mg, e.g., 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, or 900 mg) once every two weeks (Q2W.) in some cases, a PD-1 axis binding antagonist (e.g., a fixed dose), an effective amount of an anti-PD-L1 antagonist antibody (e.g., atelizumab) or an anti-PD-1 antagonist antibody (e.g., paribizumab)) is a dose of about 840mg every two weeks (e.g., 840mg ± 10mg, e.g., 840 ± 6mg, e.g., 840 ± 5mg, e.g., 840 ± 3mg, e.g., 840 ± 1mg, e.g., 840 ± 0.5mg, e.g., 840 mg) every two weeks. In some cases, an effective amount of attritumab is a dose of about 840mg every two weeks.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palivizumab) or an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between about 0.01mg/kg to about 50mg/kg of the subject's body weight per dose week (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 5mg/kg to about 15mg/kg, e.g., between about 7.5mg/kg to about 12.5mg/kg, e.g., about 10 ± 2mg/kg, about 10 ± 1mg/kg, about 10 ± 0.5mg/kg, e.g., about 10.g., about 10 ± 0.g., about 10mg/kg, or about 10mg/kg, e.g., about 10 mg/kg. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., palivizumab) or an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 0.01mg/kg to about 10mg/kg of the subject's body weight (e.g., between about 0.1mg/kg to about 10mg/kg, e.g., between about 0.5mg/kg to about 10mg/kg, e.g., between about 1mg/kg to about 10mg/kg, e.g., a dose of between about 2.5mg/kg and about 10mg/kg, such as, for example, between about 5mg/kg and about 10mg/kg, such as, for example, between about 7.5mg/kg and about 10mg/kg, such as, for example, between about 8mg/kg and about 10mg/kg, such as, for example, between about 9mg/kg and about 10mg/kg, such as, for example, between about 9.5mg/kg and about 10mg/kg, such as, for example, about 10 + -1 mg/kg, such as, for example, about 10 + -0.5 mg/kg, such as, for example, about 10 + -0.2 mg/kg, such as, for example, about 10 + -0.1 mg/kg, such as, for example, about 10 mg/kg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., pabulizumab) or an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is a dose between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 5mg/kg and 15mg/kg, e.g., between 7.5mg/kg and 12.5mg/kg, e.g., 10 ± 2mg/kg, 10 ± 1mg/kg, 10 ± 0.5mg/kg, 10 ± 0.2mg/kg, or 10 ± 0.1mg/kg, e.g., 10 mg/kg) every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-1 antagonist antibody (e.g., pabulizumab) or an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is between 0.01mg/kg and 10mg/kg of the subject's body weight (e.g., between 0.1mg/kg and 10mg/kg, e.g., between 0.5mg/kg and 10mg/kg, e.g., between 1mg/kg and 10mg/kg, e.g., a dose of between 2.5mg/kg and 10mg/kg, such as between 5mg/kg and 10mg/kg, such as between 7.5mg/kg and 10mg/kg, such as between 8mg/kg and 10mg/kg, such as between 9mg/kg and 10mg/kg, such as between 9.5mg/kg and 10mg/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, an effective amount of the palivizumab is a dose of about 10mg/kg every two weeks. In some cases, an effective amount of palbociclizumab is a dose of 10mg/kg every two weeks.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) to treat a subject with cancer is a dose of between about 0.01mg/kg to about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, or about 15mg/kg, e.g., about 15mg/kg, about 15 ± 0.g., about 15mg/kg, about 1mg/kg, e.g., about 25mg/kg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is between about 0.01mg/kg to about 15mg/kg of the subject's body weight (e.g., between about 0.1mg/kg to about 15mg/kg, e.g., between about 0.5mg/kg to about 15mg/kg, e.g., not between about 1mg/kg to about 15mg/kg, e.g., between about 2.5mg/kg to about 15 mg/kg) every three weeks, e.g., between about 5mg/kg and about 15mg/kg, e.g., between about 7.5mg/kg and about 15mg/kg, e.g., between about 10mg/kg and about 15mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., between about 14mg/kg and about 15mg/kg, e.g., about 15 + -1 mg/kg, e.g., about 15 + -0.5 mg/kg, e.g., about 15 + -0.2 mg/kg, e.g., about 15 + -0.1 mg/kg, e.g., about 15 mg/kg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) to treat a subject with cancer is a dose between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg or 15 ± 0.1mg/kg, e.g., 15 mg/kg) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose of between 0.01mg/kg and 15mg/kg of subject body weight (e.g., between 0.1mg/kg and 15mg/kg, e.g., between 0.5mg/kg and 15mg/kg, e.g., between 1mg/kg and 15mg/kg, e.g., between 2.5mg/kg and 15mg/kg, e.g., between 5mg/kg and 15mg/kg, e.g., between 7.5mg/kg and 15mg/kg, e.g., between 10mg/kg and 15mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., between 14mg/kg and 15mg/kg, e.g., 15 ± 1mg/kg, e.g., 15 ± 0.5mg/kg, e.g., 15 ± 0.2mg/kg, e.g., 15mg/kg, e.g., 15mg/kg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 15mg/kg administered every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 15mg/kg administered every three weeks, and the maximum dose is 1200mg every three weeks. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attentizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh) can be reduced compared to a standard dose of a PD-1 axis binding antagonist administered as a monotherapy. In some embodiments, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered at a maximum dose of 1200mg every three weeks.

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

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab) or an anti-PD-1 antagonist antibody (e.g., paribizumab)) is a dose of between about 10mg and about 800mg (e.g., between about 10mg and about 800mg, e.g., between about 20mg and about 700mg, e.g., between about 50mg and about 600mg, e.g., between about 75mg and about 500mg, e.g., between about 100mg and about 400mg, e.g., between about 100mg and about 300mg, e.g., between about 125mg and about 275mg, e.g., between about 150mg and about 250mg, e.g., between about 175mg and about 225mg, e.g., between about 190mg and about 210mg, e.g., about 200mg ± 10mg, e.g., 200mg ± 7.5mg, e.g., 200mg ± 5mg, e.g., 200mg, 2.5mg, e.g., 200mg, 0.g., 0mg ± 0 mg) once every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab) or an anti-PD-1 antagonist antibody (e.g., paribizumab)) is a dose of about 200mg every three weeks (e.g., 200mg ± 10mg, e.g., 200 ± 6mg, e.g., 200 ± 5mg, e.g., 200 ± 3mg, e.g., 200 ± 1mg, e.g., 200 ± 0.5mg, e.g., 200 mg) every three weeks. In some cases, an effective amount of an anti-PD-1 antagonist antibody (e.g., palbociclumab) is a dose of about 200mg every three weeks (e.g., 200mg ± 10mg, e.g., 200 ± 6mg, e.g., 200 ± 5mg, e.g., 200 ± 3mg, e.g., 200 ± 1mg, e.g., 200 ± 0.5mg, e.g., 200 mg) every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., paribizumab)) is a dose of between 10mg and 800mg (e.g., between 10mg and 800mg, e.g., between 20mg and 700mg, e.g., between 50mg and 600mg, e.g., between 75mg and 500mg, e.g., between 100mg and 400mg, e.g., between 100mg and 300mg, e.g., between 125mg and 275mg, e.g., between 150mg and 250mg, e.g., between 175mg and 225mg, e.g., between 190mg and 210mg, e.g., 200mg ± 10mg, e.g., 200mg ± 7.5mg, e.g., 200mg ± 5mg, e.g., 200 ± 2.5mg, e.g., 200 ± 1.0mg, e.g., 200 ± 0.5mg, e.g., 200 mg), e.g., 200 ± 0.g., 200 mg) once every three weeks (Q3W). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab) or an anti-PD-1 antagonist antibody (e.g., paribizumab)) is a dose of 200mg every three weeks (e.g., 200mg ± 10mg, e.g., 200 ± 6mg, e.g., 200 ± 5mg, e.g., 200 ± 3mg, e.g., 200 ± 1mg, e.g., 200 ± 0.5mg, e.g., 200 mg) every three weeks. In some cases, an effective amount of an anti-PD-1 antagonist antibody (e.g., palbociclumab) is a dose of 200mg every three weeks (e.g., 200mg ± 10mg, e.g., 200 ± 6mg, e.g., 200 ± 5mg, e.g., 200 ± 3mg, e.g., 200 ± 1mg, e.g., 200 ± 0.5mg, e.g., 200 mg) every three weeks. In some cases, an effective amount of palbociclizumab is a dose of 200mg every three weeks. In some cases, an effective amount of palbociclizumab is a dose of 200mg every three weeks.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab) or an anti-PD-1 antagonist antibody (e.g., pabulizumab)) is between about 80mg to about 3000mg (e.g., between about 80 to 200mg, between about 200 to 400mg, between about 400 to 600mg, between about 600 to 800mg, between about 800 to 1000mg, between about 1000 to 1200mg, between about 1200 to 1400mg, between about 1400 to 1600mg, between about 1600 to 1800mg, between about 2200 to 2000mg, between about 2400 to 2400mg, between about 2600 to 2800mg, or between about 0 to 3000mg, e.g., between about 100mg to about 3000mg, e.g., between about 200mg and about 2900mg, e.g., between about 500mg to about 2800mg, e.g., between about 2700 to about 650mg, e.g., between about 2600mg, between about 700mg and about 2500mg, for example between about 1000mg and about 2400mg, for example between about 1100mg and about 2300mg, for example between about 1200mg and about 2200mg, for example between about 1300mg and about 2100mg, for example between about 1400mg and about 2000mg, for example between about 1500mg and about 1900mg, for example between about 1600mg and about 1800mg, for example between about 1620mg and about 1700mg, for example between about 1640mg and about 1690mg, for example, between about 1660mg to about 1680mg, e.g., about 80mg, about 200mg, about 400mg, about 600mg, about 800mg, about 1000mg, about 1200mg, about 1400mg, about 1600mg, about 1800mg, about 2000mg, about 2200mg, about 2400mg, about 2600mg, about 2800mg, or about 3000mg, e.g., about 1600mg, about 1610mg, about 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, or about 1700 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituzumab) or an anti-PD-1 antagonist antibody (e.g., palbociclumab)) is a dose of between 500mg to 3000mg (e.g., between 500mg to 2800mg, e.g., between 600mg to 2700mg, e.g., between 650mg to 2600mg, e.g., between 700mg to 2500mg, e.g., between 1000mg to 2400mg, e.g., between 1100mg to 2300mg, e.g., between 1200mg to 2200mg, e.g., between 1300mg to 2100mg, e.g., between 1400mg to 2000mg, e.g., between 1500mg to 1900mg, e.g., between 1600mg to 1600mg, e.g., between 1620mg to 1700mg, e.g., between 1640mg to 1690mg, e.g., between 1660mg to 1680mg, 1600mg, 1660mg, 16500 mg, 1660mg, or 16950 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., pabolbizumab)) is a dose of 1680mg every four weeks (e.g., 1680mg ± 10mg, e.g., 1680 ± 6mg, e.g., 1680 ± 5mg, e.g., 1680 ± 3mg, e.g., 1680 ± 1mg, e.g., 1680 ± 0.5mg, e.g., 1680 mg). In some cases, the effective amount of atezumab is a dose of about 1680mg every four weeks. In some cases, the effective amount of atelizumab is a dose of 1680mg every four weeks.

In some cases, an effective amount of an anti-PD-1 antagonist antibody (e.g., palivizumab) is between about 50mg to about 2000mg (e.g., between about 50 to 100mg, between about 100 to 250mg, between about 250 to 500mg, between about 500 to 750mg, between about 750 to 1000mg, between about 1000 to 1250mg, between about 1250 to 1500mg, between about 1500 to 1750mg, or between about 1750 to 2000mg, for example, between about 100mg to about 1000mg, between about 120mg to about 900mg, between about 150mg to about 800mg, between about 200mg to about 700mg, between about 250mg to about 600mg, between about 300mg to about 500mg, or between about 350mg to about 450mg, for example, between about 50mg to about 100mg, between about 100mg to about 200mg, between about 200mg to about 300mg, between about 300mg to about 400mg, between about 400mg to about 500mg, between about 500mg to about 600mg, between about 600mg to about 700mg, between about 700mg to about 800mg or between about 800mg to about 1000mg, for example, about 50mg, about 100mg, about 250mg, about 500mg, about 750mg, about 1000mg, about 1250mg, about 1500mg, about 1750mg or about 2000mg, for example, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg or about 500mg, for example, about 400 mg). In some cases, an effective amount of an anti-PD-1 antagonist antibody (e.g., palboclizumab) is a dose of between 50mg to 2000mg (e.g., between 100mg to 1000mg, between 120mg to 900mg, between 150mg to 800mg, between 200mg to 700mg, between 250mg to 600mg, between 300mg to 500mg, or between 350mg to 450mg, such as between 50mg to 100mg, between 100mg to 200mg, between 200mg to 300mg, between 300mg to 400mg, between 400mg to 500mg, between 500mg to 600mg, between 600mg to 700mg, between 700mg to 800mg, or between 800mg to 1000mg, such as 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 500mg, or 500mg, per six weeks (Q6W). In some cases, an effective amount of an anti-PD-1 antagonist antibody (e.g., pabulizumab) is a dose of about 400mg every six weeks (e.g., 400mg ± 10mg, e.g., 400 ± 6mg, e.g., 400 ± 5mg, e.g., 400 ± 3mg, e.g., 400 ± 1mg, e.g., 400 ± 0.5mg, e.g., 400 mg) every six weeks. In some cases, the dose of the PD-1 axis binding antagonist is a fixed dose. In some cases, an effective amount of palbociclizumab is a dose of about 400mg every six weeks (e.g., a fixed dose). In some cases, an effective amount of palbociclizumab is a dose of 400mg every six weeks (e.g., a fixed dose).

In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist ansetron (e.g., palboclizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh itumumab) can be reduced compared to a standard dose of a PD-1 axis binding antagonist administered as a monotherapy.

In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., palboclizumab)) is administered intravenously. Alternatively, in some embodiments, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) or an anti-PD-1 antagonist antibody (e.g., palboclizumab)) is administered subcutaneously. In some cases, the attritumab is administered to the patient intravenously at a dose of about 840mg every 2 weeks, at a dose of about 1200mg every 3 weeks, or at a dose of about 1680mg every 4 weeks. In some cases, the attritumab is administered to the patient intravenously at a dose of 840mg every 2 weeks, 1200mg every 3 weeks, or 1680mg every 4 weeks.

In some cases, a total of 1 to 20 doses of the PD-1 axis binding antagonist are administered to the subject, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses. In some cases, a total of 1 to 50 doses of the PD-1 axis binding antagonist are administered to the subject, e.g., 1 to 50 doses, 1 to 45 doses, 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 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 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, 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 to 40 doses, 15 to 35 doses, 15 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 to 30 doses, 30 to 50 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. In certain instances, the dose may be administered intravenously.

Effective doses of anti-TIGIT antagonist antibody and PD-1 axis binding antagonist

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose (e.g., a fixed dose) between about 30mg to about 600mg (e.g., between about 50mg to about 600mg, e.g., between about 60mg to about 600mg, e.g., between about 100mg to about 600mg, e.g., between about 200mg to about 550mg, e.g., between about 250mg to about 600mg, e.g., between about 300mg to about 500mg, e.g., between about 350mg to about 450mg, e.g., between about 400mg to about 440mg, e.g., between about 410mg to about 430mg, e.g., about 420mg ± 10mg, e.g., 420 ± 6mg, e.g., 420 ± 5mg, e.g., 420 ± 3mg, e.g., 420 ± 1mg, e.g., 420 ± 0.5mg, e.g., 420 mg) biweekly. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a dose (e.g., a fixed dose) of between 30mg to 600mg (e.g., between 50mg to 600mg, e.g., between 60mg to 600mg, e.g., between 100mg to 600mg, e.g., between 200mg to 550mg, e.g., between 250mg to 600mg, e.g., between 300mg to 500mg, e.g., between 350mg to 450mg, e.g., between 400mg to 440mg, e.g., between 410mg to 430mg, e.g., 420mg ± 10mg, e.g., 420 ± 6mg, e.g., 420 ± 5mg, e.g., 420 ± 3mg, e.g., 420 ± 1mg, e.g., 420 ± 0.5mg, e.g., 420 mg) biweekly. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 420mg every two weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 420mg every two weeks.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose between about 30mg to about 1200mg (e.g., between about 30mg to about 1100mg, e.g., between about 60mg to about 1000mg, e.g., between about 100mg to about 900mg, e.g., between about 200mg to about 800mg, e.g., between about 300mg to about 800mg, e.g., between about 400mg to about 750mg, e.g., between about 450mg to about 750mg, e.g., between about 500mg to about 700mg, e.g., between about 550mg to about 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh uzumab) is a dose of between 30mg to 1200mg (e.g., between 30mg to 1100mg, e.g., between 60mg to 1000mg, e.g., between 100mg to 900mg, e.g., between 200mg to 800mg, e.g., between 300mg to 800mg, e.g., between 400mg to 750mg, e.g., between 450mg to 750mg, e.g., between 500mg to 700mg, e.g., between 550mg to 650mg, e.g., 600mg ± 10mg, e.g., 600 ± 6mg, e.g., 600 ± 5mg, e.g., 600 ± 3mg, e.g., 600 ± 1mg, e.g., 600 ± 0.5mg, e.g., 600 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a dose of about 600mg every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 600mg every three weeks.

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of between about 600mg to about 1200mg (e.g., between about 600mg to about 1100mg, e.g., between about 600mg to about 1000mg, e.g., between about 700mg to about 950mg, e.g., between about 800mg to about 900mg, e.g., between about 820mg to about 860mg, e.g., about 840 ± 10mg, e.g., 840 ± 6mg, e.g., 840 ± 5mg, e.g., 840 ± 3mg, e.g., 840 ± 1mg, e.g., 840 ± 0.5mg, e.g., about 840 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of between 600mg to 1200mg (e.g., between 600mg to 1100mg, e.g., between 600mg to 1000mg, e.g., between 700mg to 950mg, e.g., between 800mg to 900mg, e.g., between 820mg to 860mg, e.g., 840 ± 10mg, e.g., 840 ± 6mg, e.g., 840 ± 5mg, e.g., 840 ± 3mg, e.g., 840 ± 1mg, e.g., 840 ± 0.5mg, e.g., 840 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 840mg every four weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 840mg every four weeks.

In some cases, the dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., terayleigh mab) administered in a combination therapy (e.g., a combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palbociclumab, previously referred to as pembrolizumab)) may be reduced compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy. In some cases, the dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) administered in a combination therapy (e.g., a combination therapy with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) with or without one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel or nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin)) and/or G-CSF or GM-CSF) can be reduced compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is between about 20mg to about 1600mg (e.g., between about 20 to 100mg, between about 100 to 200mg, between about 200 to 400mg, between about 400 to 600mg, between about 600 to 800mg, between about 800 to 1000mg, between about 1000 to 1200mg, between about 1200 to 1400mg, or between 1400 to 1600mg, e.g., between about 80mg to about 1200mg, e.g., between about 100mg to about 1200mg, e.g., a dose of between about 200mg to about 1200mg, e.g. between about 300mg to about 1200mg, e.g. between about 400mg to about 1200mg, e.g. between about 500mg to about 1200mg, e.g. between about 600mg to about 1100mg, e.g. between about 700mg to about 1000mg, e.g. between about 740mg to about 940mg, e.g. between about 790mg to about 890mg, e.g. between about 815mg to about 865mg, e.g. between about 830mg to about 850mg, e.g. 840mg ± 5mg, e.g. 840 ± 2.5mg, e.g. 840 ± 1.0mg, e.g. 840 ± 0.5mg, e.g. 840 mg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) is a dose of between 80mg and 1200mg (e.g., between 80mg and 1200mg, e.g., between 100mg and 1200mg, e.g., between 200mg and 1200mg, e.g., between 300mg and 1200mg, e.g., between 400mg and 1200mg, e.g., between 500mg and 1200mg, e.g., between 600mg and 1100mg, e.g., between 700mg and 1000mg, e.g., between 740mg and 940mg, e.g., between 790mg and 890mg, e.g., between 815mg and 865mg, e.g., between 830mg and 850mg, e.g., 840mg ± 5mg, e.g., 840 ± 2.5mg, e.g., 840 ± 1.0mg, e.g., 840 ± 0.5mg, e.g., 840 mg) every two weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attlizumab)) is about 20mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1200mg, 1400mg, or 1600mg every two weeks, in some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attlizumab)) is a dose of about 840mg every two weeks, in some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attlizumab)) is a dose of 840mg every two weeks.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between about 80mg to about 2000mg (e.g., between about 100mg to about 2000mg, e.g., between about 200mg to about 1900mg, e.g., between about 300mg to about 1700mg, e.g., between about 400mg to about 1600mg, e.g., between about 500mg to about 1600mg, e.g., between about 600mg to about 1600mg, e.g., between about 700mg to about 1600mg, e.g., between about 800mg to about 1600mg, e.g., between about 900mg to about 1500mg, e.g., between about 1000mg to about 1400mg, e.g., between about 1050mg to about 1350mg, e.g., between about 1100mg to about 1300mg, e.g., between about 1150mg to about 1250mg, e.g., between about 1175mg to about 1225mg, e.g., between about 0mg to about 1200mg, e.g., 0.g., 1200mg, e.g., 0mg, 1200mg, e.g., 0mg ± 1200mg, e.g., 1200mg, 0mg, e.g., 1200mg, about 1200mg, every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between 80mg to 2000mg (e.g., between 100mg to 2000mg, e.g., between 200mg to 1900mg, e.g., between 300mg to 1700mg, e.g., between 400mg to 1600mg, e.g., between 500mg to 1600mg, e.g., between 600mg to 1600mg, e.g., between 700mg to 1600mg, e.g., between 800mg to 1600mg, e.g., between 900mg to 1500mg, e.g., between 1000mg to 1400mg, e.g., between 1050mg to 1350mg, e.g., between 1100mg to 1300mg, e.g., between 1150mg to 1250mg, e.g., between 1175mg to 1225mg, e.g., between 1190mg to 1210mg, e.g., 1200mg ± 5mg, e.g., 1200mg ± 2.5, e.g., 1250mg, e.g., 0.g., 1200mg, 1200.g., 1200mg, 0.g., 1200mg, 0mg, 1200mg, e.g., 1200 mg. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1200mg every three weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1200mg every three weeks.

In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between about 1200mg to about 2000mg (e.g., between about 1200mg to about 1900mg, e.g., between about 1200mg to about 1800mg, e.g., between about 1300mg to about 1800mg, e.g., between about 1400mg to about 1800mg, e.g., between about 1500mg to about 1800mg, e.g., between about 1580mg to about 1780mg, e.g., between about 1630mg to about 1730mg, e.g., between about 1655mg to about 1705mg, e.g., between about 1670mg to about 1690mg, e.g., 1680mg ± 5mg, e.g., 1680 ± 2.5mg, e.g., 1680 ± 1.0mg, e.g., 0 ± 0.5mg, e.g., 1680 mg) every four weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of between 1200mg to 2000mg (e.g., between 1200mg to 1900mg, e.g., between 1200mg to 1800mg, e.g., between 1300mg to 1800mg, e.g., between 1400mg to 1800mg, e.g., between 1500mg to 1800mg, e.g., between 1580mg to 1780mg, e.g., between 1630mg to 1730mg, e.g., between 1655mg to 1705mg, e.g., between 1670mg to 1690mg, e.g., 1680mg ± 5mg, e.g., 1680 ± 2.5mg, e.g., 1680 ± 1.0mg, e.g., 1680 ± 0.5mg, e.g., 1680 mg) every four weeks. In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of about 1680mg every four weeks. In some cases, the effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose of 1680mg every four weeks.

In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody such as an anti-TIGIT antagonist antibody disclosed herein (e.g., tenecteuzumab)) can be reduced compared to a standard dose of the anti-PD-L1 antagonist antibody administered as a monotherapy. In some cases, the dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., teneruizumab, with or without one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (e.g., an alkylating agent (e.g., cyclophosphamide), a taxane (e.g., paclitaxel or nab-paclitaxel) and/or a topoisomerase II inhibitor (e.g., doxorubicin))) and/or G-CSF or GM-CSF) can be reduced compared to a standard dose of the PD-1 axis binding antagonist administered as a monotherapy.

Dosing cycle for anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists

In any of the methods and uses of the invention, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tenellulomab) and/or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) can be 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 dosing cycle of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atelizumab)) is continued until clinical benefit is lost (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity). In some cases, each dosing cycle is about 7 to 42 days in length (e.g., 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 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, 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 anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered on about day 1 (e.g., day 1 ± 3 days) of each dosing cycle, in some cases, the anti-TIGIT antagonist antibody is administered on about day 15 (e.g., day 15 ± 3 days) of each dosing cycle, anti-TIGIT antagonist antibodies (e.g., anti-TIGIT antagonist antibodies as disclosed herein, e.g., ibritumomab tiuxetan) are administered at about day 22 (e.g., day 22 ± 3) of each dosing cycle. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is administered at about day 29 (e.g., day 29 ± 3) of each dosing cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 600mg (e.g., a fixed dose), on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 600mg (e.g., a fixed dose) (i.e., at a dose of about 420mg every two weeks) on days 1 and 15 of each 28-day cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose (e.g., fixed dose) of about 600mg (i.e., at a dose of about 420mg every two weeks) on days 1, 15, and 29 of each 42-day cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 600mg (e.g., a fixed dose) (i.e., at a dose of about 600mg every three weeks) on days 1 and 22 of each 42-day cycle. In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) is administered at about day 1 (e.g., day 1 ± 3 days) of each dosing cycle. In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) is administered at about day 15 (e.g., day 15 ± 3 days) of each dosing cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) is administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks). For example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is administered intravenously at a dose of about 1200mg on days 1 and 15 of each 28-day cycle (i.e., at a dose of about 840mg every two weeks). In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of 600mg (e.g., a fixed dose) (i.e., at a dose of 600mg every three weeks) on day 1 of each 21-day cycle. In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., MDX-1106 (nivolumab) or MK-3475 (palboclizumab, previously referred to as pembrolizumab))) is administered on day 1 (e.g., day 1 ± 3 days) of each dosing cycle. For example, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) is administered intravenously at a dose of 1200mg on day 1 of each 21-day cycle (i.e., at a dose of 1200mg every three weeks).

In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atelizumab) are administered about day 1 (e.g., day 1 ± 3) of each dosing cycle.

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tenellulomab) is administered intravenously at a dose of about 600mg on day 1 of each 21-day cycle (i.e., at a dose of about 600mg every three weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab) is administered intravenously at a dose of about 1200mg on day 1 of each 21-day cycle (i.e., at a dose of about 1200mg every three weeks).

In other cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., cetrorelix unuzumab) is administered intravenously at a dose of about 420mg on day 1 of each 14-day cycle (i.e., at a dose of about 420mg every two weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab) is administered intravenously at a dose of about 840mg on day 1 of each 14-day cycle (i.e., at a dose of about 840mg every two weeks).

In other cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously at a dose of about 840mg on day 1 of each 28-day cycle (i.e., at a dose of about 840mg every four weeks), and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altuzumab) is administered intravenously at a dose of about 1680mg on day 1 of each 28-day cycle (i.e., at a dose of about 1680mg every four weeks).

Intravenous infusion and subcutaneous administration of anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered intravenously. Alternatively, in some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered subcutaneously. In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered intravenously. Alternatively, in some embodiments, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is administered subcutaneously.

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to a subject or population of subjects by intravenous infusion over 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). In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to a subject or population of subjects by intravenous infusion over about 60 ± 10 minutes (e.g., 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, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)) is administered to a subject by intravenous infusion over 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).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is administered to a subject by intravenous infusion over 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). In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is administered to a subject by intravenous infusion over 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).

Order of administration and observation period

In some cases where both the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered to a subject or population of subjects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered to the subject prior to the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab) anti-PD-1 antagonist antibody (e.g., paribrizumab)).

In some cases, for example, after administration of an anti-TIGIT antagonist antibody and before administration of a PD-1 axis binding antagonist, the method comprises an intermediate first observation period. In some cases, for example, following administration of the anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atlizumab)) is administered to the subject. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is first administered to the subject, and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., altlizumab)) is administered to the subject after administration of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan).

In some cases, the method further comprises a second observation period after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)).

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 a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab)). In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. Where the length of the first observation period and the second observation period are each about 60 minutes, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject over the first or second observation period about 30 ± 10 minutes after administration of the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., attritumab)). Where the length of the first observation period and the second observation period are each about 30 minutes, the method can include recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject over the first or second observation period about 15 ± 10 minutes after administration of the anti-TIGIT antagonist antibody or PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., attritumab)).

In some cases, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., paribrizumab)) is administered to the subject or population of subjects prior to an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan). In some cases, for example, after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) and before administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab), the method comprises an intermediate first observation period.

In some cases, the method further comprises a second observation period after administration of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan).

In some cases, the method includes both a first observation period after administration of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)) and a second observation period after administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan). In some cases, the first and second observation periods are each between about 30 minutes and about 60 minutes in length. Where the length of each of the first and second observation periods is about 60 minutes, the method can comprise recording the vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) of the subject for the first or second observation period about 30 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) or an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab). Where the length of each of the first and second observation periods is about 30 minutes, the method can comprise recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15 ± 10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)), an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tegraleighumab) over the first or second observation period.

In some cases, the method further comprises administering a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered after a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab) or an anti-PD-1 antagonist antibody (e.g., paribrizumab)) and an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan). In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered after a second observation period following administration of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh umab) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab) or an anti-PD-1 antagonist antibody (e.g., pabolizumab)).

In some cases, the method further comprises a third observation period after administration of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)). In some cases, the length of the third observation period is between about 30 minutes and about 120 minutes. 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.

Combination administration of anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered together with an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., ateuzumab)) in a combination therapy (e.g., a combination therapy of an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., ateuzumab)), e.g., for treating a subject having cancer, in some cases, as described in section III (K) (i) herein, the anti-TIGIT antagonist antibody is administered every two weeks, and as described in section III (K) (ii), the PD-1 axis binding antagonist is administered every two weeks, in some cases, as described in section III (K) (i) herein, the anti-TIGIT antagonist antibody is administered every two weeks, and the anti-TIGIT antagonist antibody is administered every three weeks, as described in section III (K) (ii) herein, and the PD-1 axis binding antagonist is administered every six weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every three weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every two weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every three weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every three weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every three weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every four weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every three weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every six weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every four weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every two weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every four weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every three weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every four weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every four weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every four weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every six weeks as described in section III (K) (ii) herein. In some cases, the anti-TIGIT antagonist antibody is administered every two, three, or four weeks as described in section III (K) (i) herein, and the PD-1 axis binding antagonist is administered every two, three, four, or six weeks as described in section III (K) (ii) herein.

In some cases, the dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of about 600mg every three weeks. In some cases, the dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a dose of 600mg every three weeks. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh mab) is administered in a stepwise dosing regimen (e.g., based on the subject's Body Weight (BW) or Body Surface Area (BSA)) for example every three weeks, and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atelizumab) is administered at a dose of about 0.01mg/kg to about 50mg/kg (e.g., about 15 mg/kg) and up to 1200mg, for example every three weeks. In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is administered in a stepwise dosing regimen (e.g., based on the Body Weight (BW) or Body Surface Area (BSA) of the subject) (e.g., every three weeks),and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atuzumab) is administered at a dose of, for example, 0.01mg/kg to 50mg/kg (e.g., 15 mg/kg) and up to 1200mg every three weeks. Such dosing regimens may be useful for treating subjects of relatively low body weight (e.g., 40kg or less (e.g., 5kg to 40kg, 15kg to 40kg, or 5kg to 15 kg)) and have been developed through biomimetic studies based on extrapolation of pharmacokinetic parameters estimated based on adult data. In some cases, the dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh unizumab) is a stepped dose based on the subject's body weight (e.g., body Weight (BW) > 40600mg BW > 15kg and ≦ 40kg 400mg; and BW ≦ 15kg 300mg. In some cases, the dose of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose based on the body weight of the subject (e.g., 15 mg/kg). In some cases, the dose of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is a dose based on the body surface area of the subject (e.g., body Surface Area (BSA) > 1.25 m) ² ：600mg；BSA＞0.75m ² And is less than or equal to 1.25m ² ：450mg；BSA＞0.5m ² And is less than or equal to 0.75m ² :350mg; and BSA is less than or equal to 0.5m ² :300 mg). In some cases, the dose (e.g., about 600 mg) of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tenellulomab) is administered in combination with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) at a dose based on the weight (e.g., 15 mg/kg) of the subject every three weeks. In some cases, stepped doses (e.g., body Weight (BW) > 40kg. In some cases, stepped doses (e.g., body Weight (BW) > 40kg > 600mg BW > 15kg and ≦ 40kg15kg:300 mg) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is administered to a subject based on the body surface area of the subject (e.g., BSA > 1.25 m) ² ：600mg；BSA＞0.75m ² And is less than or equal to 1.25m ² ：450mg；BSA＞0.5m ² And is less than or equal to 0.75m ² :350mg; and BSA is less than or equal to 0.5m ² :300 mg) of a dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)). In some embodiments, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered at a maximum dose of 1200mg every three weeks. In some cases, the combination therapy is administered with one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine)).

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) to treat a subject having cancer is a stepped dose based on the weight of the subject, wherein the weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 30mg to about 1200mg every three weeks (e.g., about 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose between about 250mg to about 350mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 350mg to about 450mg every three weeks (e.g., about 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 550mg to about 650mg every three weeks (e.g., about 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tigliu itumumab) is a stepped dose based on the weight of the subject, wherein the weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of about 300mg every three weeks; (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of about 400mg every three weeks; or (c) greater than 40kg and the anti-TIGIT antagonist antibody is administered at a dose of about 600mg every three weeks. In some cases, between about 0.01mg/kg to about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., 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, e.g., about 15 mg/kg) in combination with a stepped dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) based on the body weight of the subject, wherein the subject has a body weight of (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose between about 10mg to about 1000mg (e.g., about 400 mg) every three weeks; or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between about 30mg to about 1200mg every three weeks (e.g., about 600mg every three weeks). In some cases, a subject weighing less than or equal to 15kg is administered a dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) between about 10mg to about 1000mg every three weeks (e.g., about 300mg every three weeks) and between about 0.01mg/kg to about 50mg/kg body weight of the subject every three weeks (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, for example, a dose of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., attrituximab)) between about 2.5mg/kg and about 30mg/kg, e.g., between about 5mg/kg and about 25mg/kg, e.g., between about 10mg/kg and about 20mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, or about 15 ± 0.1mg/kg, e.g., about 15 mg/kg. In some cases, a subject weighing greater than 15kg and less than or equal to 40kg is administered a dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tamulizumab) between about 10mg to about 1000mg every three weeks (e.g., about 400mg every three weeks) and between about 0.01mg to about 50mg/kg body weight of the subject every three weeks (e.g., between about 0.01mg to about 45mg, e.g., between about 0.1mg to about 40mg/kg, e.g., between about 1mg to about 35mg/kg, e.g., between about 2.5mg to about 30mg/kg, e.g., between about 5mg to about 25mg/kg, e.g., between about 10mg to about 20mg/kg, e.g., between about 12.5mg to about 15mg/kg, e.g., about 15mg to about 2mg, e.g., about 1mg to about 15mg, e.g., about 1.g., about 1.1 mg to about 15mg, e.g., about 15mg to about 15mg of anti-TIGIT antagonist antibody (e.g., about PD ± 1mg to about 15 mg) per kg), e.g., about 15mg to about 15 mg/kg), e.g., about 1mg to about 15mg of anti-1.g., about 15 mg/kg). In some cases, a subject weighing greater than 40kg is administered a dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tamulizumab) between about 30mg to about 1200mg every three weeks (e.g., about 600mg every three weeks) and between about 0.01mg/kg to about 50mg/kg body weight of the subject every three weeks (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., about 15 ± 2mg/kg, about 1mg/kg, about 0.1mg/kg, e.g., about 15mg/kg, e.g., about 1.g., about 15mg/kg, e.g., about 1 mg/kg-15 mg/kg, e.g., about 1 mg/g., about 15mg/kg of anti-attrituximab (PD), e.g., PD), or about 1 mg/kg).

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) to treat a subject having cancer is a stepped dose based on the weight of the subject, wherein the weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose between 10mg and 1000mg every three weeks (e.g., 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between 30mg and 1200mg every three weeks (e.g., 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh itumumab) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of between 250mg to 350mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between 350mg and 450mg every three weeks (e.g., 400mg every three weeks); or (c) greater than 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of between 550mg to 650mg every three weeks (e.g., 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body weight of the subject, wherein the body weight of the subject is (a) less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of 300mg every three weeks; (b) Greater than 15kg and less than or equal to 40kg and the anti-TIGIT antagonist antibody is administered at a dose of 400mg every three weeks; or (c) greater than 40kg and the anti-TIGIT antagonist antibody is administered at a dose of 600mg every three weeks. In some cases, a dose of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist (e.g., attritor mab) at a dose of anti-it based on the body weight antagonist (e.g., anti-it is disclosed herein) at a dose of between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg, or 15 ± 0.1mg/kg, e.g., 15 mg/kg) is administered as a combination of anti-it antagonist (e.g., anti-it is administered at a dose equal to a) at a dose of anti-L1 antagonist, e.g., as disclosed herein, e.g., a stepwise, wherein the anti-it is equal to 300mg, e.g., tig antagonist, e.g., a antibody administered at a subject, in a subject, and wherein the subject, e.g., three weeks, e.g., a subject, e.g., a, e.g., three weeks, or more, wherein the subject, e.g., three weeks, administration is administered at a dose of anti-tig, e.g., each week; (b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose between 10mg and 1000mg (e.g., 400 mg) every three weeks; or (c) greater than 40kg and the anti-TIGIT antagonist antibody is administered at a dose of between 30mg and 1200mg every three weeks (e.g., 600mg every three weeks). In some cases, a subject having a weight of less than or equal to 15kg is administered a dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tegraleigh mab) between 10mg and 1000mg every three weeks (e.g., 300mg every three weeks) and between 0.01mg/kg and 50mg/kg of subject weight every three weeks (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg, or 15mg/kg, e.g., 1.1 mg/kg, e.g., 1mg/kg of anti-arg mab (e.g., 1 mg-1 mg) per three weeks). In some cases, a subject weighing greater than 15kg and less than or equal to 40kg is administered a dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) between 10mg to 1000mg every three weeks (e.g., 400mg every three weeks) and between 0.01mg/kg to 50mg/kg body weight of the subject every three weeks (e.g., between 0.01mg/kg to 45mg/kg, e.g., between 0.1mg/kg to 40mg/kg, e.g., between 1mg/kg to 35mg/kg, e.g., between 2.5mg/kg to 30mg/kg, e.g., between 5mg/kg to 25mg/kg, e.g., between 10mg/kg to 20mg/kg, e.g., between 12.5mg/kg to 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15mg/kg, 0.1.1 mg/kg, e.g., 1mg/kg of anti-PD antagonist antibody (e.g., PD-PD) bound to 1 mg). In some cases, a subject weighing greater than 40kg is administered a dose of anti-TIGIT antagonist antibody (e.g., anti-TIGIT antagonist antibody as disclosed herein, e.g., 600mg every three weeks) between 30mg to 1200mg every three weeks (e.g., anti-TIGIT antagonist antibody, e.g., tiryleigh euzumab), and between 0.01mg/kg to 50mg/kg body weight of the subject every three weeks (e.g., between 0.01mg/kg to 45mg/kg, e.g., between 0.1mg/kg to 40mg/kg, e.g., between 1mg/kg to 35mg/kg, e.g., between 2.5mg/kg to 30mg/kg, e.g., between 5mg/kg to 25mg/kg, e.g., between 10mg/kg to 20mg/kg, e.g., between 12.5mg/kg to 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg, or 15.5 mg/kg, e.g., 1.g., 1mg/kg, e.g., PD antagonist antibody (PD-1 mg) bound to 1mg/kg, e.g., PD-1 mg).

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) to treat a subject having cancer is a stepped dose based on the body surface area of the subject. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body surface area of the subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And anti-TIGIT antagonist antibody is between about 10mg to about 1000mg every three weeks(e.g., about 350mg every three weeks); (c) Greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 30mg to about 1200mg every three weeks (e.g., about 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a stepped dose based on the body surface area of a subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 250mg to about 350mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 300mg to about 400mg every three weeks (e.g., about 350mg every three weeks); or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 400mg to about 500mg every three weeks (e.g., about 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 550mg to about 650mg every three weeks (e.g., about 600 every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body surface area of the subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of about 300mg every three weeks; (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of about 400mg every three weeks; or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of 450mg every three weeks; or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of about 600mg every three weeks.

In some cases, the subject is at about 0.01mg/kg to about 50mg/kgA dose of PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., attritor mab) to a dose of anti-it antagonist based on the body surface area of the subject (e.g., anti-it antibody) disclosed herein, e.g., a combination of anti-it antibody (e.g., anti-it antibody) to a subject of a stepped form, e.g., anti-it antibody) disclosed herein, wherein the dose is less than about 5 ± 2mg/kg, e.g., about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.1mg/kg, e.g., about 15mg/kg, e.g., about 5mg/kg, wherein the subject is administered as a stepwise, e.g., the anti-it antibody is a, e.g., tig, wherein the anti-it antibody is administered as a stepwise, e.g., a raleighty antibody (e.g., a) to a subject of anti-it antagonist based on the body surface area of the subject ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg (e.g., about 350 mg) every three weeks; (c) Greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 10mg to about 1000mg every three weeks (e.g., about 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between about 30mg to about 1200mg every three weeks (e.g., about 600mg every three weeks). In some cases, the body-facing surface area is less than or equal to 0.5m ² The subject of (a) is administered a dose of between about 10mg to about 1000mg per three weeks (e.g., about 300mg per three weeks) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tegraleigh umab) and between about 0.01mg/kg to about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 ± 0.2mg/kg, or about 15 ± 0.1mg/kg, e.g., about 15 mg/kg) of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab)). In some cases, the body-facing surface area is greater than 0.5m ² And less than or equal to 0.75m ² The subject of (a) is administered a dose of between about 10mg to about 1000mg per three weeks (e.g., about 350mg per three weeks) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tegraleigh umab) and between about 0.01mg/kg to about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., between about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 mg/0.5 mg/kg, about 2mg/kg, about 15 mg/0.1 mg/kg, or about 15mg/kg of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT) such as disclosed herein, e.g., TIGIT binds to about 1 mg/kg). In some cases, the body-facing surface area is greater than 0.75m ² And is less than or equal to 1.25m ² The subject of (a) is administered a dose of between about 10mg to about 1000mg per three weeks (e.g., about 450mg per three weeks) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tegraleigh umab) and between about 0.01mg/kg to about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., between about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15 mg/0.5 mg/kg, about 2mg/kg, about 15 mg/0.1 mg/kg, or about 15mg/kg of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT) such as disclosed herein, e.g., TIGIT binds to about 1 mg/kg). In some cases, the body-facing surface area is greater than 1.25m ² Is administered to a subjectA dose of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., about 600mg every three weeks) at a dose of between about 30mg to about 1200mg every three weeks (e.g., an anti-TIGIT antagonist antibody, e.g., tegraleighumab, e.g., as disclosed herein) and between about 0.01mg/kg to about 50mg/kg of the body weight of the subject (e.g., between about 0.01mg/kg to about 45mg/kg, e.g., between about 0.1mg/kg to about 40mg/kg, e.g., between about 1mg/kg to about 35mg/kg, e.g., between about 2.5mg/kg to about 30mg/kg, e.g., between about 5mg/kg to about 25mg/kg, e.g., between about 10mg/kg to about 20mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., about 15 ± 2mg/kg, about 15 ± 1mg/kg, about 15 ± 0.5mg/kg, about 15mg/kg, about 0.0.0.0 mg/kg, e.g., about 1mg/kg, or about 15 mg/1 mg/kg of an anti-chargeitumab (e.g., an anti-chargeitb) such as disclosed herein) antibody, e.g., binding to about 1 mg/kg).

In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a stepped dose based on the body surface area of a subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 350mg every three weeks); (c) Greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 30mg and 1200mg every three weeks (e.g., 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tirayleigh immuzumab) is a stepped dose based on the body surface area of a subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 250mg and 350mg every three weeks (e.g., 300mg every three weeks); (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 300mg and 400mg every three weeks (e.g., 350mg every three weeks); or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 400mg and 500mg every three weeks (e.g., 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 550mg to 650mg every three weeks (e.g., 600mg every three weeks). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) is a stepped dose based on the body surface area of the subject, wherein the body surface area of the subject is (a) less than or equal to 0.5m ² And the anti-TIGIT antagonist antibody is administered at a dose of 300mg every three weeks; (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of 400mg every three weeks; or (c) greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of 450mg every three weeks; or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of 600mg every three weeks.

In some cases, between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg, or 15 ± 0.1mg/kg, e.g., 15 mg/kg) of a dose of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab)) is administered in combination with a stepped dose of an anti-TIGIT antagonist antibody based on the body surface area of the subject (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., teuyuzumab), wherein the body surface area of the subject is (a) less than or equal to 0.5m rayleigh ² And anti-TIGIT antagonist antibody at between 10mg to 1000mg every three weeks (e.g., 300mg every three weeks)(ii) dose administration; (b) Greater than 0.5m ² And less than or equal to 0.75m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg (e.g., 350 mg) every three weeks; (c) Greater than 0.75m ² And is less than or equal to 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 10mg to 1000mg every three weeks (e.g., 450mg every three weeks); or (d) greater than 1.25m ² And the anti-TIGIT antagonist antibody is administered at a dose of between 30mg to 1200mg every three weeks (e.g., 600mg every three weeks). In some cases, the body-facing surface area is less than or equal to 0.5m ² The subject(s) is (are) administered a dose of between 10mg to 1000mg per three weeks (e.g., 300mg per three weeks) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and between 0.01mg/kg to 50mg/kg of body weight of the subject (e.g., between 0.01mg/kg to 45mg/kg, e.g., between 0.1mg/kg to 40mg/kg, e.g., between 1mg/kg to 35mg/kg, e.g., between 2.5mg/kg to 30mg/kg, e.g., between 5mg/kg to 25mg/kg, e.g., between 10mg/kg to 20mg/kg, e.g., between 12.5mg/kg to 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg or 15 ± 0.1mg/kg, e.g., 15mg/kg, e.g., 1mg/kg of an anti-attritor antagonist antibody (e.g., PD-1 mg) bound to 1 kg). In some cases, the body-facing surface area is greater than 0.5m ² And less than or equal to 0.75m ² The subject of (a) is administered a dose of between 10mg to 1000mg per three weeks (e.g., 350mg per three weeks) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and between 0.01mg/kg to 50mg/kg of the subject's body weight per three weeks (e.g., between 0.01mg/kg to 45mg/kg, e.g., between 0.1mg/kg to 40mg/kg, e.g., between 1mg/kg to 35mg/kg, for example, a dose of PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) (e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 + -2 mg/kg, 15 + -1 mg/kg, 15 + -0.5 mg/kg, 15 + -0.2 mg/kg, or 15 + -0.1 mg/kg, e.g., 15 mg/kg)Attrituzumab)). In some cases, the body-facing surface area is greater than 0.75m ² And is less than or equal to 1.25m ² The subject of (a) is administered a dose of between 10mg to 1000mg per three weeks (e.g., 450mg per three weeks) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and between 0.01mg/kg to 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg to 45mg/kg, e.g., between 0.1mg/kg to 40mg/kg, e.g., between 1mg/kg to 35mg/kg, e.g., between 2.5mg/kg to 30mg/kg, e.g., between 5mg/kg to 25mg/kg, e.g., between 10mg/kg to 20mg/kg, e.g., between 12.5mg/kg to 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg or 15 ± 0.1mg/kg, e.g., 15 mg/1 mg/kg, e.g., 1 mg/1 mg of an anti-charbizumab (e.g., PD) antibody, e.g., a 1-PD) bound to 1L). In some cases, the body-facing surface area is greater than 1.25m ² The subject(s) is (are) administered a dose of between 30mg to 1200mg per three weeks (e.g., 600mg per three weeks) of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., ibritumomab tiuxetan) and between 0.01mg/kg to 50mg/kg of body weight of the subject (e.g., between 0.01mg/kg to 45mg/kg, e.g., between 0.1mg/kg to 40mg/kg, e.g., between 1mg/kg to 35mg/kg, e.g., between 2.5mg/kg to 30mg/kg, e.g., between 5mg/kg to 25mg/kg, e.g., between 10mg/kg to 20mg/kg, e.g., between 12.5mg/kg to 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg or 15 ± 0.1mg/kg, e.g., 15mg/kg, e.g., 1mg/kg of an anti-attritor antagonist antibody (e.g., PD-1 mg) bound to 1 kg).

Administration of chemotherapeutic agents

Therapeutically effective amounts of various chemotherapeutic agents are known in the art and are contemplated in the present invention. In particular instances, one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum-based chemotherapeutic agents (e.g., an alkylating agent (e.g., cyclophosphamide)), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., doxorubicin))) are administered according to the dosages described herein.

Platinum chemotherapeutic agents

In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is a dose sufficient to achieve a 1 to 50mg/ml/min (e.g., 2 to 25mg/ml/min, 3 to 15mg/ml/min, 4 to 10mg/ml/min, or 5mg/ml/min, e.g., 2mg/ml/min, 3mg/ml/min, 4mg/ml/min, 5mg/ml/min, 6mg/ml/min, 7mg/ml/min, 8mg/ml/min, 9mg/ml/min, 10mg/ml/min, 11mg/ml/min, 12mg/ml/min, 13mg/ml/min, 14mg/ml/min, 15mg/ml/min, 20mg/ml/min, 25mg/ml/min, 30mg/ml/min, 35mg/ml/min, 40mg/ml/min, 45mg/ml/min, 50 mg/ml/min). In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is a dose sufficient to achieve AUC =5 mg/ml/min. In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., 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, an effective amount of carboplatin is a dose sufficient to achieve AUC =5mg/ml/min on day 1 of a 21 day dosing cycle. In some cases, an effective amount of carboplatin is a dose sufficient to achieve AUC =6mg/ml/min on day 1 of a 21 day dosing cycle. In some cases, an effective amount of carboplatin is a dose sufficient to achieve AUC =5mg/ml/min when administered post-pemetrexed or gemcitabine. In some cases, an effective amount of carboplatin is a dose sufficient to achieve AUC =6mg/ml/min when administered post-paclitaxel.

AUC can be calculated using Calvert formula (Calvert et al, j. Clin. Oncol.1989,7:

total dose (mg) = (target AUC) x (glomerular filtration rate [ GFR ] + 25)

In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is 200mg to 1500mg (e.g., 300mg to 1200mg, 400mg to 1100mg, or 500mg to 1000mg, e.g., 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to 750mg, 750mg to 800mg, 800mg to 900mg, 900mg to 1000mg, 1000mg to 1100mg, or 1100mg to 1200mg, e.g., about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, or about 1500 mg). In some cases, the effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is about 500mg to 1000mg (e.g., about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, or about 1000 mg).

In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is at about 20mg/m ² To about 200mg/m ² Between (e.g., at about 20 mg/m) ² To about 150mg/m ² Between, for example, about 30mg/m ² To about 125mg/m ² Between, for example, about 40mg/m ² To about 110mg/m ² Between, for example, about 50mg/m ² To about 100mg/m ² Between, for example, about 60mg/m ² To about 90mg/m ² Between, for example, about 70mg/m ² To about 80mg/m ² E.g. about 75mg/m ² For example, 75mg/m ² ). In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is about 75mg/m ² . In some cases, the effective amount of cisplatin is about 75mg/m ² . In some cases, an effective amount of cisplatin is about 75mg/m every three weeks ² . In some cases, an effective amount of a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is at 20mg/m ² To 200mg/m ² In between (e.g., at 20 mg/m) ² To 150mg/m ² In between, for example, 30mg/m ² To 125mg/m ² E.g. at 40mg/m ² To 110mg/m ² E.g. 50mg/m ² To 100mg/m ² E.g. at 60mg/m ² To 90mg/m ² E.g. at 70mg/m ² To 80mg/m ² E.g. 75mg/m ² For example, 75mg/m ² ). In some cases, an effective amount of a platinum chemotherapeutic agent (e.g., carboplatin or cisplatin) is 75mg/m ² . In some cases, the effective amount of cisplatin is 75mg/m ² . In some cases, the effective amount of cisplatin is 75mg/m every three weeks ² 。

In some cases, a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered intravenously (e.g., over a 30 to 120 minute infusion) to a subject or population of subjects. In some cases, the carboplatin is administered intravenously over a 30 to 60 minute infusion. In some cases, cisplatin is administered intravenously over a 60 to 120 minute infusion. In some cases, a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered to a subject or population of subjects every three weeks. In some cases, a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) is administered to the subject or population of subjects on about day 1 (e.g., day-3, day-2, day-1, day 2, or day 3) of a 21-day dosing cycle.

Taxane derivatives

Taxanes (e.g., paclitaxel or nab-paclitaxel) for administration to humans

) Will be in the range of about 25 to about 300mg/m ² In the range (e.g., about 25 mg/m) ² About 50mg/m ² About 75mg/m ² About 80mg/m ² About 90mg/m ² About 100mg/m ² About 110mg/m ² About 120mg/m ² About 125mg/m ² About 130mg/m ² About 140mg/m ² About 150mg/m ² About 160mg/m ² About 170mg/m ² About 175mg/m ² About 180mg/m ² About 190mg/m ² About 200mg/m ² About 225mg/m ² About 250mg/m ² About 275mg/m ² Or about 300mg/m ² (e.g., 25 mg/m) ² 、50mg/m ² 、75mg/m ² 、80mg/m ² 、90mg/m ² 、100mg/m ² 、110mg/m ² 、120mg/m ² 、125mg/m ² 、130mg/m ² 、140mg/m ² 、150mg/m ² 、160mg/m ² 、170mg/m ² 、175mg/m ² 、180mg/m ² 、190mg/m ² 、200mg/m ² 、225mg/m ² 、250mg/m ² 、275mg/m ² Or 300mg/m ² ) Whether by one or more administrations. For example, in some embodiments, about 175mg/m is administered ² The paclitaxel of (1). In some embodiments, 175mg/m is administered ² The paclitaxel of (1). In some embodiments, paclitaxel is present at about 175mg/m every three weeks ² To about 200mg/m ² In between dose administration. In some embodiments, paclitaxel is administered at about 175mg/m every three weeks ² The dosage of (a). In some embodiments, paclitaxel is administered at about 200mg/m every three weeks ² The dosage of (a). In some embodiments, paclitaxel is administered at 175mg/m every three weeks ² To 200mg/m ² In between. In some embodiments, paclitaxel is administered at 175mg/m every three weeks ² The dosage of (a). In some embodiments, paclitaxel is administered at 200mg/m every three weeks ² The dosage of (a). In some embodiments, paclitaxel is administered at 175mg/m every 3 weeks ² And IV administration. In some embodiments, paclitaxel is administered at 175mg/m every 3 weeks ² IV was administered to asian ethnicity/ethnicity. In some embodiments, paclitaxel is administered at 200mg/m every 3 weeks ² And IV administration. In some embodiments, paclitaxel is administered at 200mg/m every 3 weeks ² IV is administered to non-asian ethnicities/ethnicities. In some embodiments, about 100mg/m is administered ² Nab-paclitaxel of (1)

In some embodiments, 100mg/m is administered ² Nab-paclitaxel of (1)

In some embodiments, nab-paclitaxel

At a rate of 100mg/m per week ² And IV administration. In some embodiments, nab-paclitaxel

At 100mg/m ² IV is administered three times every four weeks (e.g., on days 1, 8, and 15 of a 28-day dosing cycle). In some embodiments, the taxane (e.g., paclitaxel or nab-paclitaxel)

) Administration may be weekly, every 2 weeks, every 3 weeks, every 4 weeks, on 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 (e.g., paclitaxel or nab-paclitaxel)

) The administration to the subject or population of subjects is intravenous (e.g., over a 3 hour infusion). In some embodiments, the subject or population of subjects is administered a taxane every three weeks. In some embodiments, the taxane is administered to the subject or population of subjects on about day 1 (e.g., day-3, day-2, day-1, day 2, or day 3) of a 21-day dosing cycle. In some embodiments, the subject is administered paclitaxel every three 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, the subject or population of subjects is administered nab-paclitaxel every three weeks

In some embodiments, nab-paclitaxel

The subject or population of subjects is administered on about day 1 of a 21 day dosing cycle.

Antimetabolites

In some cases, the effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) administered as part of the methods described herein is 10 to 10000mg/m ² (e.g., 20 to 8000mg/m ² 30 to 5000mg/m ² 40 to 2500mg/m ² 50 to 2000mg/m ² 100 to 1500mg/m ² Or 400 to 1200mg/m ² For example, about 20mg/m ² About 30mg/m ² About 40mg/m ² About 50mg/m ² About 60mg/m ² About 70mg/m ² About 80mg/m ² About 90mg/m ² About 100mg/m ² About 110mg/m ² About 120mg/m ² About 130mg/m ² About 140mg/m ² About 150mg/m ² About 160mg/m ² About 170mg/m ² About 180mg/m ² About 190mg/m ² About 200mg/m ² About 250mg/m ² About 300mg/m ² About 400mg/m ² About 500mg/m ² About 600mg/m ² About 700mg/m ² About 800mg/m ² About 900mg/m ² About 1000mg/m ² About 1100mg/m ² About 1200mg/m ² About 1250mg/m ² About 1300mg/m ² About 1400mg/m ² About 1500mg/m ² About 1750mg/m ² About 2000mg/m ² About 3000mg/m ² About 4000mg/m ² About 5000mg/m ² About 6000mg/m ² About 7000mg/m ² About 8000mg/m ² About 9000mg/m ² Or about 10000mg/m ² ). In some cases, an effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) is at about 500mg/m ² To about 1250mg/m ² In between (e.g., 20 mg/m) ² 、30mg/m ² 、40mg/m ² 、50mg/m ² 、60mg/m ² 、70mg/m ² 、80mg/m ² 、90mg/m ² 、100mg/m ² 、110mg/m ² 、120mg/m ² 、130mg/m ² 、140mg/m ² 、150mg/m ² 、160mg/m ² 、170mg/m ² 、180mg/m ² 、190mg/m ² 、200mg/m ² 、250mg/m ² 、300mg/m ² 、400mg/m ² 、500mg/m ² 、600mg/m ² 、700mg/m ² 、800mg/m ² 、900mg/m ² 、1000mg/m ² 、1100mg/m ² 、1200mg/m ² 、1250mg/m ² 、1300mg/m ² 、1400mg/m ² 、1500mg/m ² 、1750mg/m ² 、2000mg/m ² 、3000mg/m ² 、4000mg/m ² 、5000mg/m ² 、6000mg/m ² 、7000mg/m ² 、8000mg/m ² 、9000mg/m ² Or 10000mg/m ² ). In some casesIn the case, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is about 500mg/m ² . In some cases, an effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) is about 1000mg/m ² . In some cases, an effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) is about 1250mg/m ² . In some cases, the effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) is 500mg/m ² . In some cases, the effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) is 1000mg/m ² . In some cases, the effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) is 1250mg/m ² 。

In some cases, an effective amount of pemetrexed administered as part of the methods described herein is 10 to 1000mg/m ² (e.g., 20 to 900 mg/m) ² 30 to 800mg/m ² 40 to 700mg/m ² 50 to 650mg/m ² 100 to 600mg/m ² Or 200 to 550mg/m ² E.g. about 20mg/m ² About 30mg/m ² About 40mg/m ² About 50mg/m ² About 60mg/m ² About 70mg/m ² About 80mg/m ² About 90mg/m ² About 100mg/m ² About 110mg/m ² About 120mg/m ² About 130mg/m ² About 140mg/m ² About 150mg/m ² About 160mg/m ² About 170mg/m ² About 180mg/m ² About 190mg/m ² About 200mg/m ² About 250mg/m ² About 300mg/m ² About 400mg/m ² About 500mg/m ² About 600mg/m ² About 700mg/m ² About 800mg/m ² About 900mg/m ² Or about 1000mg/m ² ). In some cases, an effective amount of pemetrexed is about 500mg/m ² . In some cases, an effective amount of pemetrexed is about 500mg/m every three weeks ² . In some cases, the effective amount of pemetrexed is 500mg/m ² . In some cases, an effective amount of pemetrexed is 500mg/m every three weeks ² 。

In some embodiments, pemetrexed is administered to a subject or population of subjects intravenously (e.g., over a 10 minute infusion). In some embodiments, the subject or population of subjects is administered pemetrexed every three weeks. In some embodiments, pemetrexed is administered to the subject or population of subjects on about day 1 (e.g., day-3, day-2, day-1, day 2, or day 3) of a 21-day dosing cycle.

In some cases, an effective amount of gemcitabine to be administered as part of the methods described herein is from 10 to 10000mg/m ² (e.g., 20 to 8000mg/m ² 30 to 5000mg/m ² 40 to 2500mg/m ² 50 to 2000mg/m ² 100 to 1500mg/m ² Or 400 to 1250mg/m ² For example, about 20mg/m ² About 30mg/m ² About 40mg/m ² About 50mg/m ² About 60mg/m ² About 70mg/m ² About 80mg/m ² About 90mg/m ² About 100mg/m ² About 110mg/m ² About 120mg/m ² About 130mg/m ² About 140mg/m ² About 150mg/m ² About 160mg/m ² About 170mg/m ² About 180mg/m ² About 190mg/m ² About 200mg/m ² About 250mg/m ² About 300mg/m ² About 400mg/m ² About 500mg/m ² About 600mg/m ² About 700mg/m ² About 800mg/m ² About 900mg/m ² About 1000mg/m ² About 1100mg/m ² About 1200mg/m ² About 1250mg/m ² About 1300mg/m ² About 1400mg/m ² About 1500mg/m ² About 1750mg/m ² About 2000mg/m ² About 3000mg/m ² About 4000mg/m ² About 5000mg/m ² About 6000mg/m ² About 7000mg/m ² About 8000mg/m ² About 9000mg/m ² Or about 10000mg/m ² (e.g., 20 mg/m) ² 、30mg/m ² 、40mg/m ² 、50mg/m ² 、60mg/m ² 、70mg/m ² 、80mg/m ² 、90mg/m ² 、100mg/m ² 、110mg/m ² 、120mg/m ² 、130mg/m ² 、140mg/m ² 、150mg/m ² 、160mg/m ² 、170mg/m ² 、180mg/m ² 、190mg/m ² 、200mg/m ² 、250mg/m ² 、300mg/m ² 、400mg/m ² 、500mg/m ² 、600mg/m ² 、700mg/m ² 、800mg/m ² 、900mg/m ² 、1000mg/m ² 、1100mg/m ² 、1200mg/m ² 、1250mg/m ² 、1300mg/m ² 、1400mg/m ² 、1500mg/m ² 、1750mg/m ² 、2000mg/m ² 、3000mg/m ² 、4000mg/m ² 、5000mg/m ² 、6000mg/m ² 、7000mg/m ² 、8000mg/m ² 、9000mg/m ² Or 10000mg/m ² )). In some cases, the effective amount of gemcitabine is at about 500mg/m ² To about 1250mg/m ² In the meantime. In some cases, the effective amount of gemcitabine is about 500mg/m ² . In some cases, the effective amount of gemcitabine is about 1000mg/m ² . In some cases, the effective amount of gemcitabine is about 1000mg/m when administered prior to carboplatin ² . In some cases, the effective amount of gemcitabine is about 1250mg/m ² . In some cases, the effective amount of gemcitabine, when administered prior to cisplatin, is about 1250mg/m ² . In some cases, the effective amount of gemcitabine is about 1000mg/m on days 1 and 8 of a 21 day dosing cycle ² . In some cases, the effective amount of gemcitabine is about 1250mg/m on days 1 and 8 of a 21 day dosing cycle ² . In some cases, the effective amount of gemcitabine is 1000mg/m ² . In some cases, the effective amount of gemcitabine is 1000mg/m when administered prior to carboplatin ² . In some cases, the effective amount of gemcitabine is 1250mg/m ² . In some cases, the effective amount of gemcitabine, when administered prior to cisplatin, is 1250mg/m ² . In some cases, the effective amount of gemcitabine is 1000mg/m on days 1 and 8 of a 21 day dosing cycle ² . In some cases, the effective amount of gemcitabine is 1250mg/m on days 1 and 8 of a 21 day dosing cycle ² 。

In some embodiments, gemcitabine is administered intravenously (e.g., over a 30 minute infusion) to a subject or population of subjects. In some cases, gemcitabine is administered to a subject or population of subjects on about day 1 (e.g., day-3, day-2, day-1, day 2, or day 3) of a 21-day dosing cycle. In some cases, gemcitabine is administered to a subject or population of subjects on about day 1 and about day 8 (e.g., day 5, day 6, day 7, day 8, day 9, day 10, or day 11) of a 21-day dosing cycle.

Topoisomerase II inhibitors

In some cases, an effective amount of a topoisomerase II inhibitor (e.g., etoposide) is 10 to 1000mg/m ² (e.g., 20 to 800 mg/m) ² 30 to 700mg/m ² 40 to 500mg/m ² 50 to 300mg/m ² 75 to 200mg/m ² Or 80 to 150mg/m ² For example, about 20mg/m ² About 30mg/m ² About 40mg/m ² About 50mg/m ² About 60mg/m ² About 70mg/m ² About 80mg/m ² About 90mg/m ² About 100mg/m ² About 110mg/m ² About 120mg/m ² About 130mg/m ² About 140mg/m ² About 150mg/m ² About 160mg/m ² About 170mg/m ² About 180mg/m ² About 190mg/m ² About 200mg/m ² About 250mg/m ² About 300mg/m ² About 400mg/m ² About 500mg/m ² About 600mg/m ² About 700mg/m ² About 800mg/m ² About 900mg/m ² Or about 1000mg/m ² (e.g., 20 mg/m) ² 、30mg/m ² 、40mg/m ² 、50mg/m ² 、60mg/m ² 、70mg/m ² 、80mg/m ² 、90mg/m ² 、100mg/m ² 、110mg/m ² 、120mg/m ² 、130mg/m ² 、140mg/m ² 、150mg/m ² 、160mg/m ² 、170mg/m ² 、180mg/m ² 、190mg/m ² 、200mg/m ² 、250mg/m ² 、300mg/m ² 、400mg/m ² 、500mg/m ² 、600mg/m ² 、700mg/m ² 、800mg/m ² 、900mg/m ² Or 1000mg/m ² )). In some cases, an effective amount of a topoisomerase II inhibitor (e.g., etoposide) is about 100mg/m ² . In some cases, an effective amount of a topoisomerase II inhibitor (e.g., etoposide) is about 100mg/m on days 1 to 3 every three weeks ² . In some cases, an effective amount of a topoisomerase II inhibitor (e.g., etoposide) is 100mg/m on days 1 to 3 every three weeks ² 。

In some embodiments, the topoisomerase II inhibitor (e.g., etoposide) is administered to the subject intravenously (e.g., over a 60 minute infusion).

In some cases, an effective amount of a topoisomerase II inhibitor (e.g., doxorubicin) is 10 to 1000mg/m ² (e.g., 20 to 800 mg/m) ² 30 to 700mg/m ² 40 to 500mg/m ² 50 to 300mg/m ² 75 to 200mg/m ² Or 80 to 150mg/m ² For example, about 20mg/m ² About 30mg/m ² About 40mg/m ² About 50mg/m ² About 60mg/m ² About 70mg/m ² About 80mg/m ² About 90mg/m ² About 100mg/m ² About 110mg/m ² About 120mg/m ² About 130mg/m ² About 140mg/m ² About 150mg/m ² About 160mg/m ² About 170mg/m ² About 180mg/m ² About 190mg/m ² About 200mg/m ² About 250mg/m ² About 300mg/m ² About 400mg/m ² About 500mg/m ² About 600mg/m ² About 700mg/m ² About 800mg/m ² About 900mg/m ² Or about 1000mg/m ² (e.g., 20 mg/m) ² 、30mg/m ² 、40mg/m ² 、50mg/m ² 、60mg/m ² 、70mg/m ² 、80mg/m ² 、90mg/m ² 、100mg/m ² 、110mg/m ² 、120mg/m ² 、130mg/m ² 、140mg/m ² 、150mg/m ² 、160mg/m ² 、170mg/m ² 、180mg/m ² 、190mg/m ² 、200mg/m ² 、250mg/m ² 、300mg/m ² 、400mg/m ² 、500mg/m ² 、600mg/m ² 、700mg/m ² 、800mg/m ² 、900mg/m ² Or 1000mg/m ² )). In some cases, an effective amount of a topoisomerase II inhibitor (e.g., doxorubicin) is about 60mg/m ² . In some cases, an effective amount of a topoisomerase II inhibitor (e.g., doxorubicin) is 60mg/m ² . In some cases, an effective amount of a topoisomerase II inhibitor (e.g., doxorubicin) is about 100mg/m ² . In some cases, an effective amount of a topoisomerase II inhibitor (e.g., doxorubicin) is 100mg/m ² . In some cases, the dosage of topoisomerase II inhibitor (e.g., doxorubicin) is reduced or delayed to avoid toxicity.

In some embodiments, the topoisomerase II inhibitor (e.g., doxorubicin) can be administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, on 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, a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) can be administered every 2 weeks.

In some embodiments, an alkylating agent (e.g., cyclophosphamide) is administered to the subject as an IV bolus over 3 to 5 minutes. In some embodiments, the alkylating agent (e.g., cyclophosphamide) is administered as an IV infusion over 15 to 30 minutes. In some embodiments, the topoisomerase II inhibitor (e.g., doxorubicin) is administered to the subject intravenously (e.g., over a 60 minute infusion).

Alkylating agent

The therapeutically effective amount of alkylating agent (e.g., cyclophosphamide) administered to a human will be between about 400 to about 800mg/m ² In the range (e.g., about 400 mg/m) ² About 425mg/m ² About 450mg/m ² About 475mg/m ² About 500mg/m ² About 525mg/m ² About 550mg/m ² About 575mg/m ² About 600mg/m ² About 625mg/m ² About 650mg/m ² About 675mg/m ² About 700mg/m ² About 725mg/m ² About 750mg/m ² About 775mg/m ² Or about 800mg/m ² (e.g., 400 mg/m) ² 、425mg/m ² 、450mg/m ² 、475mg/m ² 、500mg/m ² 、525mg/m ² 、550mg/m ² 、575mg/m ² 、600mg/m ² 、625mg/m ² 、650mg/m ² 、675mg/m ² 、700mg/m ² 、725mg/m ² 、750mg/m ² 、775mg/m ² Or 800mg/m ² ) Whether by one or more administrations. For example, in some embodiments, about 600mg/m is administered ² An alkylating agent (e.g., cyclophosphamide). In some embodiments, about 600mg/m is administered biweekly ² An alkylating agent (e.g., cyclophosphamide). In some embodiments, about 600mg/m is administered ² Cyclophosphamide of (1). In some embodiments, about 600mg/m is administered biweekly ² Cyclophosphamide of (1). In some embodiments, 600mg/m is administered biweekly ² An alkylating agent (e.g., cyclophosphamide). In some embodiments, the alkylating agent (e.g., cyclophosphamide) may be administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, on days 1, 8, and 15 of each 21-day cycle, on days 1 and 22 of each 28-day cycle, or on days 1, 8, and 15 of each 28-day cycle.

In some embodiments, an alkylating agent (e.g., cyclophosphamide) is administered to the subject as an IV bolus over 3 to 5 minutes. In some embodiments, the alkylating agent (e.g., cyclophosphamide) is administered as an IV infusion.

Administration of colony stimulating factor

The therapeutically effective amounts of Colony Stimulating Factor (CSF) (e.g., G-CSF (e.g., pegylated filgrastim or filgrastim) and GM-CSF (e.g., sargrastim) administered to a human will be in the range of about 1 to about 100mg (e.g., about 1mg, about 2mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 45mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, or about 100 mg), e.g., in some embodiments about 6mg is administered in some aspects a Colony Stimulating Factor (CSF) administered to a human (e.g., therapeutically effective amounts of G-CSF (e.g., pegylated filgrastim or filgrastim) and GM-CSF (e.g., sargrastim) will range from 1 to 100mg (e.g., 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, 25mg, 30mg, 45mg, 50mg, 60mg, 70mg, 80mg, 90mg, or 100 mg).

The therapeutically effective amount of colony stimulating factor (e.g., G-CSF (e.g., pegylated filgrastim or filgrastim) and GM-CSF (e.g., sargrastim) administered to a human will be in the range of about 1 to about 400 mcg/kg/day (e.g., 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 325 mcg/kg/day, about 375 mcg/kg/day, about 400 mcg/kg/day, or about 400 mcg/kg/day, in some embodiments, about 250mcg/m is administered ² The day is. In some embodiments, therapeutically effective amounts of colony stimulating factor (e.g., G-CSF (e.g., pegylated filgrastim or filgrastim) and GM-CSF (e.g., sargrastim) administered to a human will be in the range of 1 to 400 mcg/kg/day (e.g., 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, 325 mcg/kg/day, 275 mcg/kg/day, 250 mcg/kg/day, 325 mcg/kg/day, 275 mcg/kg/day, and/day ). For example, in some embodiments, 250mcg/m is administered ² The day is one. In some embodiments, colony stimulating factors (e.g., G-CSF (e.g., pegylated filgrastim or filgrastim) and GM-CSF (e.g., sargrastim)) are administered as subcutaneous injections. In some embodiments, the colony stimulating factor is sargrastim. In some embodiments, sargramostim is administered to a human at a dose of about 250mcg/m 2/day. In some embodiments, sargramostim is administered to a human at a dose of 250mcg/m 2/day.

Administration of VEGF antagonists

In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is between about 0.01mg/kg and about 50mg/kg of the subject's body weight (e.g., between about 0.01mg/kg and about 45mg/kg, e.g., between about 0.1mg/kg and about 40mg/kg, e.g., between about 1mg/kg and about 35mg/kg, e.g., between about 2.5mg/kg and about 30mg/kg, e.g., between about 5mg/kg and about 25mg/kg, e.g., between about 10mg/kg and about 20mg/kg, e.g., between about 12.5mg/kg and about 15mg/kg, e.g., a dose of 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, e.g., about 15mg/kg in some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is between about 0.01mg/kg and about 15mg/kg of the subject's body weight every three weeks (e.g., between about 0.1mg/kg and about 15mg/kg, e.g., between about 0.5mg/kg and about 15mg/kg, e.g., between about 1mg/kg and about 15mg/kg, e.g., between about 2.5mg/kg and about 15mg/kg, e.g., between about 5mg/kg and about 15mg/kg, e.g., between about 7.5mg/kg and about 15mg/kg, e.g., between about 10mg/kg and about 15mg/kg, e.g., between about 12.5mg/kg to about 15mg/kg, e.g., between about 14mg/kg to about 15mg/kg, e.g., about 15 + -1 mg/kg, e.g., about 15 + -0.5 mg/kg, e.g., about 15 + -0.2 mg/kg, e.g., about 15 + -0.1 mg/kg, e.g., about 15 mg/kg). In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of about 15mg/kg administered every three weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is between about 0.01mg/kg and about 50mg/kg of the body weight of a subject (e.g., between about 0.01mg/kg and about 45mg/kg, e.g., between about 0.1mg/kg and about 40mg/kg, e.g., between about 1mg/kg and about 35mg/kg, e.g., between about 2.5mg/kg and about 30mg/kg, e.g., between about 5mg/kg and about 25mg/kg, e.g., between about 7.5mg/kg and about 20mg/kg, e.g., between about 7.5mg/kg and about 15mg/kg, e.g., between about 5mg/kg and about 25mg/kg, e.g., between about 10.10 mg/kg, e.g., between about 10mg/kg, e.g., about 10mg/kg, e.g., between about 10mg/kg, e.g., about 1 day (e.g., day 1 day of each 14 day ± 3 days) of a 14 day of a dosing cycle). In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is between about 0.01mg/kg and about 15mg/kg of the subject's body weight (e.g., between about 0.1mg/kg and about 15mg/kg, e.g., between about 0.5mg/kg and about 15mg/kg, e.g., between about 1mg/kg and about 15mg/kg, e.g., between about 2.5mg/kg and about 15mg/kg, e.g., between about 5mg/kg and about 15mg/kg, such as, for example, between about 7.5mg/kg and about 12.5mg/kg, such as, for example, between about 8mg/kg and about 12mg/kg, such as, for example, between about 9mg/kg and about 11mg/kg, such as, for example, between about 9.5mg/kg and about 10.5mg/kg, such as, for example, about 10 + -1 mg/kg, such as, for example, about 10 + -0.5 mg/kg, such as, for example, about 10 + -0.2 mg/kg, such as, for example, about 10 + -0.1 mg/kg, such as, for example, about 10 mg/kg). In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of about 10mg/kg administered every two weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of about 5mg/kg administered every two weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of about 7.5mg/kg administered every two weeks.

In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., no between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 10mg/kg and 20mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., 15 ± 2mg/kg, 15 ± 1mg/kg, 15 ± 0.5mg/kg, 15 ± 0.2mg/kg, or 15 ± 0.1mg/kg, e.g., 15 mg/kg) every three weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of between 0.01mg/kg and 15mg/kg of the subject's body weight (e.g., between 0.1mg/kg and 15mg/kg, e.g., between 0.5mg/kg and 15mg/kg, e.g., not between 1mg/kg and 15mg/kg, e.g., between 2.5mg/kg and 15mg/kg, e.g., between 5mg/kg and 15mg/kg, e.g., between 7.5mg/kg and 15mg/kg, e.g., between 10mg/kg and 15mg/kg, e.g., between 12.5mg/kg and 15mg/kg, e.g., between 14mg/kg and 15mg/kg, e.g., 15 ± 1mg/kg, e.g., 15 ± 0.5mg/kg, e.g., 15 ± 0.2mg/kg, e.g., 15 ± 0.1mg/kg, e.g., 15mg/kg, e.g., 15 mg/kg) every three weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of 15mg/kg administered every three weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of between 0.01mg/kg and 50mg/kg of the subject's body weight (e.g., between 0.01mg/kg and 45mg/kg, e.g., between 0.1mg/kg and 40mg/kg, e.g., no between 1mg/kg and 35mg/kg, e.g., between 2.5mg/kg and 30mg/kg, e.g., between 5mg/kg and 25mg/kg, e.g., between 7.5mg/kg and 20mg/kg, e.g., between 7.5mg/kg and 15mg/kg, e.g., between 7.5mg/kg and 12.5mg/kg, e.g., 10 ± 2mg/kg, 10 ± 1mg/kg, 10 ± 0.5mg/kg, 10 ± 0.2mg/kg or 10 ± 0.1mg/kg, e.g., 10 mg/kg) every two weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of between 0.01mg/kg and 15mg/kg of the subject's body weight (e.g., between 0.1mg/kg and 15mg/kg, e.g., between 0.5mg/kg and 15mg/kg, e.g., not between 1mg/kg and 15mg/kg, e.g., between 2.5mg/kg and 15mg/kg, e.g., between 5mg/kg and 15mg/kg, e.g., between 7.5mg/kg and 12.5mg/kg, e.g., between 8mg/kg and 12mg/kg, e.g., between 9mg/kg and 11mg/kg, e.g., between 9.5mg/kg and 10.5mg/kg, e.g., 10 ± 1mg/kg, e.g., 10 ± 0.5mg/kg, e.g., 10 ± 0.2mg/kg, e.g., 10.1 mg/kg, e.g., 10 mg/kg) every two weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of 10mg/kg administered every two weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of 5mg/kg administered every two weeks. In some cases, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is a dose of 7.5mg/kg administered every two weeks.

In some cases, the dose of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) administered in a combination therapy (e.g., a combination therapy with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist disclosed herein (e.g., tipleyluzumab) and/or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atuzumab) or an anti-PD-1 antagonist antibody (e.g., paribizumab)) can be reduced compared to a standard dose of a PD-1 axis binding antagonist administered as a monotherapy.

In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered intravenously. In some cases, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered intravenously over about 90 ± 15 minutes (e.g., 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, a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) is administered subcutaneously.

Assessment of PD-L1 expression

Expression of PD-L1 in a subject treated according to any of the methods, uses, and compositions for use described herein can be assessed. The methods, uses, and compositions for use can include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from a subject. In some cases, the patient has bladder cancer and the sample is a transurethral cystectomy (TURBT) sample. In some cases, the sample is a cystectomy or nephroureterectomy sample. In some cases, the sample is a segmental resection, lobectomy, bilobalectomy, or total pneumonectomy sample. In some cases, the sample is a lymphadenectomy sample. In other examples, the PD-L1 expression level in a biological sample (e.g., a tumor sample) obtained from the subject has been determined before or after initiation of treatment. PD-L1 expression can be determined using any suitable method. For example, PD-L1 expression can be determined as described in U.S. patent application nos. US20180030138A1 and US20180037655 A1. Any suitable tumor sample may be used, for example, a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archived tumor sample, a fresh tumor sample, or a frozen tumor sample.

For example, PD-L1 expression can be determined as a percentage of a tumor sample occupied by tumor-infiltrating immune cells that express a detectable PD-L1 expression level, as a percentage of tumor-infiltrating immune cells that express a detectable PD-L1 expression level in a tumor sample, and/or as a percentage of tumor cells that express a detectable PD-L1 expression level in a tumor sample. It is to be understood that, in any of the foregoing examples, the percentage of the tumor sample occupied by tumor-infiltrating immune cells can be the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject, e.g., as assessed by IHC using an anti-PD-L1 antibody (e.g., SP142 antibody). Any suitable anti-PD-L1 antibody may be used, including, 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 examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263. In some examples, the anti-PD-L1 antibody is 22C3. In some examples, the anti-PD-L1 antibody is 28-8.

In some examples, a tumor sample obtained from a subject has a detectable level of PD-L1 expression in less than 1% of the tumor cells in the tumor sample, in 1% or more of the tumor cells in the tumor sample, in 1% to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.

In some examples, a tumor sample obtained from the subject has a detectable PD-L1 expression level in tumor-infiltrating immune cells that occupy less than 1% of the tumor sample, more than 1% of the tumor sample, 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

In some aspects, a tumor sample obtained from a subject has a detectable PD-L1 expression level in tumor-infiltrating immune cells that comprise 5% to 19% (e.g., TIC 5% to 19%) of the tumor sample; for example, there is a low expression level of PD-L1 with PD-L1. In some aspects, a tumor sample obtained from a subject has a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise ≧ 20% of the tumor sample (e.g., TIC ≧ 20%); for example, there is a high expression level of PD-L1 with PD-L1. In some embodiments, tumor samples having greater than or equal to 5% TIC have been determined to be comparable to a CPS of greater than or equal to 1.

In some embodiments, tumor samples can be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or tumor cells according to the diagnostic assessment criteria shown in table 1 and/or table 2, respectively.

TABLE 1 tumor infiltrating Immune Cell (IC) IHC diagnostic criteria

TABLE 2 Tumor Cell (TC) IHC diagnostic criteria

In some cases, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1-selected tumor (e.g., a proportion of tumor area in the tumor sample occupied by PD-L1-expressing tumor-infiltrating Immune Cells (ICs) is greater than or equal to 5%, as determined by IHC using an SP142 antibody). In some cases, the tumor selected for PD-L1 is a tumor in which the proportion of tumor area occupied by Immune Cells (IC) expressing PD-L1 is greater than or equal to 5% as determined by an Immunohistochemistry (IHC) assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142, SP263, 22C3, or 28-8. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. 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 22C3. In some cases, the IHC assay uses the anti-PD-L1 antibody 22C3. In some cases, the IHC assay uses anti-PD-L1 antibody 28-8.

In some cases, the IC has been determined to be greater than or equal to 5% (e.g., as determined using the Ventana (SP 142) PD-L1IHC assay). In some cases, the IC score has been determined to be 2 or 3 (e.g., as determined using the Ventana (SP 142) PD-L1IHC assay). In some cases, the IC has been determined to be greater than or equal to 1% (e.g., as determined using the Ventana (SP 142) PD-L1IHC assay). In some cases, the IC has been determined to be greater than or equal to 10% (e.g., as determined using the Ventana (SP 142) PD-L1IHC assay). In some cases, the IC has been determined to be greater than or equal to 1% and less than 50% (e.g., as determined using the Ventana (SP 142) PD-L1IHC assay). In some cases, the IC has been determined to be greater than or equal to 1% and less than 30% (e.g., as determined using the Ventana (SP 142) PD-L1IHC assay).

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1. In some cases, a detectable protein expression level of PD-L1 has been determined by an IHC assay. In some cases, the IHC assay uses the anti-PD-L1 antibody SP142. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% of tumor-infiltrating immune cells of the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% of tumor-infiltrating immune cells of the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 1% and less than 5% of the tumor sample. In some cases, a tumor sample has been determined to have a detectable level of PD-L1 expression in tumor-infiltrating immune cells that comprise greater than or equal to 5% and less than 10% of the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 10% of tumor-infiltrating immune cells of the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 1% and less than 5% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 5% and less than 50% of the tumor cells in the tumor sample. In some cases, a tumor sample has been determined to have a detectable PD-L1 expression level in greater than or equal to 50% of the tumor cells in the tumor sample.

In some cases, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1 selected tumor (e.g., PD-L1 is high (e.g., PD-L1 Tumor Proportion Score (TPS) in the tumor sample is greater than or equal to 50%, as determined by using the IHC antibody for SP 263.) in some cases, a PD-L1 selected tumor is a PD-L1 high selected tumor in some cases, a PD-L1 selected tumor is a tumor in which TPS is greater than or equal to 50%, has been determined by an Immunohistochemistry (IHC) assay, in some cases, the IHC assay uses anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some cases, the IHC assay uses anti-PD-L1 antibody sp263 in some cases the IHC assay uses anti-PD-L1 antibody sp142 in some cases the IHC assay uses anti-PD-L1 antibody 22C3 in some cases it has been determined that TPS is greater than or equal to 50% (e.g., as determined using the Ventana (SP 263) PD-L1 IHC assay), in some cases it has been determined that TPS is less than 50% (e.g., as determined using the Ventana (SP 263) PD-L1 IHC assay), in some cases it has been determined that TPS is greater than or equal to 1% and less than 50% (e.g., as determined using the Ventana (SP 263) PD-L1C assay).

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable level of protein expression of PD-L1. In some cases, a detectable protein expression level of PD-L1 has been determined by IHC assay. 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 PD-L1 positive tumor cell fraction greater than or equal to 50% of the tumor sample. In some cases, the tumor sample has been determined to have a PD-L1 positive tumor cell fraction of less than 50% of the tumor samples. In some cases, the tumor sample has been determined to have a PD-L1 positive tumor cell fraction 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 anti-PD-L1 antibody 22C3. In some embodiments, the tumor sample has been determined to have a Combined Positive Score (CPS) of greater than or equal to 10 or a Tumor Proportion Score (TPS) in greater than or equal to 1% of the tumor sample, e.g., as determined using anti-PD-L1 antibody 22C3 as part of a pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than or equal to 10 or TPS in greater than or equal to 1% and less than 50% of the tumor sample, e.g., as determined using anti-PD-L1 antibody 22C3 as part of a pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than or equal to 20 or TPS in greater than or equal to 50% of the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of a pharmDx 22C3 IHC assay. In some embodiments, tumor samples having a CPS greater than or equal to 1 have been determined to be comparable to a TIC of greater than or equal to 5%.

In some cases, the IHC assay uses anti-PD-L1 antibody 28-8. In some cases, the IHC assay is a pharmDx 28-8 IHC assay. In some cases, the fraction of PD-L1-positive tumor cells is greater than or equal to 50%, as determined by positive staining with anti-PD-L1 antibody 28-8.

In some cases, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable level of nucleic acid expression of PD-L1. In some cases, a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-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 infiltrating tumor immune cells, tumor cells, stromal cells, and any combination thereof.

Assessment of tigit expression

Expression of TIGIT in a subject treated according to any of the methods, uses, and compositions for use described herein can be assessed. The methods, uses, and compositions for use may include determining an expression level of TIGIT in a biological sample (e.g., a tumor sample) obtained from a subject. In other examples, the level of TIGIT expression in a biological sample (e.g., a tumor sample) obtained from the subject has been determined prior to initiation of treatment or after initiation of treatment. TIGIT expression may be determined using any suitable method. Any suitable tumor sample may be used, for example, a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archived tumor sample, a fresh tumor sample, or a frozen tumor sample.

For example, TIGIT expression can be determined as a percentage of a tumor sample occupied by tumor-infiltrating immune cells that express a detectable TIGIT expression level, as a percentage of tumor-infiltrating immune cells that express a detectable TIGIT expression level in a tumor sample, and/or as a percentage of tumor cells that express a detectable TIGIT expression level in a tumor sample. It will be appreciated that in any of the foregoing examples, the percentage of the tumor sample occupied by tumor-infiltrating immune cells may be the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject, e.g., as assessed by IHC using anti-TIGIT antagonist antibodies. Any suitable anti-TIGIT antagonist antibody can be used. In some examples, the anti-TIGIT antagonist antibody is 10A7 (WO 2009/126688A3; U.S. patent No. 9,499,596).

Assessment of EGFR and ALK aberrations

In some cases, in any of the methods, uses, or compositions for use described herein, the subject does not have Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. In some cases, in any of the methods, uses, or compositions for use described herein, the subject does not have an EGFR gene mutation (e.g., a sensitizing or activating EGFR gene mutation) or an ALK gene rearrangement (e.g., an ALK fusion oncogene). In some cases, the Eastern Cooperative Oncology Group (ECOG) physical Performance Status (PS) of the subject is 0 or 1.

Methods for detecting the mutant states EGFR and ALK are well known in the art and include, but are not limited to, targeting gene pulldown (gene pulldown) and sequencing methods described by Frampton et al (Nature Biotechnology.31 (11): 1023-1033 (2013), which is incorporated herein by reference in its entirety), for samples from clinical use (e.g., tumor biopsy)Sample or blood sample (e.g., circulating tumor DNA in blood)). Such next generation sequencing methods can be used in conjunction with any of the methods disclosed herein to detect various mutations (e.g., insertions, deletions, base substitutions, focal gene amplifications, and/or homozygous gene deletions), while enabling the use of small samples (e.g., from small core needle biopsies, fine needle aspirations, and/or cell clumps) or fixed samples (e.g., formalin-fixed and paraffin-embedded (FFPE) samples). Other methods of detecting the status of EGFR and ALK mutations include Fluorescence In Situ Hybridization (FISH) and Immunohistochemistry (IHC) methods. An exemplary method for detecting the status of ALK mutations is disclosed in U.S. patent No. 9,651,555, which is incorporated herein by reference in its entirety. In some cases, it is possible to use,

an anti-ALK (D5F 3) IHC assay is used to determine the mutational status of the ALK gene.

In some cases of any of the methods described herein, the mutation is an allergenic EGFR mutation. Sensitizing EGFR mutations are well known in the art and are included in U.S. patent publication nos: those described in US 2018/0235968 and Juan et al (Therapeutic Advances in Medical oncology.9 (3): 201-216, 2017), which are incorporated herein by reference in their entirety. In some cases, the sensitizing EGFR mutation is a mutation in any one of exons 18 to 21 (e.g., a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some cases, the sensitizing EGFR mutation is a deletion of exon 19 (del 19). In other cases, the sensitizing EGFR mutation is an L858R point mutation in exon 21. In some cases, the sensitizing EGFR mutation is a G719X point mutation in exon 18, where "X" is most commonly C, a, or S. In some cases, the sensitizing EGFR mutation is a G719S point mutation in 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 a T790M point mutation. In some cases, the sensitizing EGFR mutation is an E709X point mutation, where "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 well known in the art and include those described in U.S. Pat. Nos. 9,651,555 and Du et al (Thorac cancer.9:423-430, 2018), which are incorporated herein by reference in their entirety. In some cases, ALK gene rearrangement results in the production of oncogenic ALK tyrosine kinases, which activate downstream signaling pathways leading to increased cell proliferation and survival. In some cases, the ALK gene rearranges to an ALK rearrangement with 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, which rearrangement results in the formation of a fused oncogene. In some cases, the ALK gene rearranges to an EML4 rearrangement with ALK, which leads to the formation of the fusion oncogene EML4-ALK.

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 useful for treating a subject (e.g., a human) having cancer according to the inventive methods, uses, and compositions for use described herein.

A. Exemplary anti-TIGIT antagonist antibodies

The invention provides anti-TIGIT antagonist antibodies useful for treating cancer in a subject (e.g., a human).

In some cases, the anti-TIGIT antagonist antibody is tegraleigh immuzumab (CAS accession No. 1918185-84-8). The tirayleigh itumumab (gene tack) is also known as MTIG7192A.

In certain instances, an anti-TIGIT antagonist antibody comprises at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of KTYRRFKWYSDYYAVSVKG (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) HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6), or one or more of the above HVRs and a nucleotide sequence identical to SEQ ID NO:1-6 (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) of one or more variants thereof.

In some cases, an anti-TIGIT antagonist antibody can include: (a) HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of KTYYRRFKWYSDYYAVSVKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) HVR-L1 comprising an amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some cases, an anti-TIGIT antagonist antibody has: <xnotran> VH , EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 17) 90% (, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99% ) SEQ ID NO: </xnotran> <xnotran> 17 , QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 18) 90% (, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99% ) SEQ ID NO: </xnotran> 18, or a sequence of seq id no; <xnotran> / VL , DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 19) 90% (, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99% ) SEQ ID NO: </xnotran> 19 in the sequence listing. In some cases, an anti-TIGIT antagonist antibody has: a VH domain comprising a VH domain identical to sequence SEQ ID NO:17 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO:17, and (ii) a sequence of (d); and/or a VL domain comprising a sequence identical to SEQ ID NO:19 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO:19 in the sequence listing. In some cases, an anti-TIGIT antagonist antibody has: a VH domain comprising SEQ ID NO: 17; and a VL domain comprising SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain comprising a VH domain identical to sequence SEQ ID NO:18 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or SEQ ID NO:17, and (ii) a sequence of (d); and/or a VL domain comprising a sequence identical to SEQ ID NO:19 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 19. In some cases, an anti-TIGIT antagonist antibody has: a VH domain comprising SEQ ID NO:1, 1 amino acid sequence; and a VL domain comprising SEQ ID NO: 19.

In some cases, an anti-TIGIT antagonist antibody comprises heavy and light chain sequences, wherein: (ii) (a) the heavy chain comprises the amino acid sequence:

<xnotran> EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33); </xnotran> And (b) the light chain comprises the amino acid sequence:

DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO：34)。

in some cases, the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of the following light chain variable region Framework Regions (FRs): FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLLGERANC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (SEQ ID NO: 9); and/or FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), or a combination of one or more of the above FRs with one or more variants thereof that differ from the amino acid sequence of SEQ ID NO: any of 7-10 have at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). In some cases, for example, the antibody further comprises: FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLAVSLERRATINC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (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 further comprises at least one, two, three, or four of the following heavy chain variable region FRs: FR-H1 comprising X ₁ Amino acid sequence of VQLQQSGPGLVKPQTLSLTCASGDSVS (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 a group of one or more of the above FRs with one or more variants thereofAnd one or more variants thereof that differ from the amino acid sequence of SEQ ID NO: 11-14 have at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). The anti-TIGIT antagonist antibody may further comprise, for example, at least one, two, three, or four of the following heavy chain variable region FRs: 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/or FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the foregoing FRs with one or more variants thereof that hybridize to the amino acid sequence of SEQ ID NO: 12-15 have at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). In some cases, an anti-TIGIT antagonist antibody comprises: FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPQTLSLTCASGDSVS (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 another instance, for example, an anti-TIGIT antagonist antibody can further comprise at least one, two, three, or four of the following heavy chain variable region FRs: FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPQTLSLTCASGDSVS (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 a combination of one or more of the foregoing FRs with one or more variants thereof that hybridize to the amino acid sequence of SEQ ID NO: any of 12-14 and 16 have at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity). In some cases, anti-TIGIT antagonist antibodies The method comprises the following steps: FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPQTLSLTCASGDSVS (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 the antibody comprises a VH as provided above in any case and a VL as provided above in any case, wherein one or both variable domain sequences comprise a post-translational modification.

In some cases, any of the anti-TIGIT antagonist antibodies described above can bind to rabbit TIGIT in addition to human TIGIT. In some cases, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT and cynomolgus monkey (cyno) TIGIT. In some cases, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some cases, any of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not to murine TIGIT.

In some cases, the anti-TIGIT antagonist antibody has a K of about 10nM or less _D Binds to human TIGIT and has a K of about 10nM or less _D Bind to cyno TIGIT (e.g., with a K of about 0.1nM to about 1 nM) _D Binds to human TIGIT with a K of about 0.5nM to about 1nM _D In combination with cyno TIGIT, e.g. with a K of about 0.1nM or less _D Binds to human TIGIT with a K of about 0.5nM or less _D In combination with cyno TIGIT).

In some cases, an anti-TIGIT antagonist antibody specifically binds to TIGIT and inhibits or blocks TIGIT interaction with a poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR). In some cases, the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10nM or less (e.g., 1nM to about 10 nM). In some cases, an anti-TIGIT antagonist antibody specifically binds to 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 50nM or less (e.g., 1nM to about 50nM, e.g., 1nM to about 5 nM). In some cases, an anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 with TIGIT. In some cases, an anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.

In some cases, the methods or uses described herein can include using or administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with any of the anti-TIGIT antagonist antibodies described above. For example, the method can include administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with an anti-TIGIT antagonist antibody having the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of KTYYRRFKWYSDYYAVSVKG (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 (f) HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). The methods described herein can further comprise administering an isolated anti-TIGIT antagonist antibody that binds the same epitope as the anti-TIGIT antagonist antibody described above.

In some aspects, the anti-TIGIT antagonist antibody is an antibody having intact Fc-mediated effector function (e.g., ibritumomab tiuxetan, wiborlizumab, etiglimab, EOS084448, or TJ-T6) or enhanced effector function (e.g., SGN-TGT).

In other aspects, the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector function (e.g., dommaralimab, BMS-986207, ASP8374, or COM 902).

In some aspects, the anti-TIGIT antagonist antibody is an IgGl class antibody, e.g., ibritumumab tiuxetan, beborrelizumab, domvanalimab, BMS-986207, etiglimab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308.

In other aspects, the anti-TIGIT antagonist antibody is an IgG4 class antibody, e.g., ASP8374 or COM902.

anti-TIGIT antagonist antibodies (e.g., tegraleigh mab), including compositions comprising such antibodies, useful in the invention can bind to PD-1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atelizumab), PD-1 binding antagonists (e.g., anti-PD-1 antagonist antibodies, e.g., palivizumab), and PD-L2 binding antagonists (e.g., anti-PD-L2 antagonist antibodies)).

In some embodiments, an anti-TIGIT antagonist antibody acts to inhibit TIGIT signaling. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT binding to its binding partner. Exemplary TIGIT binding partners include CD155 (PVR), CD112 (PVRL 2 or Nectin-2), and CD113 (PVRL 3 or Nectin-3). In some embodiments, an anti-TIGIT antagonist antibody is capable of inhibiting binding between TIGIT and CD 155. In some embodiments, an anti-TIGIT antagonist antibody can inhibit binding between TIGIT and CD 112. In some embodiments, the anti-TIGIT antagonist antibody inhibits binding between TIGIT and CD 113. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT-mediated cell signaling in an immune cell. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT (e.g., when engaging Fc γ R) by depleting regulatory T cells.

In some embodiments, the anti-TIGIT antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antibody is selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') ₂ Antibody fragments of the group consisting of 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, the anti-TIGIT antibodies described herein bind to human TIGIT. In some embodiments, the anti-TIGIT antibody is an Fc fusion protein.

In some embodiments, the anti-TIGIT antibody is selected from the group consisting of: tirayleigh immuzumab (MTIG 7192A, RG6058 or RO 7092284), veborlizumab (MK-7684), ASP8374 (PTZ-201), EOS884448 (EOS-448), SEA-TGT (SGN-TGT)), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), IBI939, domonalimab (AB 154), M6223, AB308, AB154, TJ-T6, MG1131, NB6253, HLX301, HLX53, SL-9258 (TIGIT-Fc-LIT), STW264 and YBL-012. In some embodiments, the anti-TIGIT antibody is selected from the group consisting of: tirayleigh Eusumab (MTIG 7192A, RG6058 or RO 7092284), velbolizumab (MK-7684), ASP8374 (PTZ-201), EOS-448 and SEA-TGT (SGN-TGT). The anti-TIGIT antibody may be tirayleigh eculizumab (MTIG 7192A, RG6058, or RO 7092284).

Non-limiting examples of anti-TIGIT antibodies that can be used in the methods disclosed herein and methods of making the same are described in PCT publications WO2018183889A1, WO2019129261A1, WO2016106302A9, WO2018033798A1, WO2020020281A1, WO2019023504A1, WO2017152088A1, WO2016028656A1, WO2017030823A2, WO2018204405A1, WO2019152574A1, and WO2020041541A2; U.S. Pat. nos. US 10,189,902, US 10,213,505, US 10,124,061, US 10,537,633 and US 10,618,958; and U.S. patent publication nos. 2020/0095324, 2019/0112375, 2018/0371083 and 2020/0062859, each of which is incorporated herein by reference in its entirety. Further non-limiting examples of anti-TIGIT antibodies that may be used in the methods disclosed herein and methods for their preparation are disclosed in PCT publication nos. WO2018204363A1, WO2018047139A1, WO2019175799A2, WO2018022946A1, WO2015143343A2, WO2018218056A1, WO2019232484A1, WO2019079777A1, WO2018128939A1, WO2017196867A1, WO 2012019154415 A1, WO2019062832A1, WO2018234793a, WO2018102536A1, WO2019137548A1, WO2019129221A1, WO2018102746A1, WO2018160704A9, WO 2022020040040041 A2, WO 20190637 A9, WO 20170707 A1, WO 2012019168382 A1, WO 200616100457004718 A3, WO 616170215201702012156671, WO 2012025720170579 A1, WO 20120276817626 a, WO 20257201579, WO 20257739, WO 202817646 A1, WO 202579, WO 202577314 A1, WO 2028170479, WO 20220170479 A1, WO 202201202579, WO 202579 A1, WO 202817314 A1, WO 20281471 A1, WO 202817646 a; U.S. Pat. nos. US 9,617,338, US 9,567,399, US 10,604,576 and US 9,994,637; and US patent publication nos. US 2018/0355040, US 2019/0175654, US 2019/004010154, US 2019/0382477, US 2019/0010246, US 2020/0164071, US 2020/0131267, US 2019/0338032, 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 201/0283496, CN 1094806A, and CN110818795A, each of which is incorporated herein by reference in its 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, domcanalimab (AB 154), vibrizumab (MK-7684), and SEA-TGT (SGN-TGT). Other 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 (seikagaku biotechnology group limited), 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 (anstelai pharmaceuticals (Astellas Pharma/potenta Therapeutics)), antibody clones hu1217-1-1 and hu1217-2-2 (baiji sheng (BeiGene)), antibody clones 4D4 and 19G (bungen and Hospital (Brigham & men's hospittal), antibody clone 11G11, 10D7, 15A6, 15A 2a (brij), and heavy chain having constant regions including migu 1, 12 a (migao), while (migao), and while heavy chain antibody (mighal 265); 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); 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 (yokuri immune drug research, 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 (iTeos Therapeutics); antibody clones m1707, m1708, m1709, m1710, m1711, h1707, h1708, h1709, h1710 and h1711 (henry pharmaceutical products, inc. Of Jiangsu); antibody clones TIG1, TIG2 and TIG3 (JN Biosciences LLC); <xnotran> (, 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 ( 2) Tool TIGIT ( 4) (Kymab Limited); 1D05 ( PD-L1) Kymab TIGIT (ABS) 1D05/ TIGIT with (Bispecific 1), Kymab TIGIT 1D05 ABS TIGIT/1D05 (Bispecific 2), Toon TIGIT Tool PD-L1 ABS Tool TIGIT/Tool PD-L1 (Bispecific 3), Tool PD-L1 Tool TIGIT ABS Tool PD-L1/Tool TIGIT (Bispecific 4) (Kymab Limited); 14D7, 26B10, hu14D7, hu26B10, 14A6, hu14A6, 28H5, 31C6, hu31C6, 25G10, MBS43, 37D10, 18G10, 11A11, c18G10 LB155.14A6.G2.A8 ( (Merck)); etigilimab (OMP-313M 32) (Mereo BioPharma); 64G1E9B4, 100C4E7D11, 83G5H11C12, 92E9D4B4, 104G12E12G2, 121C2F10B5, 128E3F10F3F2, 70A11A8E6, 11D8E124A, 16F10H12C11, 8F2D8E7, 48B5G4E12, 139E2C2D2, 128E3G7F5, AS19584, AS19852, AS19858, AS19886, AS19887, AS19888, AS20160, AS19584VH26, AS19584VH29, AS19584VH30, AS19584VH31, AS19886VH5, AS19886VH8, AS19886VH9, AS19886VH10, AS19886VH19, AS19886VH20, AS19584VH28-Fc, AS19886VH5-Fc, AS19886VH8-Fc, AS19584-Fc AS19886-Fc ( ); ARE : ab58, ab69, ab75, ab133, </xnotran> 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, ab 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, 13A, 13B, 13C, 13D, 14, 16C, 16D, 16E, 18, 21, 22, 25A, 25B, 25C, 25D, 25E, 27, 54, 13 IgG2a afucosylated, 13hIgG1 wild-type and 13LALA-PG (seattle genetics); JS006 (shanghai jun shi bio-medical science and technology gmbh); anti-TIGIT Fc and bispecific antibodies PD1 x TIGIT (xenocor), antibody clones VSIG9#1 (VSIG 9.01) and 258-CS1#4 (# 4) (yisong Research Development ltd, university Of Hebrew (diabetes Research Development Company Of The Hebrew University Of Hebrew University)); 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 (Yuhan Co, ltd.); anti-zB 7R1 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 selected from the group consisting of: tenerriuzumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domfanalimab (AB 154), vibrizumab (MK-7684), and SEA-TGT (SGN-TGT). ASP874 (PTZ-201) is an anti-TIGIT monoclonal antibody described in PCT publication No. WO2018183889A1 and U.S. patent publication No. 2020/0095324. BGB-a1217 is an anti-TIGIT antibody as described in PCT publication No. WO2019129261 A1. BMS-986207 (ONO-4686) is an anti-TIGIT 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 antibody as described in PCT publication No. WO2018033798A1 and U.S. patent nos. 10,213,505 and 10,124,061. IBI939 is an anti-TIGIT antibody as described in PCT publication No. WO2020020281 A1. EOS884448 (EOS-448) is an anti-TIGIT antibody described in WO2019023504A1 in PCT publication. Domvan alimab (AB 154) is an anti-TIGIT monoclonal antibody as described in PCT publication No. WO2017152088A1 and U.S. patent No. 10,537,633. Wiborlizumab (MK-7684) is an anti-TIGIT antibody 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. SEA-TGT (SGN-TGT) is an anti-TIGIT antibody as described in PCT publication No. WO2020041541A2 and U.S. patent publication No. 2020/0062859.

In some embodiments, the anti-TIGIT antagonist antibody is tegraleigh immuzumab (CAS accession No. 1918185-84-8). Tirayleigh itumumab (genetaike corporation) is also known as MTIG7192A, RG6058 or RO7092284. The tireylauezumab is an anti-TIGIT antagonist monoclonal antibody described in PCT publication nos. WO2003072305A8, WO2004024068A3, WO2004024072A3, WO2009126688A2, WO2015009856A2, WO2016011264A1, WO2016109546A2, WO2017053748A2 and WO2019165434A1, and U.S. patent publication nos. US 9873756/0044256, 2017/0037127, 2017/0145093, 2017/260594, 2017/0088613, 2018/010175, 2019/0119376, and U.S. patent nos. US9873740B2, US10626174B2, US10611836B2, US9499596B2, US 31331350B 2, US10047158B2 and US10017572B 2.

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 six CDRs of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises six CDRs of any one of the antibodies selected from the group consisting of Teyleryitumumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domonalizab (AB 154), veborlizumab (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 comprises a light chain variable region (VL) of the same antibody. In some embodiments, the anti-TIGIT antibody comprises the VH and VL of an anti-TIGIT antibody selected from the group consisting of tenerriitumumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domonalimab (AB 154), vibrizumab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises a heavy chain and a light chain of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises a heavy chain and a light chain of an anti-TIGIT antibody selected from the group consisting of Teyleryitumumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domonalizab (AB 154), wiborlizumab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, an anti-TIGIT antagonist antibody according to any one of the embodiments described herein can bind any feature described in section C below, alone or in combination.

PD-1 axis binding antagonists

Provided herein are methods for treating cancer in a subject (e.g., a human), the method comprising administering to the subject an effective amount of a PD-1 axis binding antagonist. The PD-1 axis binding antagonists can include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist can be used.

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 the binding of PD-L1 to PD-1. In still other cases, the PD-L1 binding antagonist inhibits the binding of PD-L1 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 can be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some cases, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK 041). 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 TIM 3. In some cases, the small molecule is a compound described in WO 2015/033301 and WO 2015/033299.

In some cases, the PD-L1 binding antagonist is an anti-PD-L1 antibody. Various anti-PD-L1 antibodies are contemplated and described herein. In any case herein, the isolated anti-PD-L1 antibody can bind to human PD-L1, e.g., human PD-L1 as set forth in UniProtKB/Swiss-Prot accession No. Q9NZQ7-1, or a variant thereof. In some cases, it is possible to use,the anti-PD-L1 antibody is capable of inhibiting 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 selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') ₂ Antibody fragments of the group consisting of 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 include alemtuzumab, MDX-1105, MEDI4736 (Dewaruzumab), MSB0010718C (Avermentimab), SHR-1316, CS1001, envollizumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cachilizumab, lodalizumab, 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 invention and methods of making the same are described in international patent application publication No. WO 2010/077634 and U.S. patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

In some cases, an anti-PD-L1 antibody (e.g., atlizumab) comprises at least one, two, three, four, five, or six HVRs selected from: (a) the HVR-H1 sequence is GFTFSDSWIH (SEQ ID NO: 20); (b) The HVR-H2 sequence is AWISPYGGSTYYADSVKG (SEQ ID NO: 21); (c) HVR-H3 sequence is RHWGGFDY (SEQ ID NO: 22), (d) HVR-L1 sequence is RASQDVSTAVA (SEQ ID NO: 23); (e) HVR-L2 sequence is SASFLYS (SEQ ID NO: 24); and (f) the HVR-L3 sequence is QQYLLYHPAT (SEQ ID NO: 25).

In some cases, the anti-PD-L1 antibody comprises:

(a) HVR-H1, HVR-H2 and HVR-H3 sequences, which are SEQ ID NO: 20. SEQ ID NO:21 and SEQ ID NO:22, and

(b) HVR-L1, HVR-L2 and HVR-L3 sequences, which are SEQ ID NO: 23. SEQ ID NO:24 and SEQ ID NO:25.

in some cases, the anti-PD-L1 antibody (atelizumab) comprises heavy and light chain sequences, wherein: (a) the heavy chain Variable (VH) region sequence comprises the amino acid sequence:

<xnotran> EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 26); </xnotran> And (b) a light chain Variable (VL) region sequence comprising the amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR(SEQ ID NO：27)。

in some cases, the anti-PD-L1 antibody (atelizumab) comprises heavy and light chain sequences, wherein: (ii) (a) the heavy chain comprises the amino acid sequence:

<xnotran> EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 28); </xnotran> And (b) the light chain comprises the amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO：29)。

in some cases, the anti-PD-L1 antibody comprises (a) a VH domain comprising an amino acid sequence identical to SEQ ID NO:26 (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity), or an amino acid sequence comprising the sequence of SEQ ID NO:47, sequence; (b) a VL domain comprising a sequence identical to SEQ ID NO:27 (e.g., at least 95%, 96%, 97%, 98%, or 99%) or an amino acid sequence comprising a sequence of SEQ ID NO:48, or a sequence of SEQ ID NO; or (c) a VH domain as described in (a) and a VL domain as described in (b). In one embodiment, the anti-PD-L1 antibody comprises atelizumab comprising: (a) SEQ ID NO:28, and (b) the heavy chain amino acid sequence of SEQ ID NO:29, light chain amino acid sequence of seq id no.

In some cases, the anti-PD-L1 antibody is avizumab (CAS registry No.: 1537032-82-8). Avermectin, 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 de Waiumab (CAS registry No.: 1428935-60-7). Dewaruzumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 kappa anti-PD-L1 antibody (MedImmune, aslicon) described in WO 2011/066389 and US 2013/034559.

In some cases, the anti-PD-L1 antibody is MDX-1105 (beware beauty). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874.

In some cases, the anti-PD-L1 antibody is LY3300054 (lilay).

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 conning jerry corporation (Suzhou Alphamab)). KN035 is a single domain antibody (dAB) generated from a camelid phage display library.

In some cases, the anti-PD-L1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates the antibody antigen-binding domain to cause it to bind its antigen, e.g., by removing the non-binding spatial moiety. 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 (e.g., three heavy chain HVRs and three light chain HVRs) and/or a heavy chain variable domain and a light chain variable domain from an anti-PD-L1 antibody described in: US 20160108123, WO 2016/000619, WO 2012/145493, U.S. patent No. 9,205,148, WO 2013/181634, or WO 2016/061142.

In a still further specific aspect, the anti-PD-L1 antibody has reduced or minimal effector function. In a further specific aspect, the minimal effector function results from "should-not-be Fc-mutated" or aglycosylation-free mutations. In still further cases, the null effector Fc mutation is an N297A or D265A/N297A substitution in the constant region. In still further cases, the null effector Fc mutation is an N297A substitution in the constant region. In some cases, the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is usually N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid other than proline, are recognition sequences for enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Thus, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid (most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used). Glycosylation sites can be conveniently removed from the antibody by altering the amino acid sequence to remove one of the above-mentioned tripeptide sequences (for N-linked glycosylation sites). Variations may be made by substituting an asparagine, serine, or threonine residue within a glycosylation site for another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

PD-1 binding antagonists

In some cases, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some cases, a PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. In some cases, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In other cases, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In still other cases, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. The PD-1 binding antagonist can be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some cases, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence)). 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 (Pierre Fabre/Aurigene). See, e.g., 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 can bind 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 selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') ₂ Antibody fragments of the group consisting of fragments. In some cases, the anti-PD-1 antibody is a humanized antibody. In other cases, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pabolizumab, MEDI-0680, PDR001 (sibatuzumab), REGN2810 (cimaprimab), BGB-108, palonolizumab, carpilizumab, sedilizumab, tirezumab, tereprizumab, dolaprimab, refelimab, sarastimab, peraprimab, CS1003, HLX10, SCT-I10A, sepiolizumab, batilizumab, garuzumab, 754091, cetilizumab, YBL-006, BAT1306, HX008, breglizumab, AMG 404, CX-188, JTX-4014, 609A, sym021, LZM, STI 520, SG001, AM0001, um ENUM 244C8, 388 um end D4, ha-1110, AK-103, and b21.

In some cases, the anti-PD-1 antibody is nivolumab (CAS registry number: 946414-94-4). Nivolumab (Beckman Meishibaobao/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558 and

is an anti-PD-1 antibody as described in WO 2006/121168.

In some cases, the anti-PD-1 antibody is palboclizumab (CAS registry number: 1374853-91-4). Pabolilizumab (Merck), also known as MK-3475, merck 3475, pembrolizumab, SCH-900475, and

is an anti-PD-1 antibody as described in WO 2009/114335.

In some cases, the anti-PD-1 antibody is MEDI-0680 (AMP-514; aslicon). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is PDR001 (CAS registry number 1859072-53-9; nowa). 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 (baiji, usa).

In some cases, the anti-PD-1 antibody is BGB-a317 (baiji, usa).

In some cases, the anti-PD-1 antibody is JS-001 (shanghai kaffir lii). 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 incsar-1210 (Incyte). INCSFR-1210 is a human IgG4 anti-PD-1 antibody.

In some cases, the anti-PD-1 antibody is PF-06801591 (pfeiffer).

In some cases, the anti-PD-1 antibody is TSR-042 (also known as ANB011; 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 (acoustic biological Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits the function of PD-1 without preventing the binding of PD-L1 to PD-1.

In some cases, the anti-PD-1 antibody is ENUM 388D4 (acoustic biological Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits binding of PD-L1 to PD-1.

In some cases, the anti-PD-1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and/or a heavy chain variable domain and a light chain variable domain from an anti-PD-1 antibody described in: WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769, WO2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 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.

In a still further specific aspect, the anti-PD-1 antibody has reduced or minimal Fc-mediated effector function. In yet another specific aspect, the minimal Fc-mediated effector function is from a "null effector Fc mutation" or aglycosylation mutation. In still further cases, the null effector Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some cases, the isolated anti-PD-1 antibody is aglycosylated.

PD-L2 binding antagonists

In some cases, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some cases, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partner. In a specific aspect, the PD-L2 binding ligand partner is PD-1. The PD-L2 binding antagonist can be, but is not limited to, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a 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 can bind 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 selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') ₂ Antibody fragments of the group consisting of fragments. In some cases, the anti-PD-L2 antibody is a humanized antibody. In other casesThe anti-PD-L2 antibody is a human antibody. In a further specific aspect, the anti-PD-L2 antibody has reduced or minimal effector function. In a further specific aspect, the minimal effector function results from "null effector Fc mutations" or aglycosylation mutations. In still further cases, the null effector Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some cases, the isolated anti-PD-L2 antibody is aglycosylated.

PD-1 axis binding antagonists (e.g., atelizumab) useful in the present invention, including compositions comprising such molecules, can 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 one of the above, alone or in combination with features as described in section C below.

C. Antibody formats and characteristics

1. Affinity of antibody

In certain instances, the dissociation constant (K) of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist antibody (e.g., 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 _D ) Is ≤ 1 μ M, ≦ 100nM, ≦ 10nM, ≦ 1nM, ≦ 0.1nM, ≦ 0.01nM, or ≦ 0.001nM (e.g., 10 nM) ^-8 M or less, e.g. 10 ^-8 M to 10 ^-13 M, e.g. 10 ^-9 M to 10 ^-13 M)。

In one example, K is measured by a radiolabeled antigen binding assay (RIA) _D . In one example, the RIA is performed using a Fab form of the antibody of interest and its antigen. For example, by titration with a minimum concentration in the presence of a series of unlabeled antigens: ( ¹²⁵ I) The solution binding affinity of the Fab to the antigen was measured by equilibration of the Fab with labeled antigen and then capture of the bound antigen with an anti-Fab antibody coated plate (see, e.g., chen et al, j.mol.biol.293:865-881 (1999)). To determine the conditions for the assay, capture anti-Fab antibodies (Cappel Labs) were coated with 5. Mu.g/ml in 50mM sodium carbonate (pH 9.6)

The plate (Thermo Scientific) was blocked overnight, then for two to five hours at room temperature (about 23 ℃) with 2% (w/v) bovine serum albumin in PBS. In the non-adsorption plate (Nunc # 269620), mixing 100pM or 26pM ¹²⁵ I]Mixing of antigen with serial dilutions of Fab of interest (e.g., following assessment of anti-VEGF antibodies (Fab-12) in Presta et al, cancer Res.57:4593-4599 (1997)). Then incubating the target Fab overnight; however, incubation may be continued for a longer period of time (e.g., about 65 hours) to ensure equilibrium is reached. Thereafter, the mixture is transferred to a capture plate for incubation at room temperature (e.g., one hour). The solution was then removed and used with 0.1% polysorbate 20 in PBS

The plate was washed eight times. When the plates had dried, 150. Mu.l/well of scintillator (MICROSCINT-20) was added ^TM (ii) a Packard) and in TOPCOUNT ^TM The gamma counter (Packard) counts the plate for tens of minutes. The concentration of each Fab that gave less than or equal to 20% maximal binding was selected for use in a competitive binding assay.

According to another case, use

Surface plasmon resonance measurement of K _D . For example, use

-2000 or

-3000 (BIAcore, inc., piscataway, NJ) was assayed in-10 Response Units (RU) at 25 ℃ with an immobilized antigen CM5 chip. In one case, carboxymethylated dextran biosensor chips (CM 5, BIACORE, inc.) were activated with N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to supplier's instructions. Antigen was diluted to 5. Mu.g/ml (about 0.2. Mu.M) with 10mM sodium acetate pH 4.8, followed by injection at a flow rate of 5. Mu.L/min toApproximately 10 Response Units (RU) of conjugated protein were obtained. After injection of the antigen, 1M ethanolamine was injected to block unreacted groups. For kinetic measurements, polysorbate 20 (TWEEN-20) was injected at a rate of about 25. Mu.l/min at 25 ℃ in a volume of 0.05% ^TM ) Two-fold serial dilutions (0.78 nM to 500 nM) of Fab in PBS of surfactant (PBST). Using a simple one-to-one Langmuir binding model: (

Evaluation Software version 3.2) for calculating association rates (k) by simultaneous fitting of association and dissociation sensor maps _on ) And dissociation rate (k) _off ). Equilibrium dissociation constant (K) _D ) Is calculated as the ratio k _off /k _on . See, e.g., chen et al, j.mol.biol.293:865-881 (1999). If the association rate exceeds 10 as determined by the above surface plasmon resonance ⁶ M ¹ s ¹ The rate of association can then be determined by using a fluorescence quenching technique, e.g., in a spectrometer such as an Aviv Instruments or 8000 series SLM-AMINCO ^TM The increase or decrease in fluorescence emission intensity (excitation =295nM; emission =340nm, band pass at 1691m) of 20nM anti-antigen antibody (Fab form) in PBS pH 7.2 at 25 ℃ was measured in a spectrophotometer (ThermoSpectronic) with a stirred cuvette in the presence of increasing concentrations of antigen.

2. Antibody fragments

In certain instances, an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) provided herein is an antibody fragment. Antibody fragments include, but are not limited to, fab '-SH, F (ab') ₂ Fv, and scFv fragments, as well as other fragments described below. For a review of certain antibody fragments, see Hudson et al, nat. Med.9:129-134 (2003). For reviews on scFv fragments see, for example, pluckth ü n in The pharmacolgy of Monoclonal Antibodies, vol.113, rosenburg and Moore eds. (Springer-Verlag, new York), pp.269-315 (1994); see also WO 93/16185; and U.S. Pat. No. 5,571,894 and 5,587,458. See U.S. Pat. No. 5,869,046 for a discussion of Fab and F (ab') 2 fragments that contain salvage receptor binding epitope residues and have increased half-life in vivo.

Diabodies are antibody fragments with 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). Trisomy and tetrasome antibodies are also described in Hudson et al, nat. Med.9:129-134 (2003).

A single domain antibody is an antibody fragment comprising all or part of a heavy chain variable domain or all or part of a 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, e.g., U.S. Pat. No. 6,248,516B1).

Antibody fragments can be prepared by a variety of techniques, including but not limited to proteolytic digestion of intact antibodies and production by recombinant host cells (e.g., e.coli or phage), as described herein.

3. Chimeric and humanized antibodies

In certain instances, an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) provided herein is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Pat. No. 4,816,567 and Morrison et al, proc.natl.acad.sci.usa,81:6851-6855 (1984). In one example, a chimeric antibody comprises non-human variable regions (e.g., variable regions derived from a mouse, rat, hamster, rabbit, or non-human primate (such as a monkey)) and human constant regions. In another example, a chimeric antibody is a "class switch" antibody in which the class or subclass has been altered from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In certain examples, the chimeric antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Typically, humanized antibodies comprise one or more variable domains in which HVRs, e.g., CDRs (or portions thereof), are derived from a non-human antibody and FRs (or portions thereof) are derived from a human antibody sequence. The humanized antibody optionally will also comprise at least a portion of a human constant region. In some examples, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

Humanized antibodies and methods for their preparation are described, for example, in Almagro and Fransson, front.biosci.13:1619-1633 (2008), and further described, for example, in Riechmann et al, nature 332:323-329 (1988); queen et al, proc.nat' l acad.sci.usa 86:10029-10033 (1989); U.S. Pat. nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; kashmiri et al, methods 36:25-34 (2005) (specificity determining region (SDR) transplantation is described); padlan, mol.immunol.28:489-498 (1991) (described as "surface remodeling"); dall' Acqua et al, methods 36:43-60 (2005) (described for "FR shuffling"); and osbaum et al, methods 36:61-68 (2005) and Klimka et al, br.J. cancer,83:252-260 (2000) (describing the "guided selection" method for FR shuffling).

Human framework regions that may be used for humanization include, but are not limited to: framework regions selected using the "best fit" method (see, e.g., sims et al, J.Immunol.151:2296 (1993)); the framework regions of consensus sequences of human antibodies derived from a particular subset of light or heavy chain variable regions (see, e.g., carter et al, proc. Natl. Acad. Sci. USA,89 4285 (1992); and Presta et al, J.Immunol.,151 (1993)); human mature (somatic mutation) framework regions or human germline framework regions (see, e.g., almagro and Fransson, front. Biosci.13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., baca et al, J.biol. Chem.272:10678-10684 (1997) and Rosok et al, J.biol. Chem.271:22611-22618 (1996)).

4. Human antibodies

In certain instances, an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, cutt. 368-74 (2001) and Lonberg, curr. Opin. Immunol.20:450-459 (2008).

Human antibodies can be made by: the immunogen is administered to a transgenic animal that has been modified to produce a fully human antibody or a fully antibody with human variable regions in response to antigen challenge. Such animals typically contain all or part of a human immunoglobulin locus that replaces an endogenous immunoglobulin locus, or is present extrachromosomally or randomly integrated into the chromosome of the animal. In such transgenic mice, the endogenous immunoglobulin loci have typically been inactivated. For an overview of the method for obtaining human antibodies from transgenic animals, see Lonberg, nat. Biotech.23:1117-1125 (2005). See also, for example, the description of XENOMOUSE ^TM U.S. Pat. nos. 6,075,181 and 6,150,584 to technology; description of the invention

U.S. Pat. nos. 5,770,429; description of K-M

U.S. Pat. No. 7,041,870 to the Art, and description

U.S. patent application publication No. US 2007/0061900) of the art. The human variable regions from intact antibodies produced by such animals may be further modified, for example by combination with different human constant regions.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human hybrid myeloma cell lines for the production of human monoclonal antibodies have been described. (see, 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 Boemer et al, J.Immunol.,147, 86 (1991); human antibodies produced via human B-cell hybridoma technology are also like Li et al, proc.Natl.Acad. Sci.USA,103:3557-3562 (2006). Additional methods include, for example, those described in U.S. Pat. No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, xiandai Mianyixue,26 (4): 265-268 (2006) (human-human hybridomas are described). Human hybridoma technology (Trioma technology) is also 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 produced by isolating Fv clone variable domain sequences selected from a human phage display library. 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. Antibodies derived from libraries

anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies and/or anti-PD-1 antagonist antibodies) of the invention can be isolated by screening combinatorial libraries for antibodies having the desired activity. For example, various methods are known in the art for generating phage display libraries and screening such libraries to obtain antibodies with desired binding characteristics. Such Methods are described, for example, in Hoogenboom et al, methods in Molecular Biology 178:1-37 (O' Brien et al, eds., human Press, totowa, NJ, 2001) and are further described, for example, in McCafferty et al, nature 348:552 to 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, repertoires of VH and VL genes are individually cloned by Polymerase Chain Reaction (PCR) and randomly recombined in a phage library, from which antigen-binding phage can then be screened, as described in Winter et al, ann. 433-455 (1994). Phage typically display antibody fragments as single chain Fv (scFv) fragments or Fab fragments. Libraries from immunized sources provide high affinity antibodies to the immunogen without the need to construct hybridomas. Alternatively, all natural components (e.g., all natural components from humans) can be cloned to provide a single source of antibodies to a wide range of non-self antigens and self antigens without any immunization, as in Griffiths et al, EMBO J,12:725-734 (1993). Finally, natural libraries can also be made by: cloning unrearranged V gene segments from stem cells; and using PCR primers containing random sequences to encode the highly variable CDR3 regions and complete in vitro rearrangement, as described by Hoogenboom and Winter, j.mol.biol.,227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Pat. No. 5,750,373, and U.S. 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 (e.g., anti-PD-L1 antagonist antibodies) or antibody fragments isolated from a human antibody library are considered herein as human antibodies or human antibody fragments.

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 (e.g., an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) of the present invention are contemplated. As described in detail herein, the anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies) can be optimized based on the 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 prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into, 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, provided that the final construct possesses the desired characteristics, e.g., antigen binding.

I. Substitution, insertion and deletion variants

In certain instances, anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies) variants having one or more amino acid substitutions are provided. Sites of interest for substitution mutations include HVRs and FRs. Conservative substitutions are shown under the heading "preferred substitutions" in table 3. More substantial changes are provided under the heading "exemplary substitutions" of table 3 and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the product screened for a desired activity (e.g., retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC).

TABLE 3 exemplary and preferred amino acid substitutions

Amino acids can be grouped according to common side chain properties:

(1) Hydrophobicity; norleucine, met, ala, val, leu, ile;

(2) Neutral hydrophilicity: cys, ser, thr, asn, gln;

(3) Acidity: asp and Glu;

(4) Alkalinity: his, lys, arg;

(5) Residues affecting chain orientation: gly, pro;

(6) Aromatic: trp, tyr, phe.

Non-conservative substitutions will require the exchange of a member of one of these classes for another.

One type of substitution variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Typically, one or more resulting variants selected for further study will be altered (e.g., improved) in certain biological properties (e.g., increased affinity, decreased immunogenicity) and/or will substantially retain certain biological properties of the parent antibody relative to the parent antibody. Exemplary substitution variants are affinity matured antibodies, which can be conveniently generated, for example, using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

For example, HVRs can be altered (e.g., substituted) to improve antibody affinity. Such changes may occur in HVR "hot spots", i.e., residues encoded by codons that undergo high frequency mutations during somatic maturation (see, e.g., chowdhury, methods mol. Biol.207:179-196 (2008)) and/or residues that are contacted with antigen (to test the binding affinity of the resulting variant VH or VL). Affinity maturation by construction and re-selection from secondary libraries has been described, for example, in Hoogenboom et al, methods in Molecular Biology 178:1-37 (O' Brien et al eds., human Press, totowa, NJ, (2001)). In some examples of affinity maturation, diversity is introduced into variable genes selected for maturation purposes by any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide directed mutagenesis). A secondary library is then created. The 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 (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. In particular CDR-H3 and CDR-L3 are frequently targets.

In certain examples, substitutions, insertions, or deletions may occur within one or more HVRs, so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative changes that do not substantially reduce binding affinity (e.g., conservative substitutions as provided herein) may be made in HVRs. Such changes may be outside of the antigen contacting residues of the HVRs. In certain instances of the variant VH and VL sequences provided above, each HVR remains unchanged, or comprises no more than one, two, or three amino acid substitutions.

A method that can be used to identify antibody residues or regions that can be targeted for mutagenesis is referred to as "alanine scanning mutagenesis" such as Cunningham and Wells (1989) Science,244: 1081-1085. In this method, a residue or set of target residues (e.g., charged residues such as Arg, asp, his, lys, and Glu) is identified and replaced with a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. Additional substitutions may be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively or additionally, the crystal structure of the antigen-antibody complex is used to identify the contact points between the antibody and the antigen. Such contact residues and adjacent residues that are candidates for substitution may be targeted or eliminated. Variants can be screened to determine if they possess the desired properties.

Amino acid sequence insertions include amino and/or carboxyl terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of one or more amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include fusions to the N-terminus or C-terminus of an antibody of an enzyme (e.g., for ADEPT) or polypeptide that increases the serum half-life of the antibody.

Glycosylation variants

In certain instances, an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) of the invention can be altered to increase or decrease the degree of antibody glycosylation. Addition or deletion of glycosylation sites to an anti-TIGIT antagonist antibody and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody) of the invention can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

When the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Natural antibodies produced by mammalian cells typically comprise bi-antennary oligosaccharides with a branched chain, typically attached through an N-bond to Asn297 of the CH2 domain of the Fc region. See, for example, wright et al TIBTECH 15:26-32 (1997). Oligosaccharides can include a variety of carbohydrates, for example, mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some cases, the oligosaccharides in the antibodies of the invention are modified to produce antibody variants with certain improved properties.

In one instance, an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody) variant is provided that has a carbohydrate structure that lacks fucose linked (directly or indirectly) to an Fc region. For example, the content of fucose in such antibodies may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose at Asn297 in the sugar chain relative to the sum of all sugar structures attached to Asn297 (e.g., complex, hybrid and high mannose structures) as determined by MALDI-TOF mass spectrometry, as described in WO 2008/077546. Asn297 refers to the asparagine residue at about position 297 in the Fc region (EU numbering of Fc region residues); however, due to minor sequence variations in antibodies, asn297 may also be located approximately ± 3 amino acids upstream or downstream of position 297, i.e. between positions 294 and 300. Such fucosylated variants may have improved ADCC function. See, e.g., U.S. patent publication No. US 2003/0157108 (Presta, l.); US 2004/0093621 (Kyowa Hakko Kogyo Co., ltd.). Reference to "defucosylated" or "fucosyldeficient" antibody variants includes: 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 defucosylated antibodies include protein fucosylation deficient Lec13 CHO cells (Ripka et al Arch. Biochem. Biophys.249:533-545 (1986); U.S. patent application Ser. No. US 2003/0157108A 1, presta, L; and WO 2004/056312A 1, adams et al, especially example 11), and knock-out cell lines, such as alpha-1, 6-fucosyltransferase gene (FUT 8) knock-out CHO cells (see, e.g., yamane-Ohnuki et al Biotech. Bioeng.87:614 (2004); kanda, Y. Et al, biotechnol. Bioeng.,94 (4): 680-688 (2006); and WO 2003/085107).

In view of the above, in some cases, the methods of the invention comprise administering to the subject an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tenellitituzumab)) and/or a PD-1 axis binding antagonist antibody comprising a deglycosylation site mutation (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab) or an anti-PD-1 antagonist antibody) variant in the context of a fractionated, up-dosing regimen. In some cases, the deglycosylation site mutation reduces the effector function of the antibody. In some cases, the deglycosylation 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 residue 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 aspect, the substitution mutation is N297A.

The anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody or anti-PD-1 antagonist antibody) variant is further provided with bisected oligosaccharides, e.g., wherein the biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Mairet et al), U.S. Pat. No. 6,602,684 (Umana et al), and US 2005/0123546 (Umana et al). Also provided are antibody variants having at least one galactose residue in an oligosaccharide linked to an Fc region. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997/30087 (Patel et al); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

Fc region variants

In certain instances, one or more amino acid modifications are introduced into the Fc region of an anti-TIGIT antagonist (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tirayleigh itumumab) antibody and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody (e.g., attritumab) or an anti-PD-1 antagonist antibody) of the invention, thereby producing an Fc region variant (see, e.g., US 2012/0251531). The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, igG2, igG3, or IgG4Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions.

In certain instances, the invention contemplates anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) variants that have some, but not all, effector functions, which make them desirable candidates for use, where the in vivo half-life of the antibody is important, while certain effector functions (such as complement and ADCC) are unnecessary or detrimental. In vitro and/or in vivo cytotoxicity assays may be performed to confirm the reduction/depletion of CDC and/or ADCC activity. For example, fc receptor (FcR) binding assays may be performed to ensure that the antibody lacks fcyr binding (and therefore may lack ADCC activity), but retains FcRn binding ability. Primary cells that mediate ADCC, NK cells, express only Fc (RIII, whereas monocytes express Fc (RI, fc (both RII and Fc (FcR expression on RIII. Hematopoietic cells are summarized in table 3 on page 464 of ravatch and Kinet, annu. Rev. Immunol.9:457-492 (1991); non-limiting examples of in vitro assays for assessing ADCC activity of molecules of interest are described in U.S. Pat. nos. 5,500,362 (see, e.g., hellstrom, i.et al proc.nat 'l acad.sci.usa 83-7063 (1986)) and Hellstrom, i.et al proc.nat' l acad.sci.usa 82 uggemann, m, et al, j.exp.med.166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be employed (see, e.g., ACTI for flow cytometry) ^TM Non-radioactive cytotoxicity assay (CellTechnology, inc. Mountain View, CA); and CYTOTOX

Non-radioactive cytotoxicity assay (Promega, madison, WI)). Useful effector cells for such assays include Peripheral Blood Mononuclear Cells (PBMC) and Natural Killer (NK) cells. Alternatively or additionally, the methods may be used, for example, in a system such as described in Clynes et al, proc.nat' l acad.sci.usa 95: the ADCC activity of the molecule of interest was assessed in vivo in an animal model disclosed in 652-656 (1998). A C1q binding assay may also be performed to confirm that the antibody is unable to bind C1q and therefore lacks CDC activity. See, e.g., the C1q and C3C binding ELISAs in WO 2006/029879 and WO 2005/100402. To assess complement activation, CDC assays can be performed (see, e.g., gazzano-Santoro et al J.Immunol. Methods 202 (1996); cragg, M.S. et al blood.101:1045-1052 (2003); and Cragg, M.S. and M.J.Glennie blood.103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life assays may also be performed using methods known in the art (see, e.g., petkova, s.b. et al, int' l.immunol.18 (12): 1759-1769 (2006)).

Antibodies with reduced effector function include those with substitutions of one or more 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 acids 265, 269, 270, 297 and 327, including so-called "DANA" Fc mutants in which residues 265 and 297 are substituted with alanine (U.S. Pat. nos. 7,332,581 and 8,219,149).

In certain instances, the proline at position 329 of the wild type human Fc region in the antibody is substituted with glycine or arginine or a sufficiently large amino acid residue to disrupt the proline sandwich within the Fc/Fc γ receptor interface formed between proline 329 of Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII (Sondermann et al: nature 406, 267-273 (20 jul.2000)). In certain instances, the antibody comprises at least one further amino acid substitution. In one instance, the further amino acid substitution is S228P, E233P, L234A, L235E, N297A, N297D or P331S, and in yet another instance, the at least one additional amino acid substitution is L234A and L235A of a human IgG1Fc region or S228P and L235E of a human IgG4Fc region (see, e.g., US 2012/0251531), and in yet another instance, the at least one additional amino acid substitution is L234A and L235A and P329G of a human IgG1Fc region.

Certain antibody variants with improved or reduced binding to FcR are described. ( See, e.g., U.S. Pat. nos. 6,737,056; WO 2004/056312; and Shields et al, j.biol.chem.9 (2): 6591-6604 (2001). )

In certain instances, an antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).

In some cases, alterations are made in the Fc region that result in altered (i.e., improved or reduced) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. nos. 6,194,551, WO 99/51642, and Idusogie et al j.immunol.164:4178-4184 (2000).

Antibodies with extended half-life and improved neonatal Fc receptor (FcRn) binding, responsible 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). Those antibodies comprise an Fc region having one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include Fc variants having substitutions at one or more of the following 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 434, for example, a substitution of residue 434 of the Fc region (U.S. Pat. No. 7,371,826).

For further examples of Fc region variants, see also: duncan and Winter, nature 322:738-40 (1988); U.S. Pat. nos. 5,648,260; U.S. Pat. nos. 5,624,821; and WO 94/29351.

In some aspects, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tenellulomuzumab) and/or an anti-PD-L1 antagonist antibody (e.g., atelizumab) comprises an Fc region comprising an N297G mutation (EU numbering).

In some cases, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumumab tiuxetan) and/or a PD-1 axis binding antagonist antibody (e.g., an anti-PD-L1 antagonist antibody (e.g., atelizumab) or an anti-PD-1 antagonist antibody) comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from the first CH1 (CH 1) and the second CH1 (CH 1) domain ₁ ) Domain, first CH2 (CH 2) ₁ ) Domain, first CH3 (CH 3) ₁ ) Domain, second CH1 (CH 1) ₂ ) Domain, second CH2 (CH 2) ₂ ) A domain and a second CH3 (CH 3) ₂ ) A domain. In some cases, at least one of the one or more heavy chain constant domain(s) is paired with another heavy chain constant domain. In some cases, CH3 ₁ And CH3 ₂ Each domain comprises a protuberance or a cavity, and wherein CH3 ₁ The protrusions or cavities in the domains may be positioned at CH3, respectively ₂ In cavities or protrusions in the domains. In some cases, CH3 ₁ And CH3 ₂ The domains meet at an interface between the protuberance and the cavity. In some cases, CH2 ₁ And CH2 ₂ Each of the domains comprises a protuberance or a cavity, and wherein CH2 ₁ The protrusions or cavities in the structural domains may be positioned at CH2, respectively ₂ In cavities or protrusions in the domains. In other cases, CH2 ₁ And CH2 ₂ The domains meet at the interface between the protuberance and the cavity. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) and/or the anti-PD-L1 antagonist antibody (e.g., altlizumab) is an IgG1 antibody.

Cysteine engineered antibody variants

In certain instances, it is desirable to generate cysteine engineered anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies), such as "thiomabs," in which one or more residues of the antibody are substituted with a cysteine residue. In particular examples, the substituted residue is present at an accessible site of the antibody. As further described herein, the reactive thiol groups are positioned at accessible sites of the antibody by substituting those residues with cysteine, and can be used to conjugate the antibody to other moieties (such as a drug moiety or linker-drug moiety) to produce an immunoconjugate. In some cases, any one or more of some of the residues are substituted with cysteine: v205 of the light chain (Kabat numbering); a118 of the heavy chain (EU numbering); and S400 of the heavy chain Fc region (EU numbering). Cysteine engineered antibodies can be produced, for example, as described in U.S. Pat. No. 7,521,541.

V. antibody derivatives

In certain instances, the anti-TIGIT antagonist antibodies of the invention (e.g., anti-TIGIT antagonist antibodies (e.g., tenellulomab) or variants thereof) and/or PD-1 axis binding antagonist antibodies of the invention (e.g., anti-PD-L1 antagonist antibodies of the invention (e.g., attlizumab or variants thereof)) provided herein are further modified to contain additional non-protein moieties known and readily available in the art. Moieties suitable for derivatization of the antibody include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers) and dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde can have advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may or may not have branches. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular property or function of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, and the like.

In another example, a conjugate of an antibody and a non-proteinaceous moiety that can be selectively heated by exposure to radiation is provided. In one example, the non-proteinaceous moiety is a carbon nanotube (Kam et al, proc.natl.acad.sci.usa 102. The radiation can be of any wavelength and includes, but is not limited to, wavelengths that are not harmful to normal cells, but that heat the non-proteinaceous part to a temperature at which cells proximal to the antibody-non-proteinaceous part are killed.

Recombinant production method

anti-TIGIT antagonist antibodies of the invention (e.g., anti-TIGIT antagonist antibodies disclosed herein, e.g., ibritumomab tiuxetan) and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies (e.g., atelizumab) or anti-PD-1 antagonist antibodies) can be produced using recombinant methods and compositions, e.g., as described in U.S. patent No. 4,816,567, which is incorporated by reference herein in its entirety.

For recombinant production of anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies), the nucleic acid encoding the antibody is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of an antibody).

Suitable host cells for cloning or expressing the antibody-encoding vector include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, particularly when glycosylation and Fc effector function are not required. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523. (see also Charlton, methods in Molecular Biology, volume 248 (compiled by B.K.C.Lo., humana Press, totowa, NJ, 2003), pp 245-254, which describes the expression of antibody fragments in E.coli.) the antibody can be isolated from the bacterial cell paste after expression in a soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast, including fungal and yeast strains, whose glycosylation pathways have been "humanized", resulting in the production of antibodies with partially or fully human glycosylation patterns, are suitable cloning or expression hosts for vectors encoding antibodies. See 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 cells and insect cells. A number of baculovirus strains have been identified which can be used with insect cells, particularly for transfecting Spodoptera frugiperda cells.

Plant cell cultures may also be used as hosts. See, e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (PLANTIBODIIES for antibody production in transgenic plants is described ^TM A technique).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for growth in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney lines (293 or 293 cells as described, for example, in Graham et al, J.Gen Virol.36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (TM 4 cells, as described, e.g., in Mather, biol. Reprod.23:243-251 (1980)); monkey kidney cells (CV 1); VERO cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); buffalo rat hepatocytes (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor cells (MMT 060562); TRI cells (as described, for example, in Mather et al, annals N.Y.Acad.Sci.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 4216 (1980)); and myeloma cell lines such as Y0, NS0, and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., yazaki and Wu, methods in Molecular Biology, volume 248 (b.k.c.lo, humana Press, totowa, NJ), pages 255-268 (2003).

Immunoconjugates

Also provided are immunoconjugates comprising an anti-TIGIT antagonist antibody (e.g., tegralyleitumumab) and/or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab) or an anti-PD-1 antagonist antibody (e.g., paribrizumab)) as disclosed herein conjugated to one or more cytotoxic agents such as a chemotherapeutic agent or drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or a fragment thereof), or a radioisotope for use or method described herein.

In some cases, the immunoconjugate is an antibody-drug conjugate (ADC) in which the antibody is conjugated to one or more drugs, including but not limited to maytansinoids (see U.S. Pat. nos. 5,208,020, 5,416,064, and european patent EP 0 425 235 B1); auristatins, such as monomethyl auristatin drug moiety DE and DF (MMAE and MMAF) (see U.S. Pat. nos. 5,635,483 and 5,780,588 and 7,498,298); dolastatin; calicheamicin or derivatives thereof (see U.S. Pat. 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 daunorubicin or doxorubicin (see Kratz et al, current Med. Chem.13:477-523 (2006); jeffrey et al, bioorganic & Med. Chem. Letters 16; methotrexate; vinblastine; taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel and otaxel (ortataxel); trichothecene and CC1065.

In another instance, the immunoconjugate comprises an anti-TIGIT antagonist antibody (e.g., tirayleigh immuzumab) or PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atuzumab)) as described herein conjugated to an enzymatically active toxin or fragment thereof, including, but not limited to, diphtheria a chain, non-binding active fragments of diphtheria toxin, exotoxin a chain (from pseudomonas aeruginosa), ricin a chain, abrin a chain, modeccin a chain, alpha-hypoxanthine, erythrin, dianilin protein (dianthin protein), pokeweed protein (phytola americana protein) (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcumin, crotin, saporin, grass inhibitor, gelatin, serin (ocellin), restrictocin, enomycin, and trichothecene.

In another instance, the immunoconjugate comprises an anti-TIGIT antagonist antibody as described herein (e.g., ibritumomab tiuxetan) and/or a PD-1 axis binding antagonist as described herein (e.g., an anti-PD-L1 antagonist antibody) (e.g., atelizumab) conjugated to a radioactive atom to form a radioconjugate. A variety of radioisotopes are available for making 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 may contain a radioactive atom for scintigraphic studies, e.g. tc99m or I123, or a spin label for Nuclear Magnetic Resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese orIron.

Conjugates of the antibody and cytotoxic agent may be prepared using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), 4- (N-maleimidomethyl) cyclohexane-1-carboxylate succinimidyl ester (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipate hydrochloride), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis- (p-diazoniumbenzoyl) -ethylenediamine), diisocyanates (such as toluene 2, 6-diisocyanate), and bis-active fluorine compounds (such as 1, 5-difluoro-2, 4-dinitrobenzene). For example, the ratio of Vittta et al, science 238:1098 (1987) ricin immunotoxins were prepared as described. Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotides to antibodies. See WO94/11026. The linker may be a "cleavable linker" that facilitates the release of the cytotoxic drug in the cell. For example, acid labile linkers, peptidase sensitive linkers, photolabile linkers, dimethyl linkers, or disulfide-containing linkers can be used (Chari et al, cancer Res.52:127-131 (1992); U.S. Pat. No. 5,208,020).

Immunoconjugates or ADCs herein expressly contemplate, but are not limited to, such conjugates prepared with a cross-linking agent, including, but not limited to, commercially available (e.g., 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) benzoate).

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 viltin-enfratuzumab or govietzetuzumab-shaxituzumab.

D. Chemotherapeutic agents

1. Platinum chemotherapeutic agents

Platinum-based chemotherapeutic agents include organic compounds that contain platinum as an integral part of the molecule. Typically, the platinum-based chemotherapeutic agent is a coordination complex of platinum. Agents include, but are not limited to, carboplatin, cisplatin, and oxaliplatin.

Platinum-based chemotherapeutic agents, such as cisplatin, carboplatin, oxaliplatin, and satraplatin (Staraplatin), are widely used antineoplastic agents that cause DNA crosslinking as a single adduct, an interchain crosslink, an intrachain crosslink, or a DNA protein crosslink. Platinum chemotherapeutics typically act on the adjacent N-7 position of guanine to form 1,2 intrachain crosslinks ((Poklar et al (1996). Proc. Natl. Acad. Sci. U.S.A.93 (15): 7606-11; rudd et al (1995). Cancer Chemotherm. Pharmacol.35 (4): 323-6).) the resulting crosslinks inhibit DNA repair and/or DNA synthesis in Cancer cells.

Carboplatin is an exemplary platinum coordination compound for use in the methods described herein. The chemical name of carboplatin is diammine [1, 1-cyclobutanedicarboxy (2-) -O, O' ] -platinum, (SP-4-2), and carboplatin has the following structural formula:

carboplatin is a crystalline powder of the formula C6H12N2O4Pt and has a molecular weight of 371.25. It is dissolved in water at a rate of about 14mg/mL and the pH of the 1% solution is 5 to 7. It is practically insoluble in ethanol, acetone and dimethylacetamide. Carboplatin predominantly produces interchain DNA cross-links, a role that is cell cycle non-specific. Carboplatin can be referred to by the trade name

BIOCARN, BLASTOCARB, BLASTOPLATIN, CARBOKEM, CARBOMAX, CARBOPA, CARBOPLAN, CARBOTEEN, CARBOTINAL, CYTOCARB, DUCARB, KARPLAT, KEMOCARB, NAPROPLAT, NEOPLATIN, NICARBO, ONCOCARBIN, TEVACARB, WOMASTIN, etc. are commercially available.

Another exemplary platinum chemotherapeutic agent useful in the methods of the present invention is cisplatin, which has the following structure:

2. non-platinum chemotherapeutic agents

Non-platinum chemotherapeutic agents are another class of chemotherapeutic agents that may be used as part of the methods, uses, and compositions described herein. Exemplary non-platinum chemotherapeutic agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., doxorubicin, etoposide, teniposide, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331), alkylating agents (e.g., cyclophosphamide), and taxanes (e.g., paclitaxel (e.g., nanoparticle-albumin bound (nab) -paclitaxel), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or ataxel).

3. Antimetabolites

Antimetabolites interfere with and inhibit endogenous (normal) metabolic processes within (all or part of) cells (e.g., 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 following structure:

in some cases, pemetrexed may be administered as part of the methods of the invention. Pemetrexed has the following structure:

4. topoisomerase II inhibitors

Inhibitors of topoisomerase II (e.g., etoposide (VP-16), teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, and HU-331) are also widely used antineoplastic agents that stabilize the topoisomerase IEDNA covalent complex (i.e., the "lytic complex") after formation of enzyme-mediated DNA breaks. Accumulation of such lytic complexes induces cell death pathways.

Anthracyclines are a type of topoisomerase II inhibitor extracted from streptomyces. Examples include doxorubicin (adriamycin), daunorubicin (daunorubicin), epirubicin, idarubicin, daunorubicin (rhodomycin), pirarubicin, valrubicin (valrubicin), N-trifluoroacetyl doxorubicin-14-pentanoic acid, aclarubicin, morpholino doxorubicin (morpholino-DOX), cyanomorpholino doxorubicin (cyanomorpholino-DOX), 2-pyrrolino doxorubicin (2-PDOX), 5-iminodaunorubicin, mitoxantrone, and aclarubicin a (aclarubicin)). In some embodiments, the anthracyclines are administered in combination with an alkylating agent, e.g., doxorubicin in combination with cyclophosphamide (treatment with AC).

Doxorubicin

Are exemplary topoisomerase II inhibitors for use in the methods described herein. Its chemical name is 10- [ (3-amino-2, 3, 6-trideoxy-alpha-L-lysu-hexopyranoside) oxy]7,8,9, 10-tetrahydro-6, 8, 11-trihydroxy-8- (2-hydroxyacetyl) -1-methoxy- (8S, 10S) -5, 12-naphthalenedione. Doxorubicin has the following structure:

etoposide is an exemplary topoisomerase II inhibitor for use in the methods described herein. Etoposide is usually administered as a prodrug etoposide phosphate with a chemical name: 4 '-demethylepipodophyllotoxin 9- [4,6-O- (R) -ethylidene-D-glucopyranoside ],4' (dihydrogen phosphate).

Etoposide phosphate has the following structure:

etoposide phosphate, i.e. the phosphate ester of etoposide, is a semisynthetic derivative of podophyllotoxin, which is converted to etoposide by dephosphorylation. Etoposide induces DNA strand breaks by interacting with DNA topoisomerase II or forming free radicals, leading to cell cycle arrest (primarily in the G2 phase of the cell cycle) and cell death. Etoposide can be used as

TOPOSAR ^TM 、VP-16、

ACTITOP, ASIDE, BIOPOSIDE, CTOP, CYTOP, EPOSED, ESIDE, ETHOPUL, ETOLON, ETONIS, ETOPLAST, ETOSID, ETOVEL, FYTOP, FYTOSID, LASTET, NZYTOP, ONCOSIDE, PLACID, POSID, RETOPSON, TEVASIDE, TOPOK, TOPOSIDE and the like are commercially available.

5. Taxane derivatives

Taxanes are chemotherapeutic agents that can bind to tubulin, promote microtubule assembly, and stabilize and/or prevent microtubule depolymerization. Included herein are taxanes including the taxane class of 10-deacetylbaccatin III and/or derivatives thereof. Exemplary taxanes include, but are not limited to, paclitaxel (i.e.,

CAS # 33069-62-4), docetaxel (i.e.,

CAS # 114977-28-5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or oraxaxel. In some embodiments, the taxane is an albumin-coated nanoparticle (e.g., nab-paclitaxel, i.e., paclitaxel)

And/or nab-docetaxel, ABI-008). In some embodiments, the taxane is nab-paclitaxel

In some embodiments, the taxane is formulated in

In (e.g.,

) And/or tween such as polysorbate 80 (e.g.,

). In some embodiments, the taxane is a liposome-encapsulated taxane. In some embodiments, the taxane is a prodrug form and/or a conjugated form of the taxane (e.g., DHA covalently conjugated to paclitaxel, polyglutamic acid paclitaxel, and/or linoleyl carbonate-paclitaxel). In some embodiments, paclitaxel is formulated to be substantially free of surfactant (e.g., in the absence of CREMAPHOR and/or tween, such as

Paclitaxel).

In some cases, paclitaxel is administered as part of the methods of the invention. Paclitaxel may have the following structure:

in some cases, the method or use comprises administering nano-albumin bound (nab) -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, but are not limited to, cyclophosphamide, 1, 3-bis (2-chloroethyl) -1-nitrosourea, 1, 4-butanediol disulfonate, (2S) -2-amino-3- {4- [ bis (2-chloroethyl) amino ] phenyl } propanoic acid, 3- (2-chloroethyl) -2- [ (2-chloroethyl) amino ] tetrahydro-2H-1, 3, 2-oxazaphosphine 2-oxide, and 1- (2-chloroethyl) -3-cyclohexyl-1-nitrosourea. In some embodiments, the alkylating agent is cyclophosphamide. Cyclophosphamide may have the following structure:

it will be appreciated by those skilled in the art that any of the above chemotherapeutic agents may be administered in various forms, for example, in salt form, which is considered to be part of the present invention.

E. Exemplary colony stimulating factors

Colony stimulating factors are proteins that stimulate cell proliferation. Colony stimulating factors include G-CSF (e.g., pegylated filgrastim or filgrastim) and GM-CSF (e.g., sargrastim). In some embodiments, the colony stimulating factor is G-CSF (e.g., pegylated filgrastim or filgrastim). In some embodiments, the G-CSF is pegylated filgrastim. In some embodiments, the G-CSF is filgrastim. In some embodiments, the colony stimulating factor is GM-CSF (e.g., sargramostim). In some embodiments, the GM-CSF is sargrastim.

F. Exemplary VEGF antagonists

The present invention provides VEGF antagonists that are useful for treating cancer in a subject (e.g., a human). The VEGF antagonists of the invention include any molecule that is capable of binding to, reducing the level of expression of, or neutralizing, blocking, inhibiting, abrogating, reducing or interfering with the biological activity of VEGF. Exemplary human VEGF is identified in UniProtKB/Swiss-Prot accession number 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 referred to as "rhuMab VEGF" or

Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody produced according to Presta et al (Cancer Res.57:4593-4599, 1997). It comprises a mutated humanIgG1 framework regions and antigen binding complementarity determining regions from the murine anti-hVEGF monoclonal antibody A.4.6.1 that block binding of human VEGF to its receptor. About 93% of the amino acid sequence of bevacizumab, including most of the framework regions, is derived from human IgG1, and about 7% of the sequence is derived from the murine antibody a4.6.1. Bevacizumab has a molecular mass of about 149,000 daltons and is glycosylated. Bevacizumab and other humanized anti-VEGF antibodies are further described in U.S. patent No. 6,884,879, granted on 26/2/2005, the entire disclosure of which is expressly incorporated herein by reference. 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.

Other preferred antibodies include the G6 or B20 series of antibodies (e.g., G6-31, B20-4.1), as described in PCT application publication No. WO 2005/012359. For other preferred antibodies, see U.S. Pat. nos. 7,060,269, 6,582,959, 6,703,020, 6,054,297; WO98/45332; WO 96/30046; WO94/10202; EP 0666868B1; U.S. patent application publication nos. 2006009360, 20050186208, 20030206899, 20030190317, 20030203409, and 20050112126; and Popkov et al (Journal of Immunological Methods 288. Other preferred antibodies include antibodies that bind to a functional epitope on human VEGF that comprises residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103, and C104, or alternatively, residues F17, Y21, Q22, Y25, D63, 183, and Q89.

In other cases, the VEGF antagonist is an anti-VEGFR 2 antibody or related molecule (e.g., ramucirumab (ramucirumab), tanibirumab, aflibercept); anti-VEGFR 1 antibodies or related molecules (e.g., irkumab (icrucumab), aflibercept (VEGF Trap-Eye;

) Or ziv-aflibercept (VEGF Trap;

) ); bispecific VEGF antibodies (e.g. MP-0250, vanucizumab (VEGF-ANG 2) or bispecific as disclosed in US 2001/0236388 Antibodies); a bispecific antibody comprising a combination of two of anti-VEGF, anti-VEGFR 1, and anti-VEGFR 2 arms; anti-VEGFA antibodies (e.g., bevacizumab, sevacizumab); anti-VEGFB antibodies; anti-VEGFC antibodies (e.g., VGX-100); anti-VEGFD antibody; or a non-peptide small molecule VEGF antagonist (e.g., pazopanib (pazopanib), axitinib (axitinib), vandetanib (vandetanib), regoranib (stivarga), cabozantinib (cabozantinib), lenvatinib (1 envatinib), nintedanib (nintedanib), olanzanib (orantinib), teratinib (telatinib), dovitinib (dovitinig), cediranib (cediranib), motesanib (motesanib), sultinib (sulfatitinib), apatinib (atiginib), fornicinib (foretinib), famitinib (famitinib), or tivozanib (tivozanib)).

In a further aspect, an anti-VEGF antagonist (e.g., an anti-VEGF antibody (e.g., bevacizumab)) according to any of the above, alone or in combination, can bind the features described above in section C.

G. Additional therapeutic agents

Additional therapeutic agents useful in the invention (e.g., in combination with anti-TIGIT antagonist antibodies) include therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (b:)

Gene tack); cetuximab (A), (B)

Imclone); panitumumab (A)

Ann (Amgen)), rituximab (a), (b), (c), and (d)

Genes Tak/Baijianfidi (Biogen Idec)), pertuzumab (b.p.)

2C4, gene Tak), trastuzumab (

Gene tacg), tositumomab (Bexxar, corixia) and antibody drug conjugate gemtuzumab ozomicin (r) ((r)

Hewlett packard). Other humanized monoclonal antibodies with therapeutic potential in combination with the compounds include: <xnotran> (apolizumab), , , , (bivatuzumab mertansine), (cantuzumab mertansine), (cedelizumab), (certolizumab pegol), (cidfusituzumab), (cidtuzumab), , (eculizumab), (efalizumab), (epratuzumab), (erlizumab), (felvizumab), (fontolizumab), , (inotuzumab ozogamicin), , (1 abetuzumab), , , , , (motovizumab), , , (nolovizumab), (numavizumab), (ocrelizumab), , , (pascolizumab), (pecfusituzumab), (pectuzumab), (pexelizumab), (ralivizumab), , (reslivizumab), (reslizumab), (resyvizumab), (rovelizumab), (ruplizumab), , , (Sontuzumab), </xnotran> Texizumab (tacatuzumab tetraxetan), taduzumab (tadocizumab), talilizumab, texizumab (tefibuzumab), tollizumab (toralizumab), simon interleukin (tutututuzumab), tucuxizumab (tucusituzumab), umalizumab (umalizumab), umbuzumab, uitlizumab (umelizumab), uitlizumab (tuque: (tuque) (tussimab)), (tutuximab) usekinumab), viclizumab, and anti-interleukin-12 (ABT-874/J695, hui's research and yapei laboratory) (anti-interleukin-12 is a recombinant human unique sequence full-length IgG1 λ antibody genetically modified to identify interleukin-12 p40 protein).

Therapeutic antibodies also include antibodies that bind to EGFR. Examples of antibodies that bind to EGFR include Mab 579 (ATCC CRL HB 8506), mab 455 (ATCC CRL HB 8507), mab 225 (ATCC CRL 8508), mab 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533,mendelsohn et al) and variants thereof, such as chimeric 225 (C225 or cetuximab;

) And remodeled human 225 (H225) (see, WO 96/40210, imclone Systems Inc.); IMC-11F8, a fully human antibody targeting EGFR (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or panitumumab (see WO98/50433, annix (Abgenix)/Amgen); EMD 55900 (Straglioto et al Eurcancer 32A 636-640 (1996)); EMD7200 (matuzumab), a humanized EGFR antibody directed against EGFR, competes with EGF and TGF- α for binding to EGFR (EMD/Merck); human EGFR antibody, huMax-EGFR (GenMab); fully human antibodies, designated E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and e7.6.3 and described in US 6,235,883; MDX-447 (Medarex Inc.); and mAb 806 or humanized mAb 806 (Johns et al, j.biol. Chem.279 (29): 30375-30384 (2004)). An anti-EGFR antibody can be conjugated to a cytotoxic agent to produce an immunoconjugate (see, e.g., ep659,439a2, merck Patent GmbH).

Additional therapeutic agents that can be used in the methods, compositions, and uses provided herein include agents that target co-inhibitory targets (e.g., CTLA-4, LAG3, TIM3, BTLA, and/or VISTA), such as CTLA-4 antagonists, e.g., anti-CTLA-4 antagonist antibodies (e.g., ipilimumab)

) (ii) a Agents that target co-stimulatory targets (e.g., CD226, OX-40, CD28, CD27, CD137, HVEM, and/or GITR); radiotherapy; an anti-angiogenic agent; an apoptotic agent; and anti-tubulin agents.

Pharmaceutical compositions, formulations and kits

Any of the anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies or anti-PD-1 antagonist antibodies), VEGF antagonists, chemotherapeutic agents (e.g., platinum-based chemotherapeutic agents (e.g., carboplatin or cisplatin) and non-platinum-based chemotherapeutic agents (e.g., alkylating agents (e.g., cyclophosphamide), taxanes (e.g., paclitaxel, e.g., nab-paclitaxel) and/or topoisomerase II inhibitors (e.g., doxorubicin))), ADCs (e.g., viltine-enrotuzumab or gavitin-sarcertuzumab), and/or CSFs (e.g., pegylated filgrastim, filgrastim or sargrastim) described herein can be used in pharmaceutical compositions and formulations. anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies), VEGF antagonists, one or more chemotherapeutic agents, ADCs (e.g., vilanteritumumab or govitegran-shaxituzumab), and/or CSFs (e.g., pegylated filgrastim, filgrastim or sargrastim) can be prepared by mixing one, two, three, four or more than four agents of desired purity with one or more optional Pharmaceutical carriers (Remington's Pharmaceutical Sciences 16 th edition, oso, a. Eds. (1980)) in lyophilized formulations or in aqueous solution. Pharmaceutically acceptable carriers are generally non-toxic to subjects at the dosages and concentrations used, and include, but are not limited to: buffers such as phosphates, citrates and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic Linear 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 (e.g., zinc protein complexes); and/or a non-ionic surfactant, such as polyethylene glycol (PEG). Exemplary pharmaceutical carriers herein also include interstitial drug dispersing agents such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), e.g., human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 (r: (r))

Baxter International, inc.). Certain exemplary shasegps and methods of use, including rHuPH20, are described in U.S. patent publication nos. 2005/0260186 and 2006/0104968. In one aspect, the sHASEGP is combined with one or more additional glycosaminoglycanases (such as chondroitinase).

Exemplary lyophilized antibody formulations are described in U.S. Pat. No. 6,267,958. Aqueous antibody formulations include those described in U.S. Pat. No. 6,171,586 and WO 2006/044908, the latter formulations comprising histidine-acetate buffer.

An exemplary alemtuzumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20, and sucrose, at pH 5.8. For example, atuzumab may be provided in a 20mL vial containing 1200mg of atuzumab formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821.6 mg) at a pH of 5.8. In another example, alemtuzumab may be provided in a 14mL vial containing 840mg of alemtuzumab formulated in glacial acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) at a pH of 5.8.

An exemplary formulation of tenecteityluzumab comprises a histidine solution comprising polysorbate 20, sucrose, L-methionine and WFI. The tenecteuzumab may be provided in a 15mL vial containing 10mL of the tenecteuzumab drug product, with an approximate concentration of the tenecteuzumab antibody of 60mg/mL.

The formulations herein may also contain more than one active ingredient necessary for the particular indication being treated, preferably active ingredients having complementary activities that do not adversely affect each other. For example, it may be desirable to further provide additional therapeutic agents. Such active ingredients are suitably present in combination in an amount effective for the intended purpose.

The active ingredient may be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively); in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules); or in a coarse emulsion. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16 th edition, osol, A. Eds (1980).

Sustained release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. The formulations to be used for in vivo administration are generally sterile. For example, sterility can be readily achieved by filtration through sterile filtration membranes.

The invention provides kits comprising, for example, 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 described herein.

In another embodiment of the invention, a kit is provided that includes, for example, 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 described herein. In some cases, the kit further comprises a PD-1 axis binding antagonist. In some cases, the article of manufacture or kit further comprises a package insert comprising instructions for using the anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist to treat or delay progression of cancer (e.g., in a patient).

In another embodiment of the invention, a kit is provided that includes 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 described 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 treating or delaying progression of cancer in a patient using a PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody (e.g., ibritumomab tiuxetan).

In another embodiment, the kit comprises tenecteuzumab for use in combination with atezumab to treat a subject with cancer according to any of the methods described herein. In some embodiments, the kit further comprises atelizumab. In some cases, the article of manufacture or kit further comprises a package insert comprising instructions for using the teneuizumab in combination with atelizumab to treat or delay progression of cancer in a patient.

In another embodiment, the kit comprises atelizumab for use in combination with tenecteuzumab to treat a subject having cancer according to any of the methods described herein. In some embodiments, the kit further comprises ibritumomab tiuxetan. In some cases, the article of manufacture or kit further comprises a package insert comprising instructions for using the atelizumab in combination with the tenestriuzumab to treat or delay the progression of cancer in a patient.

In some cases, the PD-1 axis binding antagonist and the TIGIT antagonist antibody are in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The container may be formed from a variety of materials, for example, glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloys (such as stainless steel or hastelloy). In some cases, the container contains a formulation and a label on or associated with the container may indicate instructions for use. The article of manufacture or kit may also 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 other agents (e.g., additional chemotherapeutic agents and antineoplastic agents). Suitable containers for one or more reagents include, for example, bottles, vials, bags, and syringes.

In some embodiments, a kit comprising a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody further comprises a VEGF antagonist, a chemotherapeutic (e.g., a platinum-based chemotherapeutic or a non-platinum-based chemotherapeutic), an ADC (e.g., vildagliptin or govittakang-shacetuzumab), and/or a CSF (e.g., pegylated filgrastim, or sargrastim).

Any of the PD-1 axis binding antagonists and/or anti-TIGIT antagonist antibodies described herein can be included in an article of manufacture or a kit. Any article of manufacture or kit can include instructions for administering a PD-1 axis binding antagonist and/or an anti-TIGIT antagonist antibody to a subject according to any method described herein.

VI. Examples

TABLE 4 table of contents of examples

The following are examples of the process of the present invention. It is to be understood that various other embodiments may be practiced given the general description provided above.

Example 1A phase Ia/Ib, open label, dose escalation study for safety and pharmacokinetics of tirayleigh Uuzumab administered as a single agent and in combination with atlas-Uzumab with or without chemotherapy in patients with locally advanced or metastatic tumors

This study evaluated the safety, PK, pharmacodynamics and primary anti-tumor activity of tirayleigh immuzumab (MTIG 7192A) in patients with locally advanced or metastatic tumors when administered as a single drug (phase Ia) or administered in combination with atuzumab with or without chemotherapy (phase Ib). The specific goals of the study and the corresponding endpoints are summarized in table 5 below.

TABLE 5 target and endpoint

A. Design of research

This is a phase I open label, multicenter, global, dose escalation study conducted for the first time in humans aimed at assessing safety, tolerance and PK of ibritumomab tiuxetan as a single drug in patients with locally advanced, recurrent or metastatic incurable tumors for which standard therapy is not present, has proven ineffective or intolerant or is deemed inappropriate, or for which clinical trials of study agents are recognized as standard of care. The present study also aims to make it possible to assess the safety, tolerability and PK of ibrinouzumab when administered with altuzumab, with or without chemotherapy, in patients with locally advanced, recurrent or metastatic incurable tumors for which standard therapy is not present, has proven ineffective or intolerant or is deemed inappropriate, or for which clinical trials of study agents are recognized as standard of care, or for which clinical trials of study agents in combination with anti-PD-L1 antibodies are considered as an acceptable treatment option.

FIG. 1 is a flow chart showing the extension of phase Ib chemotherapy and the extension of phase Ib Q4W dosing. In the dose escalation phase, cohorts of approximately 3 to 6 patients were each evaluated at escalating dose levels to determine the MTD or Maximum Administered Dose (MAD) of tirayleigh unizumab as a single drug or in combination with atuzumab.

In the dose expansion phase, patients were enrolled and treated with tirayleigh itumumab at or below MTD or MAD as a single agent (phase Ia) or in combination with atuzumab with or without chemotherapy (phase Ib). Tirayleigh immuzumab is administered as a single drug (phase Ia) or in combination with atuzumab (phase Ib cohort, not with chemotherapy) by IV infusion on day 1 of each 21-day cycle or day 1 of each 28-day cycle (phase Ib Q4W dose extension), wherein in the phase Ib cohort not with chemotherapy, tirayleigh immuzumab is administered before atuzumab. In the absence of unacceptable toxicity or clinically convincing evidence of disease progression, use of tirayleigh mab (phase Ia) or a combination of tirayleigh mab and atuzumab (phase Ib) continued after cycle 1 based on the investigator's favorable assessment of benefit and risk.

In the phase Ib chemotherapy extension cohort and the phase Ib Q4W dose extension cohort (fig. 1), the safety import of 3 patients was completed. IMC and researchers thoroughly review all relevant safety data from the safety imports before proceeding to the cohort.

In the chemotherapy expansion cohort, tegraleigh itumumab and atelizumab were combined with specific chemotherapy regimens in each of three cohorts: in cohort a, carboplatin or cisplatin and pemetrexed; in cohort B, carboplatin and paclitaxel; and cohort C, carboplatin or cisplatin and etoposide (see figure 1). In each cohort, treatment included an induction phase and a maintenance phase. During the induction phase, the combination of tirayleigh immuzumab and atuzumab was administered with chemotherapy by IV infusion over a 21 day period, with cohorts a and B for 4 total 6 cycles and cohort C for 4 cycles. The number of cycles of induction treatment for cohorts a and B was determined by the investigator as appropriate.

After the induction period, patients who have not experienced disease progression or unacceptable toxicity continue to be treated with maintenance therapy. During the maintenance period, patients in cohorts B and C continued to use only tirayleigh immuzumab and atelizumab, while patients in cohort a continued to use tirayleigh immuzumab and atelizumab with pemetrexed. In all chemotherapy expansion cohorts, atelizumab was administered prior to tegraleigh immuzumab. When chemotherapy is given, chemotherapy is administered after alemtuzumab and tiryleiguzumab.

All patients were closely monitored for adverse events throughout the study and at least 90 days after the last dose of study treatment or until (whichever occurred first) before another systemic anti-cancer therapy was initiated. Adverse events were graded according to NCI CTCAE version 4.0.

To characterize the PK profile, immunogenic response and pharmacodynamic effects of tirayleigh immuzumab as a single agent (phase Ia) or in combination with atelizumab with or without chemotherapy (phase Ib), blood samples were taken at different time points before and after dosing. Depending on the results of the mid-phase PK analysis, the frequency of PK sampling may be reduced at the later stage of the study.

Patients underwent tumor assessments at screening and during the study, which were measured by standard solid tumor efficacy assessment (RECIST) v1.1 criteria. Even if the RECIST v1.1 disease progression criteria are met in the phase Ia or Ib portion of the study, the patient may still be allowed to continue study treatment, provided that the patient meets the criteria for continued treatment. Patients who terminated phase Ia portion of the study may be allowed to shift to phase Ib portion of the study and receive treatment with a combination of teneuizumab and atuzumab provided they met the cross criteria and agreed to biopsy accessible lesions.

Approximately 60 to 320 patients with locally advanced, recurrent or metastatic incurable malignancies who have progressed after standard therapy is available are included in the extended cohort of studies; or for these patients, standard therapy has proven ineffective or intolerable, or is considered inappropriate; or clinical trials investigating agents are recognized as standard of care for these patients. For the phase Ib portion of the study, patients for whom clinical trials of study agents in combination with anti-PD-L1 antibodies with or without chemotherapy were considered acceptable treatment options may be included in the expanded cohort.

This extended phase includes a defined patient cohort to better characterize the safety, tolerability, PK variability, pharmacodynamic activity and primary anti-tumor activity of tiprayleigh mab as a single agent (phase Ia) or in combination with atuzumab (phase Ib) with or without chemotherapy in a specific cancer setting. The cohort of the expanded cohort was initiated at selected dose levels of MAD or MTD at or below that of tiprayleigh unizumab as a single agent (phase Ia) or in combination with atuzumab (phase Ib) with or without chemotherapy, as determined by the investigator of the study based on assessment of accumulated safety, tolerance, PK, pharmacodynamic and anti-tumor activity data.

In phase Ia portion of the study, up to about 40 patients were enrolled in a planned expanded cohort that included a variety of tumor indications of PD-L1 selection and/or TIGIT selection, including NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC (including GEJ cancer), UBC, and CRC (including MSS or MSI-Low CRC).

In phase Ib portion of the study (not with chemotherapy), approximately 20 to 40 patients were included in each of the following planned, indication-specific extended cohorts: NSCLC: initial treatment (e.g., no prior treatment with anti-PD-L1/PD-1) of Cancer Immunotherapy (CIT); NSCLC: undergoing CIT treatment (e.g., including prior treatment with anti-PD-L1/PD-1); RCC; TNBC; melanoma; HNSCC; OC; GC, including GEJ cancer; UBC; CRC, including MSS or MSI-Low CRC; biopsy cohorts for specific tumor indications (including melanoma, OC, RCC, and UBC).

In the phase Ib chemotherapy extension of the study, approximately 20 to 40 patients were enrolled in each of the following planned chemotherapy extension cohorts (see fig. 1):

and a queue A:

induction phase-atelizumab and tiryleleuuzumab with

Combination of cisplatin or carboplatin and pemetrexed

Maintenance phase-alemtuzumab and tirylereuuzumab with

Pemetrexed

And a queue B:

-induction phase-atelizumab and tenellulomuzumab and

carboplatin and paclitaxel combination

Maintenance phase-atelizumab and tirayleigh Euzumab

And a queue C:

-induction phase-atelizumab and tenellulomuzumab and

cisplatin or carboplatin and etoposide combination

Maintenance phase-attrituzumab and ibritumomab tiuxetan

The treatment combinations in each cohort are shown in table 6.

TABLE 6 treatment regimens in chemotherapy extended cohort

Phase ib chemotherapy extended cohort: administration and administration

During the induction phase, patients in a particular chemotherapy extended cohort received the following:

cohort A received 1200mg IV of atuzumab, followed by 600mg IV of ibritumumab tiuxetan, followed by 75mg/m cisplatin on day 1 of each 21-day cycle ² IV or carboplatin 6mg/mL min AUC IV and pemetrexed 500mg/m ² And (IV) combinations thereof. Four to six cycles of induction phase therapy were performed without disease progression or unacceptable toxicity.

Cohort B received 1200mg IV of atuzumab, followed by 600mg IV of ibritumomab tiuxetan, followed by 6mg/mL min AUC IV of carboplatin with 200mg/m paclitaxel on day 1 of each 21-day cycle ² And (IV) combination. Four to six cycles of induction phase therapy were performed without disease progression or unacceptable toxicity.

Cohort C received 1200mg IV of atuzumab, then 600mg IV of ibritumumab tiuxetan, followed by 75mg/m2 IV of cisplatin or 5mg/mL min IV of carboplatin AUC on days 1 to 3 of each 21 day cycle, and then 100mg/m of etoposide on days 1 to 3 of each 21 day cycle ² And IV. Four cycles of induction without disease progression or unacceptable toxicityAnd (4) treating.

After the induction period, in the absence of unacceptable toxicity, clinically convincing disease progression, and/or loss of clinical benefit, the investigator decides to continue treatment in the maintenance period as appropriate after careful evaluation and full discussion of potential risks and benefits with the patient. During the maintenance phase, patients in a particular chemotherapy extended cohort receive the following:

cohort a received atelizumab 1200mg IV on day 1 of each 21 day cycle, followed by tirayleigh itumumab 600mg IV, followed by pemetrexed 500mg/m ² IV; cohort B received 1200mg IV of atuzumab followed by 600mg IV of ibriturinitumumab on day 1 of each 21-day cycle; cohort C received 1200mg IV of atuzumab followed by 600mg IV of ibritumumab tiuxetan on day 1 of each 21-day cycle.

If a toxic event occurs but there is no disease progression, the individual chemotherapeutic or immunotherapeutic agents are terminated separately.

Extended cohort of Q4W administrations in stage c.ib

The phase Ib Q4W dosing extended cohort was targeted to better characterize safety, tolerability, PK and preliminary efficacy data and explore potential tumor biomarkers of pharmacodynamic activity in patients treated with the tiryleigh itumumab 840mg IV in combination with atuzumab 1680mg IV in a dosing schedule every 4 weeks (28 days).

The phase Ib Q4W cohort included approximately 20 to 40 tumor patients who could be PD-L1 selected and/or TIGIT selected based on prospective testing of tumor tissue during screening or rescreening. If the medical inspector deems this to be the case based on discussion with the researcher, then patients with insufficient or unavailable archival organization may be eligible for enrollment in the cohort. Patients with tumor types for which clinical trials of study agents in combination with anti-PD-L1 antibodies are considered acceptable treatment options can be included in these extended cohorts.

Additional inclusion criteria for patients in each of the extended, indication-specific cohorts of stage Ib

The NSCLC cohort (initial treatment with CIT) includes patients with histologically confirmed incurable advanced NSCLC who have not been previously treated with CIT (studied or approved), including anti-PD-L1/PD-1 and/or anti-CTLA-4, for which clinical trials of study agents in combination with anti-PD-L1 antibodies are considered acceptable treatment options if CIT (including anti-PD-L1/PD-1 agents) is approved by local regulatory agencies for use as a treatment for NSCLC. Patients whose tumors have known sensitizing Epidermal Growth Factor Receptor (EGFR) mutations must also have undergone disease progression (during or after treatment) or be intolerant to treatment with EGFR tyrosine kinase inhibitors. Patients whose tumors have a known Anaplastic Lymphoma Kinase (ALK) rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ALK tyrosine kinase inhibitors. Patients whose tumors have a known ROS1 rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ROS1 tyrosine kinase inhibitors. Patients whose tumors have a known mutation in BRAFV600E must also have undergone disease progression (during or after treatment) or be intolerant to treatment with dabrafenib in combination with trametinib.

The NSCLC cohort (treated with CIT) included patients with histologically confirmed incurable advanced NSCLC who had been previously treated with CIT (studied or approved), including anti-PD-L1/PD-1. Patients whose tumors have known sensitizing EGFR mutations must also have undergone disease progression (during or after treatment) or be intolerant to treatment with EGFR tyrosine kinase inhibitors. Patients whose tumors have a known ALK rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ALK tyrosine kinase inhibitors. Patients whose tumors have a known ROS1 rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ROS1 tyrosine kinase inhibitors. Patients whose tumors have a known mutation in BRAFV600E must also have undergone disease progression (during or after treatment) or be intolerant to treatment with dabrafenib in combination with trametinib. Patients must have experienced recorded disease progression during CIT monotherapy and/or combination therapy (studied or approved), which must include prior anti-PD-L1/PD-1.

At least about 10 patients who experienced the best response to the record of confirmed PR or CR according to investigator evaluation of RECIST v1.1 at any time when receiving prior anti-PD-L1/PD-1 as monotherapy or combination therapy may be enrolled. At least about 10 patients who experienced the best response according to record of SD assessed by investigators of RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or combination therapy may be enrolled. At least about 10 patients who experienced a recorded best response to disease Progression (PD) as assessed by researchers at RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or combination therapy may be enrolled. Previous anti-PD-L1/PD-1 as monotherapy and/or as combination therapy must represent the latest systemic anti-cancer therapy administered prior to enrollment in this extended cohort. Patients who terminated prior anti-PD-L1/PD-1 monotherapy and/or combination therapy, primarily due to toxicity or intolerance, did not meet this extended cohort entry condition.

The TNBC cohort included patients with histologically confirmed incurable, advanced Estrogen Receptor (ER) negative, progesterone receptor (PgR) negative, and human EGFR 2 (HER 2) negative breast adenocarcinoma (triple negative). The triple negative status must be recorded as defined by the american society for clinical oncology, american college of pathologists (ASCO-CAP) guidelines: < 1% of the tumor cells immunoreact with ER and < 1% of the tumor cells immunoreact with progesterone receptor, and the HER2 test indicates IHC 1+, IHC 0, or In Situ Hybridization (ISH) negativity

The CRC cohort included patients with histologically confirmed incurable advanced colon or rectal adenocarcinoma. Patients with tumors of appendiceal origin are not eligible.

The GC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic, or recurrent gastric or GEJ adenocarcinomas, not amenable to curative therapy. Patients with type 1 GEJ tumors (defined by rudiger Siewert et al (2000) as distal esophageal adenocarcinoma) with tumor centers within 1 to 5cm above the anatomical esophagogastric junction met the criteria for study participation. Patients with esophageal cancer (squamous cell carcinoma or adenocarcinoma) may be eligible after discussion with a medical inspector. Patients whose tumors are HER2 positive must also have undergone disease progression (during or after treatment) or be intolerant to treatment with HER2 targeting antibodies/HER 2 inhibitors. HER2 positivity is defined as IHC 3+ or IHC 2+/ISH + (where ISH positivity is defined as HER2: CEP17 ratio ≧ 2) as assessed by local laboratory testing for primary tumors or metastatic lesions. Patients with tumors of unknown HER2 status may still be eligible because of insufficient tissue or unavailability (e.g., archiving and/or biopsy) without HER2 testing.

The HNSCC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic, recurrent or persistent head and neck squamous cell carcinoma (oral, oropharyngeal, hypopharyngeal or laryngeal), not amenable to curative treatment. Patients with HNSCC from any other primary anatomical site of the head and neck, patients with HNSCC of unknown primary, or patients with non-squamous histological tumors are not eligible. Patients with nasopharyngeal HNSCC may be eligible. The HPV status of HNSCC must be known.

The UBC cohort includes patients with histologically confirmed incurable advanced urothelial transitional cell carcinoma (including renal pelvis, ureter, bladder and urethra). Patients with mixed histology are required to have a dominant transitional cell pattern.

The melanoma cohort includes patients with histologically confirmed incurable advanced metastatic melanoma. If CIT (including anti-PD-L1/PD-1 and/or anti-CTLA-4 agents) is approved by local regulatory agencies as a treatment for melanoma, clinical trials of study agents in combination with anti-PD-L1 antibodies are considered acceptable treatment options for patients with melanoma. Patients whose tumors have known mutations in BRAFV600 must also have undergone disease progression (during or after treatment) or be intolerant to treatment with BRAF inhibitors and/or MEK inhibitors. Group management is performed such that no more than about 20% of patients in the cohort are patients with ocular (uveal) melanoma.

The OC cohort includes patients with histologically confirmed incurable advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Borderline ovarian epithelial tumors (e.g., low malignant potential tumors, atypical proliferative tumors) were excluded.

The RCC cohort includes patients with histologically confirmed, incurable advanced RCCs that include clear cell histology components and/or sarcoma-like histology components. If CIT (including anti-PD-L1/PD-1 agents) is approved by local regulatory agencies as a treatment for RCC, clinical trials of study agents in combination with anti-PD-L1 antibodies are considered acceptable treatment options for patients with RCC.

E. Administration and administration

In the phase Ib portion of the study, the dose of atuzumab administered in combination with tenerayleigh itumumab was 1200mg IV every three weeks, except that atuzumab was administered 1680mg IV Q4W in the phase Ib Q4W dosing cohort. The dose is fixed and independent of body weight. In all phase Ib cohorts without chemotherapy, atuzumab was administered after infusion of tiryleiguzumab and subsequent observation periods. In the phase Ib chemotherapy extension cohort, atelizumab was administered prior to tegraleigh itumumab.

The initial dose of alemtuzumab is delivered over 60 (± 10) minutes. If a first infusion can be tolerated without adverse events associated with the infusion, a second infusion can be delivered over 30 (± 10) minutes. If a 30 minute infusion is tolerable, all subsequent infusions can be delivered over 30 (± 10) minutes. For cycle 1, the attritumab administration was followed by a 90 minute observation period. All subsequent alemtuzumab infusions may be followed by an observation period of 30 minutes. Patients who have previously received atelizumab in another clinical trial may receive the initial dose at the fastest rate that was previously tolerated.

Chemotherapy in the phase Ib extended cohort

Chemotherapy was administered after infusion of alemtuzumab and tiryleyuzumab and subsequent observation periods. During the induction period, the chemotherapy cycle counts the predetermined number of induction chemotherapy cycles as long as at least one chemotherapy component has been administered at least once over a 21 day period. Cycles without administration of the chemotherapy components do not account for the total number of induced chemotherapy cycles.

Patients received an antiemetic and IV chemotherapeutic agent hydrated according to local standard of care and manufacturer instructions. However, due to the immunomodulatory effects of steroids, prophylactic use of steroids should be minimized within clinical feasibility.

Cohort A-atezumab gazetteliyluxumab plus carboplatin/cisplatin plus pemetrexed

On day 1 of each 21-day cycle, all eligible patients received drug infusions in the following order:

induction: abiralizumab & tilletuzumab & pemetrexed & carboplatin or cisplatin

After 4 to 6 cycles in the induction phase, the patient began maintenance therapy in the following order of administration:

maintaining: abiralizumab & Tirayleigh Uzumab & pemetrexed & lt

TABLE 7 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 pemetrexed and carboplatin or cisplatin during the induction period and for pemetrexed treatment administration during the maintenance period.

TABLE 8 preventive administration of paclitaxel

IV = intravenous; PO = oral administration

Cohort B-atelizumab plus titrayleigh Uitumumab plus carboplatin plus paclitaxel

On day 1 of each 21-day cycle, all eligible patients received drug infusions in the following order:

induction: abiralizumab & Tirayleigh Uzumab & Taxol & carboplatin

Table 8 lists the suggested prophylactic medications for induction treatment of patients in cohort B. Table 9 lists the recommended infusion times for paclitaxel and carboplatin treatment administration during the induction period.

TABLE 9 treatment regimens for paclitaxel and carboplatin

AUC = area under the concentration-time curve; IV = intravenous; Q3W = every 3 weeks.

Queueing C-atelizumab plus gatran-Rayleigh Ewing mab plus Carboplatin or cisplatin plus Etoposide

On day 1 of each 21-day cycle, study drug infusions were administered to all eligible patients in the following order:

induction: abiralizumab & tilletuzumab & cisplatin & carboplatin & etoposide & lt

After the induction period, the patient began maintenance therapy in the following order of administration:

maintaining: abiralizumab & Tirayleigh Uitumumab

Table 10 lists the recommended infusion times for carboplatin or cisplatin and etoposide treatment administration during the induction period.

TABLE 10 treatment regimens for carboplatin or cisplatin and etoposide

IV = intravenous; Q3W = every 3 weeks.

Cis-platinum

Guidelines for cisplatin administration in the different cohorts are shown in table 11.

TABLE 11 timing and guidelines for cisplatin administration

IV = intravenous

Remarking: patients must receive adequate antiemetic therapy and appropriate hydration before and after receiving cisplatin. For further details, see local clinical practice guidelines.

Carboplatin

Guidelines for cisplatin administration in the different cohorts are shown in table 12.

TABLE 12 carboplatin administration timing and guidelines

AUC = area under the time-concentration curve; IV = intravenous

Remarking: according to local practice guidelines, standard antiemetic agents should be administered at the time of carboplatin administration, and the Calvert formula is used to calculate the carboplatin dose for AUC5 or 6 (Calvert et al, j. Clin. Oncol.1989,7 1748-56):

for the purposes of this study, GFR is considered equivalent to calculated creatinine clearance (CrCl). CrCl was calculated according to the institutional guidelines or the methods described in Cockcroft and Gault (1976) using the following formula:

wherein: crCl = creatinine clearance (mL/min)

Age = patient age in years

Wt = patient body weight in kg

Scr = serum creatinine (mg/dL)

For patients with abnormally low serum creatinine levels, the GFR can be estimated by using a minimum creatinine level of 0.8mg/dL or capping the estimated GFR to 125mL/min.

If the patient's GFR is estimated by isotope dilution mass spectrometry based on serum creatinine measurements, the U.S. FDA recommends physicians to consider limiting the dose of carboplatin to achieve the desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert formula described in the carboplatin label, the maximum dose can be calculated as follows:

carboplatin maximum dose (mg) = target AUC (mg · min/mL) × (GFR +25 mL/min).

For patients with normal renal function, the maximum dose is based on an estimated GFR with a capping of 150mL/min. Higher estimated GFR values should not be used.

For target AUC =6, the maximum dose was 6 × 150=900mg.

For target AUC =5, the maximum dose was 5 × 150=750mg.

For target AUC =4, the maximum dose was 4 × 150=600mg.

Pemetrexed

Guidelines for administration of pemetrexed in cohort a are shown in table 13.

TABLE 13 Pemetrexed administration timing and guidelines

IV = intravenous

The prophylactic doses administered follow the prescription information. All patients eligible for pemetrexed therapy should avoid taking non-steroidal anti-inflammatory drugs with long elimination half-lives at least 5 days before, on the day of administration, and at least 2 days after pemetrexed administration.

Paclitaxel

Guidelines for paclitaxel administration in cohort B are shown in table 14.

TABLE 14 paclitaxel administration timing and guidelines

IV = intravenous

Patients of asian race/ethnic race have a low initial dose of paclitaxel of 175mg/m2 IV over 3 hours. The lower starting dose of paclitaxel was based on the overall higher incidence of hematologic toxicity in patients in asian countries than in patients in non-asian countries, as observed in internal safety scrutiny in lung cancer clinical trials. As used in this study, asian ethnicity/ethnicity refers to a pan ethnic group, including different populations living in or ancestors originating in east asia, south-east asia, or south asia. The applicability of the term in a particular patient is at the discretion of the treatment researcher and should be based on the clinical characteristics and country of origin of the patient.

Etoposide

A guideline for the administration of etoposide in cohort C is shown in table 15.

TABLE 15 Etoposide administration timing and guidelines

IV = intravenous

Example 2 phase Ib/II, open label, randomized study of Abiralizumab and combination of chemotherapy with Tirayleigh mab

This study evaluated efficacy, safety and pharmacokinetics of atelizumab and chemotherapy (nanoparticle albumin bound paclitaxel (nab-paclitaxel) and gemcitabine) in combination with tirayleigh euzumab in patients who did not receive prior systemic therapy for metastatic Pancreatic Ductal Adenocarcinoma (PDAC). This study evaluated the efficacy, safety and pharmacokinetics of immunotherapy-based therapeutic combinations in patients with metastatic PDAC.

A. Design of research

Patients in cohort 1 were randomly assigned to either a control group (chemotherapy) or a laboratory arm consisting of atelizumab and a combination of chemotherapy and tiryleiguzumab. The experimental arm was carried out in two phases: a preliminary phase and an extension phase. During the initial period, approximately 20 patients were enrolled. Randomization was suspended to allow a safety assessment of a minimum of 6 patients. The safety assessment is based on safety data from a minimum of 6 patients who have received at least one dose of treatment (i.e., one dose of each agent of a given combination) and completed a safety follow-up assessment for at least one complete treatment cycle. If the combination is determined to be sufficiently safe, the arm's engroup is resumed. If clinical activity is observed in the experimental arm during the preliminary phase, approximately 25 additional patients may be included in the arm during the extension phase. Additional patients may be included to ensure a balance between treatment arms in terms of demographic and baseline characteristics, including potential predictive biomarkers, for further subset analysis.

Patients were randomly assigned to treatment arms and the randomization rate was dependent on the number of experimental arms opened into the group (e.g., if one arm was added or one arm was paused to await a preliminary period of outcome analysis), with a probability of assigning to a control arm not exceeding 35% being prescribed.

The end of the study was defined as the day when the last patient completed the last visit (LPLV), including survival follow-up by telephone or in the clinic. The total length of the study (from screening of the first patient to the end of the study) will be about 3 to 5 years.

Table 16 summarizes the activity schedule.

TABLE 16 Activity time Table

ADA = anti-drug antibody; atezo + Chemo + Tira = altlizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus titrayleigh eculizumab; CIT = cancer immunotherapy; CT = computed tomography; discon = terminate; ECOG = eastern cooperative group of tumors; eCRF = electronic case report table; HBV = hepatitis b virus; nab-paclitaxel = nanoparticle albumin bound paclitaxel; PK = pharmacokinetics; RBR = pool of study biological samples; RECIST v1.1= solid tumor efficacy assessment criteria version 1.1; t3= triiodothyronine; t4= thyroxine; treat. = treatment; TSH = thyroid stimulating hormone.

On the treatment day, all assessments should be made prior to dosing, unless otherwise indicated.

^a If the visit is unavailable due to holidays, or other conditions, the visit may be made outside of a designated window if consent has been obtained from the medical inspector.

^b It is recommended that treatment be initiated no later than 7 days after randomization.

^c Patients returned to the clinic for a treatment termination visit no more than 30 days after the last dose of study treatment. Visits at which disease progression is confirmed may be used as treatment termination visits. The patient was then assessed for follow-up.

^d Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure when the patient is in a sitting position, pulse oximetry, and body temperature. New or worsening clinically significant abnormalities were recorded on the adverse event eCRF. For the first infusion of alemtuzumab, vital signs should be measured within 60 minutes prior to infusion, and if clinically indicated, every 15 (+ -5) and 30 (+ -10) minutes after infusion during the infusion period. For subsequent infusions, vital signs should be measured within 60 minutes prior to infusion, and if there is a clinical indication or symptoms appear during a previous infusion, vital signs should be measured during infusion and 30 (+ -10) minutes after infusion. For the first infusion of tireyuezumab, vital signs should be measured within 60 minutes prior to infusion and every 15 (+ -5) minutes during infusion and every 30 (+ -10) minutes after infusion. For subsequent infusions of tegaserod, vital signs should be measured within 60 minutes prior to infusion, and if there is a clinical indication or symptoms appear during the previous infusion, vital signs should be measured during infusion and 15 (+/-10) minutes after infusion.

^e The overall physical examination includes the assessment of the head, eye, ear, nose and throat, as well as the cardiovascular, cutaneous, musculoskeletal, respiratory, gastrointestinal, urogenital systemsAnd the nervous system. New or worsening clinically significant abnormalities were recorded on the adverse event eCRF.

^f Limited, symptomatic examinations were performed at designated time points and at other time points according to clinical indications. New or worsening clinically significant abnormalities were recorded on the adverse event eCRF.

^g The patient is advised to rest in a supine position for at least 10 minutes before recording the ECG.

^h Hematology includes WBC counts, RBC counts, hemoglobin, hematocrit, platelet counts, and differential counts (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).

ⁱ Laboratory testing must be performed within 96 hours prior to cycle 1 day 1 and within 24 hours prior to a subsequent visit prescribed during treatment.

^j If the screening laboratory assessments were made within 96 hours prior to cycle 1 day 1, they would not need to be repeated.

^k Chemical components (serum or plasma) include bicarbonate or total carbon dioxide (if considered as the standard of care for the area), 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 in sites not subjected to free T3) and free T4 were assessed at screening and on day 1 of cycle 1 and every third cycle thereafter (i.e. cycles 4, 7, 10, etc.).

^m Patients positive for quantitative HBV DNA at screening (must < 500IU/mL according to eligibility criteria) were subjected to additional HBV DNA tests on day 1 of every three cycles (i.e., cycles 3, 6, 9, etc.), at the termination of treatment (± 7 days), and at 3, 6, 9 and 12 months (at each time point, ± 14 days) after termination of treatment. Study treatment and procedures can be performed at the same time as treatment of HBV DNA, but investigators should review the results immediately after they are obtained. If HBV DThe increase in NA to < 500IU/mL requires consultation with a medical supervisor and counseling with a hepatitis B professional hepatopathy specialist or gastroenterology specialist before continuing study treatment.

ⁿ All fertility women underwent urine or serum pregnancy tests at the indicated visit during treatment and at 3 months and 6 months after the last dose of study treatment. If the urine pregnancy test is positive, it must be confirmed by the serum pregnancy test.

^o Including pH, specific gravity, glucose, proteins, ketones, and blood; the test strip allows.

^p Autoantibody assays include antinuclear antibodies, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibodies, and perinuclear anti-neutrophil cytoplasmic antibodies.

^q Autoantibody assays should be repeated for patients who develop signs or symptoms suggestive of autoimmune disease (e.g., lupus erythematosus).

^r Not applicable to sites that are not approved for RBR sampling. Only patients who provided written informed consent at the participating sites to participate.

^s If the investigator deems it clinically viable, the patient undergoes tumor biopsy collection at a time when unacceptable toxicity or clinical benefit as determined by the investigator is lost. The biopsy should be performed within 40 days after the determination of unacceptable toxicity or loss of clinical benefit, or prior to the next anticancer treatment, whichever is earlier. Furthermore, patients enrolled in the extension phase received tumor biopsy sample collection 4 weeks (+ -7 days) after treatment initiation (if deemed clinically feasible), unless treatment-period tissue samples have been collected from a minimum of 15 patients treated with the same CIT combination and determined to be evaluable.

^t Patients who consented to optional biopsy had tumor biopsy sample collection at 4 weeks (+ -7 days) after initiation of treatment, if deemed clinically viable (not applicable to patients enrolled in the extended period and who had undergone biopsy during treatment), and possibly at the discretion of the investigator Biopsies are taken during additional treatments at any other time.

^u Patients were evaluated for tumors at baseline, every 6 weeks (+ -1 week) within the first 48 weeks following initiation of treatment, and every 12 weeks (+ -2 weeks) thereafter, regardless of dose delay, until progression of the imaging disease according to RECIST v1.1, except patients who continued treatment after progression of the imaging disease; such patients are evaluated for tumors every 6 weeks (+ -1 week) until the investigator determines a loss of clinical benefit. Thus, for patients who stop treatment for reasons other than disease progression, tumor assessment should continue as planned even if they begin a new non-regimen prescribed anti-cancer treatment.

^v All measurable and/or evaluable lesions identified at baseline should be re-assessed in each subsequent tumor assessment according to the above tumor assessment schedule (see footnote "t"). Subsequent tumor assessment should use the same radiological procedure (e.g., the same contrast agent protocol as CT scan) used to assess the disease site at the time of screening.

^w Including patients using any medication other than the study treatment prescribed by the protocol (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic medication, nutritional supplements) from 10 days prior to initiation of the study treatment until the treatment termination visit.

^x After initiation of study treatment, all adverse events were reported until 30 days after the last dose of study treatment or until initiation of a new systemic anti-cancer therapy, whichever preceded the occurrence, and critical adverse events and adverse events of particular concern continued to be reported until 135 days after the last dose of study treatment drug or until initiation of a new systemic anti-cancer therapy, whichever preceded the occurrence. After this period, all deaths should be reported, regardless of cause. The investigator should follow-up on each adverse event until the event has resolved to baseline level or better, the event is assessed by the investigator as stable, the patient is out of visit, or the patient withdraws consent. All efforts should be made to track all critical adverse events considered relevant to the study treatment or trial-related procedure until the final result can be reported.

^y Alemtuzumab was administered at a fixed dose of 840mg by IV infusion on days 1 and 15 of each 28 day cycle. The initial dose of alemtuzumab is delivered over 60 (± 15) minutes. Subsequent infusions were delivered over 30 (+ 10) minutes if the previous infusion was tolerated without infusion related adverse events, and 60 (+ 15) minutes if the patient experienced infusion related adverse events in the previous infusion.

^z Treatment is continued until unacceptable toxicity or loss of clinical benefit is determined by the investigator.

^aa Ibritumomab tiuxetan was administered at a fixed dose of 420mg by IV infusion on days 1 and 15 of each 28 day cycle. Initial doses of the anti-rayleigh immuzumab were delivered over 60 (± 10) minutes. Subsequent infusions are delivered over 30 (+ 10) minutes if the previous infusion is tolerated without infusion-related adverse events, and 60 (+ 10) minutes if the patient experienced infusion-related adverse events in the previous infusion. On day 1 of cycle 1, tenecteuzumab was administered 60 minutes after completion of the atuzumab infusion. If a previous infusion of atlizumab was tolerated without IRR, the interval between subsequent infusions was 30 minutes; if the patient experienced an IRR in a previous atlas infusion, the interval was 60 minutes.

^bb On days 1, 8 and 15, patients received nab-paclitaxel at 125mg/m ² Administered by IV infusion over 30 (+ -5) minutes, followed by gemcitabine at 1000mg/m ² Administered by IV infusion over 30 (± 5) minutes. On day 1 of cycle 1, nab-paclitaxel was administered 60 minutes after completion of the tenerayleigh immuzumab infusion for observation after tenerayleigh immuzumab administration. If the previous infusion of tirayleigh immuzumab was tolerated without IRR, the interval between subsequent infusions was 30 minutes; if the patient experienced an IRR in a previous infusion of Telrayleigh immitux, the interval was 60 minutes.

^cc After termination of treatment, collection of information about survival via telephone calls, patient medical history, and/or outpatient visits approximately every 3 monthsFollow-up and information on new anti-cancer therapies (including targeted therapies and immunotherapy) until death (unless patients withdraw consent or study termination). If the patient requests to exit the follow-up visit, the request must be recorded in the source file and signed by the researcher. If the patient exits the study, the study staff may use a common information source (e.g., family records) to obtain only information about survival status.

Assessment and monitoring

All patients were closely monitored for adverse events throughout the study and adverse events were ranked according to the national cancer institute adverse event general terminology standard version 4.0 (NCI CTCAE v 4.0). Patients were assessed for tumors every 6 weeks (from day 1 of cycle 1) for the first 48 weeks, followed by tumor assessments every 6 or 12 weeks. Responses were evaluated by investigators using RECIST v 1.1. RECIST v1.1 responses to a modified immune-based therapeutic (irrecist) were programmatically determined based on individual lesion data assessed by the investigator. If clinical activity is demonstrated in the experimental arm, a tumor assessment scan of the arm can be submitted for evaluation by an independent review agency.

Baseline tumor tissue samples were collected from all patients, e.g., by biopsy at the time of study entry. If the investigator deems the biopsy to be infeasible, the archived tumor tissue can be submitted after approval by the medical supervisor, provided that the tissue was obtained within 3 months prior to enrollment and that the patient did not receive any anti-cancer therapy since the time of biopsy. Tumor tissue from patients who terminated stage 1 due to unacceptable toxicity, disease progression according to RECIST v1.1, or loss of clinical benefit as determined by the investigator was collected if the investigator deemed clinically viable. For patients who entered the experimental arm during the extension phase, treatment-session tumor tissue samples were collected 4 weeks (if clinically feasible) after initiation of stage 1 treatment, unless treatment-session tissue samples had been collected from a minimum of 15 patients treated with the same CIT combination and determined to be evaluable. These samples were used for biomarker studies (see basic principles of biomarker assessment).

To characterize the Pharmacokinetic (PK) profile and/or immunogenicity of alemtuzumab and other therapeutic agents, blood samples were collected at various time points before and during study treatment administration (table 17). The treatment regimen may be modified based on review of the real-time safety data and available PK data.

TABLE 17 time Table of pharmacokinetic, immunogenicity, and biomarker samples

ADA = anti-drug antibody; atezo + Chemo + Tira = atelizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus rayleigh ewolizumab; nab-paclitaxel = nanoparticle albumin bound paclitaxel; PBMC = peripheral blood mononuclear cells; PK = pharmacokinetics.

Remarks for note: based on emerging safety or efficacy data, the number of PK and ADA samples may be reduced, or sample collection may be stopped altogether. Furthermore, the collected sample may not be analyzed if not necessary. Based on the newly emerging biomarker data, the number of biomarker samples may be reduced, or sample collection may be completely halted.

Laboratory, biomarker and other biological samples

Exploratory biomarker studies include, but are not limited to, analysis of genes or gene signatures associated with tumor immunobiology, PD-L1, cytokines associated with T cell activation, T cell receptor repertoires, carcinoembryonic antigens or immune cells and subpopulations thereof for density, localization, and activation status, and may involve DNA or RNA extraction, somatic mutation analysis, and use of NGS (including WES).

Samples for the following laboratory tests were sent to the local laboratory at the research site for analysis:

hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells)

Chemical composition (serum or plasma): CPK, bicarbonate or carbon dioxide (if considered as the standard of care for the area), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT and AST

Coagulation: INR and aPTT

Thyroid function test: thyroid stimulating hormone, free triiodothyronine (T3) (or total T3 at sites not subject to free T3), and free thyroxine (also known as T4)

Ferritin and gamma-glutamyltransferase

HIV serology unless local regulations do not permit

HAV serology: HAV IgM

HBV serology: HBsAg, total HBcAb and (if HBsAg tests negative and total HBcAb tests positive) HBV DNA

If the patient is negative for HBsAg and positive for total HBcAb at the time of screening, then an HBV DNA test must also be performed to determine if the patient is infected with HBV.

HCV serology: HCV antibodies and (if HCV antibodies test positive) HCV RNA

If a patient tests positive for HCV antibodies at the time of screening, an HCV RNA test must also be performed to determine if the patient has active HCV infection.

HEV serology: HEV IgM

C reactive protein

·LDH

·CA19-9

EBV serology:

-EBV VCA IgM

-EBV VCA IgG or EBNA IgG

EBV PCR (only when clinically indicated)

Pregnancy test

All women with fertility were tested for serum pregnancy at stage 1 screening. Urine or serum pregnancy tests were performed in assigned follow-up visits. If the urine pregnancy test is positive, it must be confirmed by the serum pregnancy test.

A woman is considered fertile if it is in menstrual infancy, does not reach postmenopausal status (amenorrhea for more than 12 months without established causes outside the menopause), and has not been subjected to surgical sterilization (removal of ovaries and/or uterus).

Urinalysis (pH, specific gravity, glucose, protein, ketone and blood)

Dipstick urinalysis is allowed. However, if the arm containing bevacizumab is open into the group, patients with protein ≧ 2+ in the dipstick urinalysis at screening must undergo 24-hour urine collection for protein analysis.

Samples for the following laboratory tests were sent to a central laboratory or local laboratory at a research site for analysis:

soluble CD25

The following samples were sent to one or several central laboratories or sponsors for analysis:

serum samples for analysis of autoantibodies: antinuclear antibodies, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibodies and perinuclear anti-neutrophil cytoplasmic antibodies

Plasma or serum samples for PK analysis by using validated assays

Plasma or serum samples for immunogenicity analysis by using validated assays

Plasma, serum and Peripheral Blood Mononuclear Cell (PBMC) samples for biomarker exploratory studies

Tumor tissue samples collected at baseline for exploratory studies to determine PD-L1 expression and biomarkers

Baseline tumor tissue samples from either primary or metastatic lesions are collected from all patients, preferably by biopsy at the time of study entry. If the investigator deems the biopsy to be infeasible, an archived tumor tissue can be submitted after approval by the medical supervisor, provided that the tissue was obtained from a biopsy taken within 3 months prior to enrollment and that the patient had not received any anti-cancer therapy since the time of biopsy.

Representative FFPE tumor specimens in paraffin blocks (preferred) or at least 16 slides containing unstained, newly cut serial sections must be submitted along with the relevant pathology report. If only 10 to 15 slides are available, the patient may still be eligible for study participation after approval by the medical supervisor.

Based on the total and viable tumor content, the tumor tissue should be of good quality. The sample must contain a minimum of 50 viable tumor cells that retain cellular environment and tissue architecture regardless of the needle gauge or retrieval method. Samples collected via resection, core needle biopsy (at least three cores, 18 gauge needle or larger [ preferably 16 gauge needle ], embedded in a single paraffin block) or resection, incision, punch or jaw biopsy are acceptable. Fine needle aspiration (defined as a sample that does not retain tissue architecture and produces a cell suspension and/or smear), brushing, cell precipitation from pleural effusion, and lavage of the sample are unacceptable. Tumor tissue from bone metastases that have been decalcified is unacceptable.

The remaining archived tumor tissue blocks were returned to the site as required or after the study database was finally closed for 18 months, whichever came first.

Patients enrolled in the experimental arm during the extension phase: tumor tissue samples (if the investigator deemed clinically feasible) were collected 4 weeks (+ -7 days) after initiation of treatment for exploratory study of biomarkers

Samples were not collected if tissue samples during treatment had been collected from a minimum of 15 patients treated with the same CIT combination and were determined to be evaluable.

Preferably the sample is collected by resection, core needle biopsy (preferably at least three cores) or resection, incision, punch or jaw biopsy.

Tumor tissue samples collected at unacceptable toxicity, disease progression according to RECIST v1.1, or loss of clinical benefit as determined by the investigator, for exploratory studies of biomarkers if the investigator deems clinically viable

The biopsy should be performed within 40 days after determination of unacceptable toxicity, disease progression or loss of clinical benefit, or prior to the next anticancer treatment, whichever is earlier. Preferably the sample is collected by resection, core needle biopsy (preferably at least three cores) or resection, incision, punch or jaw biopsy.

Abiralizumab doses and schedules

Alemtuzumab was administered at a fixed dose of 840mg once every two weeks (Q2W) (840 mg on days 1 and 15 of each 28 day cycle).

Tirayleigh immuzumab dosages and schedules

Ibritumomab tiuxetan was administered at a fixed dose of Q2W 420mg (420 mg on days 1 and 15 of each 28 day cycle). The average concentration after a dose of 420mg of Q2W is expected to be equivalent to an average concentration of 600mg once every three weeks (Q3W). Based on available Pharmacokinetic (PK), efficacy and safety data from study GO30103, a dose of 600mg fixed tenerrituzumab of IV Q3W was selected, in which study patients received either single drug tenerrituzumab or tenerrileituzumab plus atelizumab. MTD was not reached, and DLT was not observed with tiryleigh ewuzumab monotherapy or in combination with astuzumab 1200mg Q3W at doses ranging from 2 to 1200mg Q3W. Furthermore, among 145 evaluable patients receiving tirayleigh mab (dose of 2 to 600mg Q3W) in combination with atuzumab, the production of anti-drug antibodies (ADA) against tirayleigh mab was observed in 3 patients. Starting from a dose of 30mg Q3W of ibritumomab tiuxetan, peripheral TIGIT receptors were observed at CD4 ⁺ 、CD8 ⁺ And complete occupancy on NK cells, and remained persistent at all higher doses. Antitumor activity was observed at a dose of 30 to 600mg Q3W of tenectereumab when administered in combination with atelizumab 1200mg Q3W (partial relief of imagery).

Dosage and administration

Patients received treatment as outlined until unacceptable toxicity or loss of clinical benefit as determined by the investigator after a comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease).

Participants received an IV infusion of 840mg of alemtuzumab on days 1 and 15 of each 28-day cycle as outlined in table 18.

Participants received 420mg IV infusions of ibritumomab tiuxetan on days 1 and 15 of each 28 day cycle as outlined in table 19. On day 1 of cycle 1, tenecteuzumab was administered 60 minutes after completion of the atuzumab infusion. The interval between subsequent infusions was 30 minutes if the previous infusion of atuzumab was administered without prophylactic administration and tolerated without infusion-related reactions (IRR), or 60 minutes if the patient experienced an IRR in the previous infusion of atuzumab.

Participants received nab-paclitaxel at 125mg/m on days 1, 8 and 15 of each 28-day cycle ² IV infusion by administration over 30 (+ -5) minutes followed by gemcitabine 1000mg/m ² Administered by IV infusion over 30 (± 10) minutes. On day 1 of cycle 1, nab-paclitaxel was administered 60 minutes after completion of the infusion of tenecteuzumab. If a previous infusion of ibritumomab tiuxetan was tolerated without IRR, the interval between subsequent infusions was 30 minutes; if the patient experienced an IRR in a previous infusion of Tirayleigh Euzumab, then the interval was 60 minutes.

TABLE 18 administration of the first and subsequent attrituzumab infusions

TABLE 19 administration of the first and subsequent infusions of ibritumumab tiuxetan

Dose adjustment

In this study, there was no dose adjustment for either astuzumab or ibritumumab. For the management of drug-related toxicity, the dosage of nab-paclitaxel can be reduced by 25mg/m ² (one dose level), up to two, gemcitabine doses may be reduced by 200mg/m ² (one dose level), up to two times as summarized in table 20.

If a further reduction in the nab-paclitaxel and/or gemcitabine dose is required after two dose reductions, the drug (or both drugs, if applicable) is discontinued, but the patient may continue with other study treatments at the discretion of the investigator. After dose reduction, the investigator may increase the dose as appropriate during subsequent administrations.

TABLE 20 recommended dose reduction of Nab-paclitaxel and Gemcitabine

	Initial dose	First dose reduction	Second dose reduction
				Nab-paclitaxel	125mg/m 2	100mg/m 2	75mg/m 2
Gemcitabine	1000mg/m 2	800mg/m 2	600mg/m 2

Concomitant therapy

Concomitant therapy includes patients using any medication other than the study treatment prescribed by the regimen (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic medication, nutritional supplement) from 10 days prior to initiation of study treatment to the treatment termination visit.

Patients were allowed the following therapies during the study:

colony Stimulating Factors (CSF) such as granulocyte colony stimulating factor (G-CSF) and Erythropoiesis Stimulating Agent (ESA) according to local practice/institutional guidelines or the American society for clinical oncology hematopoietic CSF guideline (Smith et al 2006) and the American society for hematology/American society for clinical oncology ESA guideline (Rizzo et al 2010)

There is limited evidence supporting the use of long-acting (pegylated) forms of G-CSF in patients receiving weekly chemotherapy (i.e., nab-paclitaxel). Therefore, researchers should consider using conventional preparations of G-CSF to be preferred.

Oral contraceptives

Hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or low molecular weight heparin)

Inactivated influenza vaccine

Megestrol acetate as appetite stimulant after initiation of study treatment

Mineralocorticoids (e.g., fludrocortisone)

Administration of inhaled glucocorticoids for chronic obstructive pulmonary disease or asthma

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency

Hormone therapy using gonadotropin-releasing hormone agonists or antagonists for prostate cancer

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

Palliative radiation therapy is permissible as long as it does not interfere with the assessment of the tumor target lesion (e.g., the lesion to be irradiated cannot be the only site of measurable disease). Treatment with nab-paclitaxel and gemcitabine should be discontinued during palliative radiation therapy. Treatment with atelizumab and tenectereuzumab can continue during palliative radiation therapy.

Radiotherapy of the brain is outlined below:

patients whose extracranial tumor burden is stable or responsive to the study treatment and subsequent findings with three or fewer brain metastases may receive cerebral radiation therapy (stereotactic radiation housing or whole brain radiation therapy) provided that all of the following criteria are met:

no evidence of progression or bleeding in the patient after completion of CNS-directed therapy.

Patients do not have a continuous need for corticosteroids as a therapy for CNS diseases.

Patients who require corticosteroid therapy for more than 7 days after radiation therapy has been completed must terminate study treatment.

-if desired, the anticonvulsant therapy is administered in a stable dose.

At the discretion of the investigator, prophylactic administration of antihistamines, antipyretics and/or analgesics can only be administered for the second and subsequent infusions of atuzumab and tirylyuuzumab.

Generally, according to local standard practice, researchers should manage patient care using supportive care based on clinical indications. Patients experiencing infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalents of local standard practice. Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and should be managed with supportive care (e.g., supplemental oxygen and beta) according to clinical indications ₂ Adrenergic agonists).

Inclusion criteria

The patients met the following criteria:

the age when signing the informed consent is 18 years or more

ECOG physical Performance status of 0 or 1

Histologically or cytologically confirmed metastatic PDACs

Definitive diagnosis of metastatic PDAC is made by evaluating histopathological data in the context of clinical and imaging data.

Patients with endocrine or acinar pancreatic cancer were not eligible for study participation.

No prior systemic treatment for PDAC

Life expectancy > 3 months, as determined by the investigator

Availability of representative tumor specimens suitable for determining PD-L1 and/or other biomarker status via a central test

Baseline tumor tissue samples are collected from all patients, preferably by biopsy at the time of study entry. If the investigator deems the biopsy to be infeasible, an archived tumor tissue can be submitted after approval by the medical supervisor, provided that the tissue was obtained from a biopsy taken within 3 months prior to enrollment and that the patient had not received any anti-cancer therapy since the time of biopsy.

Representative formalin-fixed paraffin-embedded tumor specimens in paraffin blocks (preferred) or at least 16 slides containing unstained, freshly cut serial sections must be submitted along with relevant pathology reports prior to study inclusion. If only 10 to 15 slides are available, the patient may still be eligible for study participation after approval by a medical supervisor.

Sign informed consent

Ability to comply with the study protocol at the discretion of the investigator

Measurable disease according to RECIST v 1.1 (at least one target lesion)

Only if the site clearly records disease progression after irradiation can the previously irradiated lesion be considered a measurable disease.

Appropriate blood and end organ function, defined by the following laboratory test results obtained within 14 days prior to initiation of study treatment:

-ANC≥1.5x10 ⁹ /L (1500/. Mu.L), granulocyte-free colony stimulating factor support within 14 days prior to screening laboratory testing

-WBC count ≥ 2.5x10 ⁹ /L(2500/μL)

Lymphocyte count ≥ 0.5x10 ⁹ /L(500/μL)

Platelet count ≥ 100x10 ⁹ L (100,000/. Mu.L), no blood transfusion within 7 days before screening laboratory testing

Hemoglobin ≥ 90g/L (9.0 g/dL)

After discussion with a medical inspector, patients may be transfused with blood to meet this criteria.

AST, ALT and ALP ≦ 2.5x upper limit of normal values (ULN), with the following exceptions:

patients with liver metastases recorded: AST and ALT ≤ 5 × ULN

Patients with liver or bone metastases were recorded: ALP is less than or equal to 5x ULN

-serum bilirubin ≦ 1.5 x ULN, except for:

patients with known gilbert disease: serum bilirubin level is less than or equal to 3 x ULN

Creatinine clearance ≧ 50mL/min (calculated using the Cockcroft-Gault equation)

Serum albumin ≥ 25g/L (2.5 g/dL)

-for patients not receiving anticoagulation therapy: INR or aPTT is less than or equal to 1.5 x ULN

For patients receiving therapeutic anticoagulation: stabilized anticoagulant regimens

Tumors accessible by biopsy

For women with fertility: agreeing to maintain abstinence (avoidance of sexual intercourse) or to use contraceptive measures, and agreeing not to donate ova

For males: agrees to maintain abstinence (avoid sexual intercourse of opposite sex) or to use contraceptive measures and agrees not to donate sperm

Safety feature

Measures are taken to ensure the safety of patients participating in the study, including the use of strict inclusion and exclusion criteria and close monitoring of patients during the study. Administration of the study treatment is performed in a monitored environment where trained personnel and sufficient equipment and medications are immediately available to manage the potential critical response. Adverse events were reported as described.

The adverse event terms of the verbatim are mapped to the supervised active medical dictionary thesaurus terms and the adverse event severity is ranked according to NCI CTCAE v 4.0.

Safety was assessed by aggregating adverse events, changes in laboratory test results, changes in vital signs and ECG, and exposure to study drugs. The length of the exposure and safety follow-up of the combination treatment was summarized by treatment arm within each stage.

Adverse events that occurred in the treatment after initiation of treatment were summarized. For each patient, the maximum reported severity for each adverse event was used in the summary by severity scale. All adverse events occurring during treatment, critical adverse events, adverse events leading to withdrawal from study treatment, grade 3 adverse events, deaths, and causes of death were listed and summarized in mapping terms, appropriate synonym levels, and NCI CTCAE severity ratings. The relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry and body temperature) and ECG data are displayed over time and the scale indicated where appropriate. In addition, the baseline and maximum post-baseline severity ratings were summarized using a transpose table of selected laboratory tests. Vital signs and changes in ECG are summarized.

Atezumab is associated with risks such as: IRR and immune-mediated hepatitis, pneumonia, colitis, pancreatitis, diabetes, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, guillain-barre syndrome, myasthenia syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, and myositis. The immune-mediated response may involve any organ system and may lead to hemophagocytic lymphocytosis and macrophage activation syndrome (considered as a potential risk for alemtuzumab).

The following are the most common adverse events observed in patients with PDAC when nab-paclitaxel was used: 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, anaphylaxis, pneumonia, myalgia, arthralgia, cardiotoxicity (cardiomyopathy, heart failure, angina pectoris, tachycardia, ventricular arrhythmia), cystoid macular edema, stevens-Johnson syndrome/toxic epidermal necrolysis, septicemia, transfusion site reactions/extravasation, hepatotoxicity (drug-derived liver damage), acute renal failure, hemolytic uremic syndrome, and drug-derived lupus erythematosus.

The most common adverse events with gemcitabine are nausea/vomiting, anemia, elevated hepatic transaminase, neutropenia, increased ALP, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema.

IRR is a determined risk for tenecteuzumab. Although clinical assessments of tiregumab are limited and not all risks are known, as antagonists of TIGIT, tiregumab is expected to enhance T cell and NK cell proliferation, survival and function. Thus, tenectereuzumab may increase the risk of autoimmune inflammation (also known as immune-mediated adverse events). Furthermore, since tirayleigh antibody has intact Fc effector functions, lymphocyte depletion by antibody-dependent cellular cytotoxicity (ADCC) is a theoretical risk.

Since tenecteuzumab is a therapeutic monoclonal antibody and targets immune cells, IRR associated with allergic reactions, target-mediated cytokine release, and/or acute ADA may occur. Clinical signs and symptoms of such reactions may include chills, wheezing, itching, flushing, rash, hypotension, hypoxemia and fever. IRR was reported in patients treated with tenecteuzumab alone or in combination with atuzumab. Most events were mild to moderate and controlled.

To minimize the risk and sequelae of IRR, an initial dose of tenecteuzumab was administered over a 60 minute period, followed by an observation period of 60 minutes. If the previous infusion is well tolerated, the subsequent infusion and observation times can be shortened. All infusions of tenecteuzumab were administered in the appropriate medical setting.

Non-clinical models have demonstrated a role for TIGIT signaling interruption in autoimmunity. In a knockout model (TIGIT-/-), loss of TIGIT signaling leads to a hyperproliferative T cell response and exacerbation of Experimental Autoimmune Encephalitis (EAE). TIGIT-/-and wild-type B6 mice were immunized with suboptimal doses of myelin oligodendrocyte glycoprotein peptide to induce EAE. Most TIGIT-/-mice developed severe EAE compared to wild-type B6 mice (Joller et al 2011).

Clinical experience with therapeutic agents aimed at enhancing anti-tumor T cell responses has demonstrated that the development of autoimmune inflammatory disorders is a widespread risk and, therefore, may be considered as a potential risk for ibritumomab tiuxetan. Such immune-mediated adverse events are described for almost all organ systems, including, but not limited to, colitis, hepatitis, pneumonia, endocrinopathies, ocular toxicity, pancreatic toxicity, neurotoxicity, myocarditis, nephritis, myositis, and skin rash.

Patients with a history of autoimmune disease were excluded from the study. In addition, patients with a history of severe immune-mediated adverse events associated with prior immunotherapy or adverse events that did not resolve to baseline after termination of prior immunotherapy were excluded from the study.

In this study, the specified immune-mediated adverse events were considered to be of particular interest adverse events and were captured accordingly.

Given that the IgG1 backbone of tiryleiguzumab has intact Fc effector functions, ADCC-mediated reduction in lymphocyte counts is a potential risk. However, in repeated dose toxicity studies in cynomolgus monkeys, there was no decrease in overall lymphocyte counts associated with tiryleiguzumab.

In a phase I study of solid tumors (study GO 30103), a decrease in transient lymphocyte counts was observed in patients treated with tenecteuzumab alone or in combination with atelizumab without clinical sequelae. Because of the potential risk of this tirayleigh immuzumab inducing lymphopenia, lymphocytes were counted < 0.5x10 ⁹ Patients at/L (500/. Mu.L) were excluded from the study. The complete blood count was monitored throughout the study.

The following adverse events were potential overlapping toxicities associated with the combined use of alemtuzumab, nab-paclitaxel, gemcitabine and tiryleiguzumab: immune-mediated toxicities including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and the like; gastrointestinal toxicity; hematological toxicity; and dermatological toxicity.

On day 1 of each cycle, patients were asked to have ≧ 1.5X 10 ⁹ ANC of/L (1500/μ L) and ≥ 100X 10 ⁹ Platelet count at/L (100,000/. Mu.L) to receive treatment with nab-paclitaxel and gemcitabine.

Discontinuation of therapy due to toxicity

Pertuzumab and/or tenelluzumab may be temporarily discontinued in patients experiencing toxicity believed to be associated with study treatment. If corticosteroid treatment toxicity is initiated, it must be gradually reduced to an equivalent of less than or equal to 10 mg/day oral prednisone or equivalent dose over a period of 1 month or more before drug administration can resume. If the drug is discontinued for > 12 weeks, the patient discontinues the use of the drug. However, the drug may be discontinued for > 12 weeks, so that the patient gradually reduces the amount of corticosteroid before resuming treatment. Alemtuzumab or tenecteuzumab may be resumed after > 12 weeks of disuse if the medical supervisor consents that the patient is likely to receive clinical benefit.

Based on existing mechanism of action characteristics, tenecteuzumab may cause similar but independent adverse events to atelizumab. Tiregumab may also exacerbate the frequency or severity of adverse events associated with atelizumab, or may have toxicity that does not overlap with atelizumab. Since these conditions may not be distinguishable from each other in a clinical setting, immune-mediated adverse events should generally be attributed to both agents, and dose discontinuation or treatment termination in response to immune-mediated adverse events should be applied to both tirayleigh immuzumab and atelizumab.

Nab-paclitaxel and/or gemcitabine treatment may be temporarily discontinued in patients experiencing toxicity believed to be associated with study treatment. If nab-paclitaxel or gemcitabine is discontinued for > 56 days due to toxicity, then the use of both chemotherapeutic drugs should be discontinued. However, if the medical supervisor agrees that the patient is likely to receive clinical benefit, nab-paclitaxel or gemcitabine may be returned to use > 56 days after the discontinuation.

If the use of atelizumab is discontinued, the use of tegraluezumab should also be discontinued, but if the patient is likely to receive clinical benefit, nab-paclitaxel and gemcitabine can continue to be used, as determined by the investigator. If the use of nab-paclitaxel, gemcitabine or telithromumab is discontinued, but if the researcher determines that the patient is likely to receive clinical benefit, then the use of other drugs may be continued, as determined by the researcher.

Statistics of

The final study analysis was based on patient data collected by study termination. If not otherwise specified, the efficacy analysis is based on a efficacy evaluable population, defined as all patients receiving at least one dose of each drug in their assigned treatment regimen, and the safety analysis is based on a safety evaluable population, defined as all patients receiving any amount of study treatment.

Data are described and summarized in terms of sample amounts. Continuous variables were summarized by mean, standard deviation, median and range. Categorical variables are summarized by using counts and percentages. If the sample size is small, a list is used instead of the table.

This study is not intended to make explicit efficacy and class I error considerations for hypothesis testing. In contrast, the present study was aimed at obtaining preliminary efficacy, safety and PK data for immunotherapy-based therapeutic combinations when administered to patients with metastatic PDAC.

Table 21 shows the ORR estimated difference between the experimental arm and the control arm, and the 90% confidence interval, each with a sample volume of 15 patients in the preliminary phase, assuming asymptotic normality.

TABLE 21 estimated difference in objective remission rates between experimental and control arms for 15 patients each (preliminary period)

Table 22 shows the ORR estimated difference between the experimental arm and the control arm, along with 90% confidence intervals, with sample volumes of 40 patients each in the prime phase and the combined extended phase, assuming asymptotic normality.

TABLE 22 estimated difference in objective remission rates between experimental and control arms for 15 patients each (preliminary period)

Target and endpoint

A summary of the study objectives and corresponding endpoints can be found in table 23.

TABLE 23 targets and corresponding endpoints

ADA = anti-drug antibody; DOR = duration of remission; irrecist = improved RECIST v1.1 for use in an immune-based therapeutic; OS = overall lifetime; PFS = progression-free survival; PK = pharmacokinetics; RECIST = evaluation criteria of efficacy of solid tumor.

Researchers evaluated the overall response at a single time point using RECIST v 1.1. The overall response according to irrecist is not captured in the eCRF, but is calculated programmatically from individual lesion data recorded in the investigator's assessment of the estimated eCRF.

Analysis of therapeutic effects

The primary efficacy endpoint was objective remission. The ORR, i.e. the proportion of patients who were in complete or partial remission, and the 90% confidence interval were calculated for each arm (capper-Pearson method). The ORR difference between the experimental arm and the control arm was calculated, along with a 90% confidence interval. The confidence interval is estimated by an asymptotic normality method, depending on the sample amount.

Secondary efficacy endpoints were PFS, OS at a specific time point (e.g., 6 months), duration of remission (DOR), and disease control, as determined by investigators according to RECIST v 1.1. DOR was obtained for patients with appreciable efficacy in complete or partial remission. For patients who had not recorded disease progression or death during the study period, PFS and DOR were deleted on the day of last tumor assessment. Patients who remained alive at the time of OS analysis were missed on the last date they were known to survive.

The Kaplan-Meier method was used to estimate the median of PFS, OS and DOR and 90% confidence intervals were constructed by using the Brookmeyer and Crowley methods. The OS rate at a particular time point was estimated using the Kaplan-Meier method and a 90% confidence interval was calculated based on the Greenwood estimate for variance. Disease control rate, i.e., proportion of patients with stable disease for > 12 weeks, partial remission or complete remission, was calculated for each treatment arm and the 90% confidence interval was estimated by using the capper-Pearson exact method.

The exploratory therapeutic endpoint was objective remission, PFS, DOR and disease control as determined by the investigator according to iRECIST; and changes in CA19-9 from baseline at subsequent time points over both phases. DOR was obtained for patients with appreciable efficacy in complete or partial remission. Changes in CA19-9 over time relative to baseline were summarized. In addition, the proportion of patients with a maximum decrease of CA19-9 of > 50% from baseline or other threshold for each treatment arm can be calculated, with the 90% confidence interval estimated by using the Clopper-Pearson exact method.

Pharmacokinetic analysis

Sparse samples can be collected for potential PK analysis of atlizumab (patient receiving at least one dose of atlizumab) and a particular drug administered in combination with atlizumab (patient receiving at least one dose of the drug). Serum or plasma concentrations of each study drug can be reported as individual values and summarized in terms of treatment arm, cycle and day (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean coefficient of variation) where appropriate and data allows. Individual and median serum or plasma concentrations of the various study drugs can be plotted in terms of treatment arm and period and day. PK data for the combination drug can be compared to available historical data from internal and published prior studies. The attritumab concentration data can be merged with data from other studies using established population PK models to derive PK parameters such as clearance, volume of distribution and area under the curve.

Immunogenicity assay

If appropriate, the immunogenicity of the atelizumab and other study treatments can be assessed (see arm-specific appendix for detailed information). The immunogenicity assay included all patients evaluated for at least one anti-drug antibody (ADA). Patients were grouped according to treatment received or if no treatment was received before the study break, according to treatment assigned.

For alemtuzumab, the number and proportion of ADA positive and ADA negative patients at baseline (baseline incidence) and after baseline (post-baseline incidence) were pooled by treatment group. Patients were considered ADA positive if they were ADA negative or missing baseline data when the post-baseline incidence was determined, but an ADA response appeared after study drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units higher than the titer of the baseline samples (treatment-enhanced ADA response). A patient is considered ADA negative if they are ADA negative or missing baseline data and all post-baseline samples are negative, or if they are ADA positive at baseline but without any post-baseline sample titers are at least 0.60 titer units higher than the titer of the baseline sample (treatment unaffected).

For other study treatments that tested ADA against, ADA positivity was 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 via descriptive statistics.

Example 3A phase Ib, open label, multi-cohort study relating to the safety, efficacy and pharmacokinetics of the combination of Tirayleigh mab with Atlizumab and chemotherapy in patients with triple negative breast cancer

This example describes a phase Ib, open label, multi-cohort study aimed at assessing the safety, efficacy and pharmacokinetics of tirayleigh mab in combination with atelizumab and chemotherapy in patients with metastatic Triple Negative Breast Cancer (TNBC). The study consisted of the following cohorts:

cohort a enrolled patients with unresectable, locally advanced, or metastatic programmed death ligand 1 (PD-L1) positive TNBC (first line metastatic TNBC) who had not received prior systemic therapy for metastatic breast cancer. The patient received tiryleiguzumab in combination with atuzumab and nab-paclitaxel.

A. Design of research

This phase Ib, multiroll, open label, multicenter, global study aimed at studying the safety and tolerability, initial efficacy and pharmacokinetics of teneuizumab in combination with atelectuzumab and nab-paclitaxel in patients with unresectable locally advanced or metastatic PD-L1 positive TNBC (referred to as cohort a, metastatic TNBC) who had not received prior systemic therapy for metastatic breast cancer. PD-L1 positivity was assessed using the SP142 PD-L1 IHC assay. Figure 2 illustrates a study design for cohort a.

Eligible patients (i.e., PD-L1 positive patients) were enrolled to receive both tirayleigh immuzumab (840 mg) and atuzumab (1680 mg) by IV infusion on day 1 of each 28 day cycle plus nab-paclitaxel (100 mg/m 2) administered to the patients by IV infusion on days 1, 8, and 15 of each 28 day cycle.

Nab-paclitaxel administration targets at least six cycles without disease progression or unacceptable toxicity, with no maxima.

To assess the mechanism of action and possible resistance mechanism of the drug combination in the tumor microenvironment, tumor tissue may optionally be harvested prior to administration on day 1 of cycle 2.

To test the mechanism of resistance to drug combinations in the tumor microenvironment, all patients received a forced tumor biopsy collection (if clinically feasible) at the first evidence of disease progression as assessed by investigators according to RECIST v1.1 (before starting a new anti-cancer therapy).

Regardless of treatment delay, patients were evaluated for tumors every 8 weeks (+ -7 days) at baseline and within the first 48 weeks after day 1 of cycle 1. After completion of week 48 tumor assessments, regardless of treatment delay, tumor assessments were required every 12 weeks (+ -7 days) until disease progression, withdrawal consent, death or study termination as determined by investigator according to RECIST v1.1, whichever occurred first.

Study treatment was terminated at disease progression as determined by the investigator according to RECIST v 1.1. Treatment may be continued for ambiguous progress findings (e.g., very small or uncertain new lesions or lymph nodes; cystic changes or necrosis in existing lesions) until the next planned assessment, according to RECIST v1.1 assessed by the investigator. If progress is confirmed in the next planned assessment, the date of progress should be the earlier date when progress is suspected.

B. Administration and administration

The treatment protocol is summarized in figure 2.

On the day of planned infusion of alemtuzumab, tenecteuzumab, and chemotherapy, chemotherapy is to be administered after infusion of alemtuzumab and tenecteuzumab.

After an alemtuzumab infusion (1680 mg), the patient received 840mg of tenerayleigh mab.

The administration of atelizumab, tirletegumab, and chemotherapy is performed in a monitored environment where trained personnel, as well as sufficient equipment and medications, are immediately available to manage potential critical reactions.

For detailed description of the preparation, storage and administration of the drugs, please refer to the pharmacy manual.

Tirayleigh immuzumab and atezumab

Patients in cohort a received atelizumab at a fixed dose of 1680mg administered by IV infusion Q4W on day 1 of each 28 day cycle, followed by tiyleuthenizumab administered at a fixed dose of 840mg by IV infusion Q4W on day 1 of each 28 day cycle. The doses of securityluzumab and atelizumab were fixed and independent of body weight. Infusions of securitylyumumab and atuzumab (including the observation period) were administered according to the instructions summarized in table 24.

TABLE 24 administration of first and subsequent infusion of tireyueuzumab and infusion of atuzumab

Nab-paclitaxel

Nab-paclitaxel was administered according to local prescription information. The initial dosage level of nab-paclitaxel in this study was 100mg/m ² Intravenously over 30 minutes on days 1, 8, and 15 of each 28 day cycle, 3 weeks on/1 week off. Nab-paclitaxel should be administered after alemtuzumab and tenerayleigh. Nab-paclitaxel was administered separately on days 8 and 15 of each cycle. The frequency of Nab-paclitaxel administration should not exceed every 7 days.

The site should follow its institutional standard of care to determine the nab-paclitaxel dose for obese patients and adjust the dose in the event of a change in the patient's weight. The infusion site should be closely monitored for the presence of infiltration during drug administration.

Nab-paclitaxel administration targets at least six cycles without disease progression or unacceptable toxicity, with no maxima.

For more details on the preparation and administration of nab-paclitaxel, see local prescribing information.

Dose adjustment

In this study, there was no dose adjustment for atelizumab or tenectereuzumab. For nab-paclitaxel administration (i.e., dose adjustment and treatment discontinuation rules), see table 25.

TABLE 25 suggested dose reduction of Nab-paclitaxel

	Nab-paclitaxel
		Initial dose	125mg/m 2
First dose reduction	100mg/m 2
		Second dose reduction	Terminate

C. Concomitant therapy

Concomitant therapy includes patients using any medication other than the regimen prescribed therapy (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic medication, nutritional supplements) from 7 days prior to study drug initiation to treatment termination visit.

Approved therapies

Patients were allowed the following therapies during the study:

oral contraceptives with annual failure rate < 1%

Hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or low molecular weight heparin)

Inactivated influenza vaccine

Administration of megestrol acetate as an appetite stimulant

Mineralocorticoids (e.g., fludrocortisone)

Administration of corticosteroids for chronic obstructive pulmonary disease or asthma

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency

Bisphosphonates for the prevention of skeletal events

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

palliative radiation therapy is permissible as long as it does not interfere with the assessment of the tumor target lesion (e.g., the lesion to be irradiated cannot be the only site of measurable disease). Treatment with tirayleigh eculizumab and atlizumab may continue during palliative radiation therapy. Nab-paclitaxel treatment should be discontinued according to institutional standard of care.

At the discretion of the investigator, the prophylactic administration of antihistamines, antipyretics and/or analgesics can only be administered for the second and subsequent infusions of atelizumab and tegraleigh.

Warning therapy

Systemic corticosteroids and TNF- α inhibitors may attenuate the potentially beneficial immune effects of treatment with atelizumab. Therefore, where systemic corticosteroids or TNF- α inhibitors are routinely administered, alternatives, including antihistamines, should be considered. If alternatives are not feasible, the systemic corticosteroid and TNF-. Alpha.inhibitor can be administered at the discretion of the investigator.

At the discretion of the investigator, the use of systemic corticosteroids is recommended to treat specific adverse events associated with the treatment with astuzumab.

Treatment inhibition

The following concomitant therapies were prohibited, as follows:

concomitant therapies aimed at treating cancer (including but not limited to chemotherapy, hormonal therapy, immunotherapy, radiotherapy and herbal therapy), whether approved or experimental by the health authorities, for different periods of time (depending on the agent) before the start of the study treatment and during the study treatment, until disease progression is recorded and the patient has terminated the study treatment except palliative radiotherapy

Investigational therapy within 28 days before initiation of study treatment and during study treatment

Live attenuated vaccines (e.g.,

)

systemic immune stimulants (including but not limited to interferon and IL-2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) before initiation of study treatment and during study treatment, as these drugs may increase the risk of developing autoimmune disease when administered in combination with atelizumab and tiryleyuzumab

Systemic immunosuppressive drugs (including but not limited to azathioprine, methotrexate, and thalidomide) are administered during study treatment because these drugs may alter the efficacy and safety of alemtuzumab and tenecteuzumab

Plinabulin (Plinabulin) is an in-progress molecule for reducing neutropenia caused by chemotherapy, and is not allowed as a substitute for G-CSF/GMCSF.

D. Inclusion criteria

Patients must meet the following general criteria to enter the study:

sign informed consent

Female and male aged 18 years or more when signing informed consent

Ability to comply with the study protocol

ECOG physical Performance status of 0 or 1

Adequate hematology and end organ function, defined as the laboratory results obtained within 14 days before the start of study treatment (day 1 of cycle 1):

ANC ≧ 1.5X 109/L (1500/μ L), no G-CSF support for 2 weeks before day 1 of cycle 1

Lymphocyte count ≥ 0.5X 109/L (≥ 500/μ L)

Platelet count ≧ 100X 109/L (. Gtoreq.100,000/μ L), no transfusion occurred within 2 weeks before day 1 of cycle 1

Patients with hemoglobin > 90g/L (. Gtoreq.9 g/dL) may require transfusion or receive erythropoietic therapy to meet this criterion.

AST, ALT and ALP ≦ 2.5 × Upper Normal value (ULN)

-serum bilirubin ≦ 1.5 × ULN, except for:

patients with known Gilbert disease with serum bilirubin levels of ≦ 3 × ULN are included.

-INR and aPTT. Ltoreq.1.5 XULN

This applies only to patients who do not receive anticoagulation therapy; patients receiving anticoagulation therapy should maintain a stable dosage.

Creatinine clearance ≥ 30mL/min (calculated using Cockcroft-Gault formula)

Serum albumin ≥ 25g/L (≥ 2.5 g/dL)

HIV test negative at screening

Test negative for hepatitis B surface antigen (HBsAg) at screening

Positive hepatitis B surface antibody (HBsAb) test or negative HBsAb test at screening

Accompanying the screening is either:

total hepatitis B core antibody (HBcAb) negative

Positive in total HBcAb test, followed by quantitative Hepatitis B Virus (HBV) DNA < 500IU/mL

HBV DNA testing was performed only on patients who were negative for the HBsAg test, negative for the HBsAb test, and positive for the total HBcAb test.

Hepatitis C Virus (HCV) antibody test negative at screening; or positive HCV antibody test and then negative HCV RNA test when screened

Only patients positive for the HCV antibody test were tested for HCV RNA.

For fertile women: consent was either to remain abstinent (avoid sexual intercourse) or to use contraceptive methods, and consent was not to donate ova, defined as follows:

during the treatment period and for at least 5 months after the last administration of atuzumab, 90 days after the last administration of ibritumumab, 1 month after the last administration of nab-paclitaxel, 6 months after the last administration of carboplatin or doxorubicin or 12 months after the last administration of cyclophosphamide, the female must remain abstinent or use a contraceptive method that results in a yearly failure rate of < 1%, whichever is later. During this same period, women must avoid donating eggs.

A woman is considered fertile if it is in menstrual infancy, does not reach postmenopausal status (amenorrhea for more than 12 months without established causes outside the menopause), and has not been subjected to surgical sterilization (removal of ovaries and/or uterus).

Examples of contraceptive methods with annual failure rates < 1%, if used continuously and correctly, include combined (estrogen and progestin containing) hormonal contraception associated with ovulation inhibition, progestin only contraceptive contraception associated with ovulation inhibition, bilateral tubal embolization, male sterilization, intrauterine devices, intrauterine hormone release systems, and sexual desire.

The reliability of sexual abstinence should be assessed according to the duration of the clinical study and the patient's preference and usual lifestyle.

Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

Women who want to be pregnant after termination of the study treatment should seek advice on oocyte preservation before initiation of the study treatment, as chemotherapy treatment may lead to irreversible infertility.

For males: consent to maintain abstinence (avoid sexual intercourse) or to use contraceptive measures, and to not donate sperm, are defined as follows:

during the treatment period and 90 days after the last administration of ibritumomab tiuxetan or within 6 months after the last sequential administration of nab-paclitaxel, carboplatin, doxorubicin or cyclophosphamide, the male must remain abstinent or use a condom plus an additional contraceptive method with a annual failure rate of < 1%, based on the later, with a female partner with fertility or a female partner during pregnancy. During this same period, the male must avoid donation of sperm.

The reliability of sexual intercourse should be assessed according to the duration of the clinical trial and the patient's preference and usual lifestyle.

Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

Men who want to live their child after the study treatment is initiated should seek advice on sperm preservation before the study treatment is initiated because chemotherapy treatment may lead to irreversible infertility.

For non-postmenopausal women (non-treatment-induced amenorrhea of > 12 months) or women who have undergone sterilization surgery, negative serum pregnancy test results need to be obtained within 14 days before the study treatment is initiated

Patients in the visit within compliance program, treatment program, willingness and ability of laboratory tests and other research procedures cohort a must meet the following cancer-specific criteria for entry into the study:

life expectancy greater than or equal to 12 weeks

Metastatic or locally advanced unresectable, histologically documented TNBC (absence of HER2, ER and progesterone receptor (PgR) expression, as determined by local testing)

Local laboratory assessments defined HER2 negativity as either of the following (Wolff et al, 2018):

in Situ Hybridization (ISH) non-amplified (ratio HER2 to CEP17 < 2.0 or single probe mean HER2 gene copy number < 4 signals/cell), or IHC 0 or IHC 1+.

ER and PgR negativity was defined as < 1% of cells expressing hormone receptors as determined by IHC assay.

Inclusion of only patients with metastatic TNBC tumors that were tested intensively and found to be positive for PD-L1

If clinically feasible, tumor specimens obtained from recurrent metastatic or locally advanced disease (if applicable) must be submitted.

Representative FFPE tumor specimens (archived specimens or fresh pre-treated tissue from recurrent disease) in paraffin blocks (preferred) or at least 20 unstained slides

Tumor tissue should have good quality based on total and viable tumor content and PD-L1 expression must be assessed prior to enrollment using the Ventana (SP 142) PD-L1 IHC assay, where positive is defined as ≧ 1% of the area of the tumor occupied by PD-L1-expressing tumor-infiltrating immune cells of any intensity, as determined by the central laboratory. Patients whose tumor tissues were not assessable for PD-L1 expression were ineligible.

If multiple tumor specimens are submitted, the patient may be eligible if at least one specimen is evaluable and PD-L1 expression is positive (whether the tissue is from an archived specimen or from a relapsed disease).

Acceptable samples include core needle biopsies for deep tumor tissue (a minimum of three core needles) or for excision, incision, perforation or jaw biopsies of skin, subcutaneous or mucosal lesions.

FFPE tumor specimens in paraffin blocks are preferred.

Fine needle aspiration, brushing, pleural effusion cell precipitation, bone metastases, and lavage samples are unacceptable. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and therefore unacceptable.

No prior chemotherapy or targeted systemic therapy against inoperable, locally advanced or metastatic TNBC

Previous radiation therapy for metastatic disease was allowed. Radiation therapy does not have the minimum required clearance period. The patient should have recovered from the effects of radiation therapy.

If treatment is completed ≧ 12 months prior to initiation of study treatment, prior chemotherapy (including taxanes) and/or CIT (only anti-PD-L1 or anti-PD-1 agents) is allowed in a neoadjuvant or adjuvant setting.

Measurable disease, as assessed by investigators according to RECIST v1.1

Only if the site clearly records disease progression after irradiation can the previously irradiated lesion be considered a measurable disease.

E. Exclusion criteria

Patients who met any of the following criteria were excluded from the study:

pregnancy or lactation, or pregnancy is intended at the following times: during study treatment, longer subjects were treated within 90 days after treatment with tireyuezumab, within 5 months after treatment with astuzumab, within 6 months after treatment with nab-paclitaxel, carboplatin, or doxorubicin, or within 12 months after treatment with cyclophosphamide

A female with fertility must be negative for serum pregnancy test results within 14 days before study treatment initiation.

There is evidence that there is significant uncontrolled co-disease, possibly affecting compliance with the regimen or interpretation of the outcome, including significant liver disease (such as cirrhosis, uncontrolled severe seizures or superior vena cava syndrome)

Significant cardiovascular diseases, such as New York Heart Association heart disease (grade II or higher), myocardial infarction occurring within 3 months prior to initiation of study treatment, unstable arrhythmias or unstable angina

Patients with known LVEF < 53% were excluded.

Patients with known coronary artery disease or congestive heart failure who do not meet the above criteria.

Severe infection occurred within 4 weeks before initiation of study treatment, including, but not limited to, hospitalization due to complications of infection, bacteremia, or severe pneumonia

Eligible patients receiving conventional antibiotic prophylaxis (e.g., preventing chronic obstructive pulmonary disease exacerbations or for tooth extractions) were treated with oral or IV antibiotics within 2 weeks prior to initiation of study treatment.

Major surgery was performed within 28 days before initiation of study treatment or was expected to require major surgery in addition to diagnosis during the study

Placement of a central venous access catheter (e.g., port or similar catheter) is not considered a major procedure and is therefore permissible.

History of severe allergic, allergic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

Known to have allergic or allergic reactions to any component of the biopharmaceutical or temeliitumumab or atelizumab preparation produced in CHO cells

Activity or history of autoimmune diseases, including, but not limited to, 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-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis

Patients with a history of autoimmune-mediated hypothyroidism and who are receiving stable doses of thyroid replacement hormone meet the criteria of this study.

Patients with type 1 diabetes who are receiving a stable insulin regimen are eligible for this study.

Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only dermatological manifestations (e.g., no psoriatic arthritis) are allowed provided that they meet the following conditions:

A rash must cover < 10% of the body surface area

A disease is well controlled at baseline and only low potency topical corticosteroids need be used

An acute exacerbation of an underlying condition that did not occur within the past 12 months requiring psoralen plus ultraviolet a radiation, methotrexate, retinoids, biologicals, oral calcineurin inhibitors or high potency or oral corticosteroids

Care should be taken when considering the use of atzumab for patients who have previously experienced severe or life-threatening adverse skin reactions when receiving another immunostimulatory anticancer agent.

Previous allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonia), drug-induced pneumonia, organized pneumonia (i.e. bronchiolitis obliterans, cryptogenic organized pneumonia), or evidence of active pneumonia at the time of screening at chest Computed Tomography (CT) scan

A history of radiation pneumonitis (fibrosis) in the radiation field was allowed.

Positive EBV Virus Capsid Antigen (VCA) IgM testing at the time of screening EBV Polymerase Chain Reaction (PCR) testing should be performed according to clinical indications to screen for active infection or suspected chronic active infection.

Patients who were positive for the EBV PCR test were excluded.

Active Tuberculosis (TB)

Inoculation of live attenuated vaccines within 4 weeks before initiation of study treatment or the need to inoculate such live attenuated vaccines during the study is anticipated

Patients must agree not to receive a live attenuated vaccine within 28 days prior to initiation of study treatment, during treatment or within 5 months after the last dose of study treatment (e.g.,

)。

previous treatments with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, 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 treatment or within 5 drug elimination half-lives (whichever is longer) of the drug

Treatment with systemic immunosuppressive drugs (including, but not limited to, prednisone, dexamethasone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [ anti-TNF ] agents) within 2 weeks prior to initiation of study treatment, or the anticipated need for use of systemic immunosuppressive drugs during the study

Patients who had received acute, low dose, systemic immunosuppressive medication (e.g., a single dose of dexamethasone to treat nausea) could be enrolled in the study.

Baseline and follow-up tumor assessment using Magnetic Resonance Imaging (MRI) should be performed on patients with an allergic history to IV contrast agents who require steroid pretreatment

Allows for the treatment of chronic obstructive pulmonary disease with inhaled corticosteroids, treatment of orthostatic hypotension with mineralocorticoids (such as fludrocortisone), and treatment of adrenal insufficiency with low dose supplemental corticosteroids.

Patients in cohort a who met any of the following cancer-specific exclusion criteria were excluded from the study:

PD-L1 negative FFPE tumor tissue, as determined according to the SP142 PD-L1 IHC assay, wherein positive is defined as ≧ 1% of the tumor area occupied by any intensity of PD-L1-expressing tumor-infiltrating immune cells

Spinal cord compression without definitive treatment by surgery and/or radiotherapy, or spinal cord compression previously diagnosed and treated, but no evidence of clinically stable pre-screening disease for > 2 weeks

Known Central Nervous System (CNS) diseases, with the exception of asymptomatic CNS metastases that have been treated, provided that all of the following criteria are met:

allowing only supratentorial and cerebellar metastases (i.e. no metastasis to the midbrain, pons, medulla or spinal cord)

Treatment of CNS disorders without the need for continuous use of corticosteroids

No stereotactic radiation within 7 days or no whole brain radiation within 14 days before initiation of study treatment

Clinical evidence of no intermediate progression between completion of CNS-directed therapy and screening imaging studies

Remarking: patients who detect new asymptomatic CNS metastases at the time of the screening scan must receive radiation therapy and/or surgery for CNS metastases. After treatment, these patients may be eligible if all other criteria are met, without the need for additional brain scans prior to enrollment.

Leptomeningeal disease

Uncontrolled pleural effusion, pericardial effusion or ascites

An indwelling catheter (for example,

) Is allowed.

Uncontrolled tumor-related pain

Patients requiring narcotic analgesics must adopt a stable treatment regimen at the time of study entry.

Symptomatic lesions (e.g., bone metastases or metastases that cause nerve contact) suitable for post-palliative radiation therapy should be treated prior to enrollment. The patient should have recovered from the effects of radiation therapy. A minimum recovery period is not required.

Further growth of asymptomatic metastatic lesions may lead to functional defects or intractable pain (e.g. epidural metastasis which is not currently associated with spinal cord compression), and patients should be considered for (if appropriate, prior to enrollment in) regional treatment.

Uncontrolled hypercalcemia (> 1.5mmol/L ionized calcium or calcium > 12mg/dL or corrected serum calcium greater than ULN) or symptomatic hypercalcemia requiring continued bisphosphonate treatment

Patients who are receiving bisphosphonate therapy specifically for the prevention of skeletal events and have no clinically significant history of hypercalcemia are eligible.

Malignancies other than TNBC within 5 years prior to initiation of study treatment, except for negligible risk of metastasis or death (e.g., 5 years OS > 90%) and malignancies that are treated to achieve the desired cure outcome (such as well-treated cervical or basal carcinoma in situ, localized prostate cancer or squamous cell skin cancer)

Known to be allergic to nab-paclitaxel or any of its excipients

F. Analysis of

A safety analysis was performed on all patients.

Efficacy analysis the ITT method was used for cohorts a and B, with any enrolled patients included in the analysis, regardless of whether the patients received any of the indicated study drugs. An analysis based on a subset of the ITT population may also be performed.

Unless otherwise stated, the test is assumed to be a two-sided test.

Sample size

The purpose of cohort a was to evaluate the effect of tiryleiguzumab in combination with atuzumab and nab-paclitaxel on the primary efficacy endpoint (defined as objective remission). The proportion of responses compared to historical data is considered to have or not further development potential. There is no formal hypothesis testing. Statistical data are presented as two sides 90% CI. In proposing recommendations to continue or stop development, the totality of data, including the results of secondary efficacy endpoints, including but not limited to PFS, OS, and subgroup analysis results, is considered.

The primary efficacy analysis is to estimate the true proportion of patients who are expected to acquire CR or PR (i.e., ORR). Data from studies completed and ongoing in similar disease settings can be used as historical controls for row comparisons. The currently available data indicate that the historically confirmed response rate is about 53% (ii) in locally advanced unresectable or metastatic PD-L1 positive TNBC

U.S.Package Insert)。

Assuming an observed response rate of 67.5%, the sample size of 40 patients appeared to be sufficient to provide sufficient accuracy for point estimation and for the bilateral 90% ci lower limit to exclude clinically insignificant response probabilities < 53%. Specifically, if at least 27 out of 40 patients achieved a response, it can be concluded that the response rate was higher than 53%. In anticipation of efficacy analysis, an updated estimate of the proportion of patients expected to achieve a response may be obtained from ongoing studies and used as reference data.

Table 26 lists the double-sided 90% Clopper-Pearson exact CI that achieves the true probability of response within the range of ratios observed, based on samples from 40 patients. Tables 27 and 28 give the probabilities of detecting positive and negative signals based on the observed ORR point estimates and the potential true ORR at various thresholds.

TABLE 26 two-sided Clopper-Pearson exact confidence intervals to achieve true probability of response

TABLE 27 probability of declaring a positive signal (observed ORR greater than or equal to a selected threshold)

TABLE 28 probability of declaring a negative signal (observed ORR less than a selected threshold)

Security analysis

Safety assessments include the incidence, nature and severity of adverse events, protocol-specific vital signs, laboratory abnormalities and other protocol-specific tests deemed critical to the safety assessment of the study. Adverse events were graded according to NCI CTCAE v 5.0.

Safety was assessed by aggregating adverse events, changes in laboratory test results, changes in vital signs, study treatment exposure and immunogenicity as measured by ADA and presented by the treatment arm.

The verbatim description of the adverse event maps to the MedDRA term.

Events occurring during treatment (defined as events occurring during or after the first dose of study treatment) are summarized in terms of MedDRA terminology, appropriate MedDRA levels, and NCI CTCAE v5.0 rating, regardless of the relationship to study drug as assessed by the investigator. For each patient, the reported maximum severity was used in the summary if the same adverse event occurred multiple times.

Adverse events occurred in the following treatments were individually summarized: adverse events leading to study drug withdrawal, adverse events leading to dose reduction or discontinuation, grade ≧ 3 adverse events, grade 5 adverse events, critical adverse events, and adverse events of particular concern.

All deaths and causes of death were summarized.

The relevant laboratory values were summarized by time point and (when appropriate) NCI CTCAE grade 3 and grade 4 values were determined. Changes in NCI CTCAE grade are listed by treatment group.

Analysis of exposure, adverse events, laboratory data, and vital sign data

Safety was assessed by summarizing study treatment exposure, adverse events, changes in laboratory test results, and changes in vital signs and ECG.

Study treatment exposures (such as treatment duration, total dose received, and number of cycles and dose modifications) were summarized with descriptive statistics.

All verbatim adverse event terms map to MedDRA thesaurus terms and the adverse event severity is graded according to NCI CTCAE v 5.0. All adverse events, critical adverse events, adverse events leading to death, adverse events of particular concern, and adverse events leading to termination of study treatment (i.e., adverse events occurring during treatment) that occurred during or after administration of the first study treatment were summarized by mapped terminology, appropriate thesaurus levels, and severity levels. The highest ranking was used in the summary for events of varying severity. Mortality and cause of death were summarized.

Relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry and body temperature) and ECG data are displayed over time and rated where appropriate. In addition, the baseline and maximum post-baseline severity ratings were summarized using a transpose table of selected laboratory tests. Vital signs and changes in ECG are summarized.

Analysis of efficacy

Main efficacy goals

The primary efficacy objective of cohort a was to assess the efficacy of the combination of tenerriitumumab with atuzumab and nab-paclitaxel based on the following endpoints:

ORR, defined as the proportion of patients with CR or PR, as determined by the investigator using RECIST v1.1

Either PR or CR needs to be confirmed. Patients who did not meet this criteria (including patients who did not receive any post-baseline tumor assessment) were considered non-responders. ORR is defined as the proportion of patients that experience objective remission.

The earliest review of the efficacy data was performed once all patients had undergone at least two tumor assessments.

Secondary efficacy goals

The secondary efficacy objective of cohort a was to obtain preliminary data regarding the efficacy of the combination of tirayleigh mab with atuzumab and nab-paclitaxel based on the following endpoints:

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 according to RECIST v1.1

Data from patients who did not experience disease progression or who did not die was last known to be alive and not progressing before the clinical expiration date of the respective analyses or was deleted on the day of the clinical expiration date. Patients without post-baseline information were missed on the day of enrollment.

DOR, defined as the time from the first occurrence of recorded objective remission to the onset of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1

Data from patients who did not experience disease progression or who had not yet died were deleted on the day of the last tumor assessment. If no tumor assessment is made after the first date of CR or PR, the DOR data is deleted on the first date of CR or PR.

OS, defined as the time from group to death due to any cause

Patients that were not reported as dead at the time of analysis were missed on the last day they were known to survive. Patients without post-baseline information were censored on the day of enrollment.

Pharmacokinetic analysis

Samples were collected for PK analysis and exposure in this study was compared to exposure obtained in previous studies. Serum concentrations of both tirayleigh mab and atuzumab and plasma concentrations of nab-paclitaxel, carboplatin, doxorubicin, and cyclophosphamide were reported as individual values and summarized as appropriate and data allowed for treatment arm and period (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation).

Individual and median serum tetrayleigh immitumab and atelizumab concentrations are plotted on treatment arm and day. The tenellituzumab and atelizumab concentration data can be merged with data from other studies using established population PK models to derive PK parameters such as clearance, volume of distribution and AUC as data is warranted. Potential correlations of relevant PK parameters with dose, safety, efficacy, or biomarker outcome can be explored.

Immunogenicity assays

Immunogenicity analysis included patients undergoing any ADA assessment, grouped according to treatment received. The number and proportion of ADA positive and ADA negative patients appearing during treatment were summarized by treatment arm during both treatment and follow-up.

The relationship between ADA status and safety, efficacy and PK endpoint can be analyzed and reported by descriptive statistics.

Biomarker analysis

Although no formal statistical analysis of exploratory biomarkers was performed, the data can be analyzed in the context of this study and summarized as a population with the data of other studies.

Example 4A phase Ia/Ib, open label, dose escalation study on the safety and pharmacokinetics of Ulvacizumab as a single agent and in combination with Attributizumab and/or other anti-cancer therapies in patients with locally advanced or metastatic tumors

This example describes a phase I open label, multicenter, global, dose escalation study conducted for the first time in humans aimed at evaluating:

(stage Ia) safety, tolerability and PK of tirayleigh uzumab as a single agent in patients with locally advanced, recurrent or metastatic incurable tumors for which standard therapy is not present, has proven ineffective or intolerant or is deemed inappropriate, or for which clinical trials of study agents are recognized as standard of care; and

(stage Ib) safety, tolerability and PK of tireylauzumab when administered in combination with standard of care therapy in the following patients: patients with locally advanced, recurrent or metastatic incurable tumors for which standard therapy is not present, has proven ineffective or is intolerant or is deemed inappropriate; or patients for whom clinical trials of the study agent are recognized as standard of care, or for whom clinical trials of the study agent in combination with an anti-PD-L1 antibody are considered to be an acceptable treatment option.

A. Design of research

This first phase I open label, multicenter, global, dose escalation study in humans aimed at assessing safety, tolerance and PK of tiryleigh ewuzumab as a single agent in patients with locally advanced, recurrent or metastatic incurable tumors for which standard therapy is not present, has proven ineffective or intolerant or is deemed inappropriate, or for which clinical trials of study agents are recognized as standard of care. This was assessed in the phase Ia part of the study.

The present study also aims to enable safety, tolerability and PK of tiryleparticularly in the following patients when administered in combination with standard of care therapy: patients with locally advanced, recurrent or metastatic incurable tumors for which standard therapy is not present, has proven ineffective or is intolerant or is deemed inappropriate; or patients for whom clinical trials of the study agent are recognized as standard of care, or for whom clinical trials of the study agent in combination with an anti-PD-L1 antibody are considered to be an acceptable treatment option. This was studied in several cohorts of the phase Ib part of the study:

ib stage: dose escalation cohort of terayleigh immuzumab and atlas (fig. 4)

Ib stage: indication-specific tipleyumab and atelizumab dose escalation cohort (figure 4)

Ib stage: tirayleigh eculizumab and atelizumab series biopsy cohort (FIG. 4)

Ib stage: extended cohort of dosing every 4 weeks (Q4W) with tirayleigh immuzumab and atezumab (fig. 4)

Ib stage: extended cohort of tiryleuyitumumab and atelizumab in combination with chemotherapy (cohorts A to D; FIG. 5)

Stage Ib: extended cohort of tiryleaveucimab in combination with non-chemotherapy (cohorts NC1 and NC2; FIG. 6)

Phase Ib portion of the study was initiated after DLT assessment of at least two dose levels of single drug tegraluretumab had been completed, and investigators and IMCs had thoroughly reviewed all relevant single drug safety data. Phase Ib fraction was initiated at a dose level no higher than the initial tireylauzumab dose level, if deemed appropriate, using the same dose escalation protocol and comprehensive safety monitoring plan as in phase Ia fraction. In addition, patients with progression in phase Ia portion of the study using the single drug tirayleigh immumab may be selected for transfer into phase Ib portion of the study.

Both fractions of study phase Ia and Ib consisted of screening phase, treatment phase and post-treatment follow-up phase. Patients were enrolled in two phases, one up-dosing phase and one dose extension phase; see fig. 3 and fig. 4 for phase Ia and Ib, respectively. In addition, fig. 4 shows a series of biopsies and a Q4W cohort, while fig. 5 shows a phase Ib chemotherapy expansion cohort, and fig. 6 shows a phase Ib non-chemotherapy expansion cohort. In the dose escalation phase, cohorts of approximately 3 to 6 patients were each evaluated at escalating dose levels to determine the MTD or Maximum Administered Dose (MAD) of tirayleigh unizumab as a single drug or in combination with atuzumab. To obtain additional safety and pharmacodynamic data to more fully inform extended cohort dose selection, more patients may enter a group complementary (backsfill) cohort at a dose level that has been shown not to exceed the relevant MTD based on the dose escalation criteria described below. These patients were not included as part of the population evaluable for DLT for dose escalation decision purposes.

In the dose expansion phase, patients are enrolled and treated with tenerayleigh itumumab at or below the MTD or MAD as a single agent (phase Ia) or in combination with atuzumab and/or other anti-cancer therapies (phase Ib).

Tirayleigh itumumab was administered as a single drug (phase Ia), or a combination of tirayleigh itumumab and atelizumab, tirayleigh itumumab and atelizumab (phase Ib cohort not combined with chemotherapy) with bevacizumab or tirayleigh itumumab and parilizumab by IV infusion on day 1 of each 21 day cycle or on day 1 of each 28 day cycle (phase Ib Q4W dosing extension). In the phase Ib cohort without chemotherapy, securityluzumab was administered prior to atlizumab, bevacizumab or palboclizumab. In the absence of unacceptable toxicity or clinically convincing evidence of disease progression, tirayleigh mab (phase Ia) or combinations of tirayleigh mab with atuzumab and/or other anti-cancer therapies (phase Ib predominates cohort) can continue to be used after cycle 1 based on the researcher's favorable assessment of benefit and risk.

The safety introductions of 3 patients were completed in the phase Ib chemotherapy and non-chemotherapy extension cohort and in the phase Ib Q4W dose extension cohort. IMC and researchers thoroughly review all relevant safety data from the safety imports before proceeding to the cohort.

In each of the four chemotherapy expansion cohorts, both tirayleigh itumumab and atelizumab were combined with a specific chemotherapy regimen: carboplatin or cisplatin and pemetrexed in cohort a, carboplatin and paclitaxel in cohort B, carboplatin or cisplatin and etoposide in cohort C, and capecitabine in cohort D. In cohorts a, B and C, treatment consisted of an induction phase and a maintenance phase. During the induction period, the combination of tirayleigh itumumab and atuzumab was administered with chemotherapy by IV infusion on a 21 day cycle basis, cohorts a and B for 4 to 6 cycles, and cohort C for 4 cycles. The number of induction treatment cycles for cohorts a and B was determined by the investigator as appropriate.

After the induction period, patients who have not experienced disease progression or unacceptable toxicity continue to be treated with maintenance therapy. During the maintenance period, patients in cohorts B and C continued to use only tirayleigh immuzumab and atuzumab, while patients in cohort a continued to use tirayleigh immuzumab and atuzumab with pemetrexed.

During the maintenance period, cohort a continued to use atezumab, tenerayleigh immuzumab and pemetrexed for a 21 day period. In cohort B, patients enrolled according to protocol GO30103 version 4 continued to use atelizumab and tenectereuzumab for a 21 day period. In cohort B, patients enrolled according to the protocol GO30103 version 5 later in the cohort continued to use atelizumab and tenectereuzumab for a 28 day period. Cohort C began using atelizumab and tenectereuzumab in a 28 day cycle.

In cohort D, patients were treated with tirayleigh mab, atelizumab, and capecitabine until unacceptable toxicity or loss of clinical benefit, as determined by the investigator. The patient is administered 1250mg/m on days 1 to 14 of each 21-day cycle ² The dose of (b) is twice daily (BID) oral capecitabine. On day 1 of cycle 1, the first dose of capecitabine was administered in the clinic prior to infusion of atuzumab and tenectereuzumab. The combination of tirayleigh mab and atezumab was administered by IV infusion over a 21 day period.

In all chemotherapy expansion cohorts, atelizumab was administered prior to tegraleigh immuzumab.

All patients were closely monitored for adverse events throughout the study. Adverse events were graded according to NCI CTCAE version 4.0.

To characterize the PK profile, immunogenic response and pharmacodynamic effects of tirayleigh immuzumab as a single agent (phase Ia) or in combination with atelizumab with or without chemotherapy (phase Ib), blood samples were taken at different time points before and after dosing. Depending on the results of the mid-phase PK analysis, the frequency of PK sampling can be reduced in the late phase of the study.

Patients underwent tumor assessments at screening and during the study, which were measured by standard solid tumor efficacy assessment (RECIST) v1.1 criteria.

Even if the RECIST v1.1 disease progression criteria met in the phase Ia or Ib portion of the study, the patient may still be allowed to continue study treatment provided the patient met the criteria for continuing treatment (fig. 7). Patients who terminated phase Ia portion of the study may be allowed to shift to phase Ib portion of the study and receive treatment with a combination of teneuizumab and atuzumab provided they met the cross criteria and agreed to biopsy accessible lesions (fig. 8).

Patients who permanently stop tirayleigh immuzumab (phase Ia) or tirayleigh immuzumab and atuzumab with chemotherapy, tirayleigh immuzumab and atuzumab with bevacizumab or tirayleigh immuzumab and palboceprizumab (phase Ib) will return to the clinic for study treatment termination visit within 30 days after the last dose of study treatment. Adverse events of particular concern were further monitored and recorded up to 90 days after the last dose of study treatment, regardless of whether another systemic anti-cancer therapy was initiated. All other adverse events were monitored and recorded for up to 90 days after the last dose of study treatment or until another systemic anti-cancer therapy was initiated (whichever occurred first). Unless patients require withdrawal from follow-up, all patients in the study were followed approximately every 3 months for survival and subsequent anti-cancer treatment information until death, loss of follow-up, or termination of the study.

The IMC periodically assessed the cumulative safety data for all patients treated in this study. Safety summary data were evaluated by IMC after the first two dose cohorts of the phase Ia (single drug tirayleigh eculizumab) portion of the study had completed DLT assessments. The IMC reviews the security data to give advice on whether to proceed with the group without changing the phase Ia regimen; begin enrollment of phase Ib portion of the study using tirayleigh mab in combination with atuzumab to review safety data from the safety import cohort and give recommendations on whether to proceed with phase Ib chemotherapy extension cohort, non-chemotherapy extension cohort and Q4W dosing extension cohort enrollment; modifying security monitoring and/or qualification criteria; adding additional security scrutiny to address emerging security issues; or terminate the study. In the absence of safety issues that would preclude it, the accumulation (acctual) was continued in phase Ia part of the study while safety analysis was performed.

To further mitigate the risk of potential unexpected adverse events, the IMC also periodically reviews safety data for patients who enter the extended cohort of phase Ia and phase Ib portions of the study, and specifically proposes recommendations for study performance based on emerging trial safety data to ensure patient safety while receiving study treatment. Interim analysis of invalidity by IMC was also performed in the extended cohort during phase Ia and Ib. In addition, medical auditors may require additional safety reports to be provided, and IMC meetings may be held at any time during the study to review ongoing safety data to balance risk gains.

During the up-dosing phase, at least 3 patients were treated at each tirayleigh mab dose level according to the up-dosing rule described below to determine the MTD or MAD of tirayleigh mab as a single agent or in combination with atuzumab. The cohorts of the first 3 patients in each new dose escalation cohort for the new dose levels of tegaserod examined at phase Ia or Ib were staggered so that their respective cycle 1, day 1 treatment intervals were administered for 7 days or more. All patients were closely monitored for adverse events during the DLT assessment window defined as 21 days (cycle 1, days 1 to 21).

Any dose-escalated patient who does not complete the DLT assessment window for reasons other than DLT is considered to be unevaluable for dose-escalation decision-making and MTD assessment and can be replaced by other patients at the same dose level. During the DLT assessment window, patients who receive supportive care affecting DLT assessment (excluding supportive care described below) and who have not experienced DLT may be replaced as appropriate by a medical supervisor. Patients who have delayed administration of the next planned dose by more than 7 days due to any component of study treatment remaining for reasons other than DLT during the DLT assessment window are considered to be unevaluable for dose escalation decision-making and MTD or MAD assessment and may be replaced by other patients at the same dose level.

Patients receiving treatment in phase Ia portion of the study and developing disease progression when only using tiryleiguzumab are likely eligible to receive treatment in phase Ib portion of the study (fig. 8) provided that specific cohort eligibility criteria are met.

Definition of dose limiting toxicity

In both the Ia and Ib fractions of the study, any of the following events were considered DLT if they occurred during the DLT assessment window and were assessed by the investigator as being relevant to study treatment:

grade 3 non-blood, non-liver adverse events, except:

grade 3 nausea, vomiting or diarrhea, which resolved to grade 2 in < 3 days using standard of care therapy

Grade 3 fatigue, which subsides to grade 2 in < 3 days

Grade 3 fever (defined as > 40 ℃ for ≦ 24 hours)

Grade 3 tumorigenic adverse events (defined as local pain, irritation or rash at known or suspected tumor sites) that regress to grade 2 in 7 days

Grade 3 laboratory abnormalities, asymptomatic and not considered clinically significant by researchers

Grade 3 rash, administered a therapy equivalent to prednisone 10 mg/day or less, which regresses to grade 2 in 7 days or less

Grade 3 arthralgia, which can be adequately managed by supportive care or subsides to grade ≦ 2 in 7 days

Grade 3 autoimmune thyroiditis or other endocrine abnormalities which can be managed by endocrine therapy which does not require the initiation of systemic corticosteroids (except for steroids replacing adrenal insufficiency)

Not less than grade 4 neutropenia (absolute neutrophil count (ANC) < 500/. Mu.L) for more than 7 days

3 or more grade febrile neutropenia

Anemia No. 4

Not less than 4 grade thrombocytopenia or grade 3 thrombocytopenia associated with clinically significant bleeding

Elevation of liver transaminase (ALT or AST) in level 3 or higher for more than 7 days

For patients with grade 1 ALT or AST elevations at baseline due to liver metastasis, only grade 3 elevations, also at 3 × baseline, lasting > 7 days were considered DLT.

Not less than 3 grade serum total bilirubin increase

ALT or AST > 3 × Upper Limit of Normal (ULN) and total bilirubin > 2 × ULN

Rule of dose escalation

Enrollment first started in phase Ia part of the study. The initial dose of tireylaumazumab was 2mg administered IV every 21 days. The dose of tirleiuzumab increased by ≤ 4-fold between consecutive dose levels, and suggested approximate dose levels for evaluating tirleiuzumab were 2mg, 8mg, 30mg, 100mg, 400mg, and 1200mg. The maximum dose increase between successive dose levels can be reduced. Additional intermediate dose levels of teneuimumab may be assessed based on emerging non-clinical efficacy, clinical safety, and/or clinical PK data.

In addition to any DLT, other relevant demographic, adverse events, laboratory, dose management, PK (if available), and pharmacodynamic (if available) data available to be made by medical supervisors and major researchers and committees including, but not limited to, safety scientists, statisticians, PK scientists, and/or clinical trial administrators, are reviewed prior to dose escalation decisions.

Dose escalation follows the following rules.

A minimum of 3 patients were enrolled per dose level (cohort).

If none of the first 3 patients evaluable for DLT experienced DLT during the DLT assessment window, the next cohort may continue to be enrolled with increasing dose levels determined as described above.

If 1 of the first 3 patients evaluable for DLT in a given cohort experienced DLT, then at least 3 additional patients were enrolled at the same dose level (e.g., cohort expanded to 6 patients). If less than one-third of the evaluable patients experienced DLT (e.g., < 2 out of 6 patients), dose escalation continues and grouping with increasing dose levels into the next cohort may continue.

If DLT is observed in at least one third of the patients evaluable for DLT at the dose level in one cohort (e.g., > 2 out of 6 patients), the MTD is exceeded and dose escalation is stopped. The former cohort was expanded to a minimum of 6 patients unless 6 patients had been evaluated at this level. However, if the dose level exceeding the MTD is greater than or equal to 2-fold higher than the previous dose level, 6 patients can be evaluated at intermediate dose levels.

If the MTD is exceeded at any dose level, the highest dose is declared to be the MTD, at which less than one third of the patients with evaluable DLT (i.e. < 2 out of 6 patients) experience DLT.

The highest dose administered in this study was declared to be MAD if the MTD was not exceeded at any dose level.

Any dose level that has been shown not to exceed the MTD can be expanded if warranted based on the investigator's assessment of non-DLT adverse events (including events occurring after cycle 1 and events observed in the expanded cohort).

Dose escalation during phase Ia and/or Ib may be halted or limited as deemed appropriate based on review of available preliminary real-time safety data and available preliminary PK data (collected from phase Ia and/or Ib studies).

After the first two dosing cohorts of the phase Ia part of the study completed DLT assessments, the investigator and IMC reviewed the safety data and suggested whether to initiate the phase Ib part of the study. If it is deemed appropriate to initiate phase Ib, enrollment can continue simultaneously in both portions of the study. The starting dose of the combination of tiregumab and atlizumab was 2mg, and atlizumab was administered at a fixed dose of 1200mg IV, with both drugs administered every 21 days. The dosage of ibritumomab tiuxetan in phase Ib portion of the study did not exceed the highest dose in phase Ia portion of the study at any time, which had been shown to not exceed the MTD. If the combined MTD is exceeded in cohort 1 in phase Ib portion of the study, a lower dose of tenecteuzumab in combination with atuzumab may be considered.

To obtain additional safety and pharmacodynamic data to more fully inform extended cohort dose selection, more patients may be included at dose levels in phase Ia and/or phase Ib portions of the study that have been shown not to exceed the MTD or MAD based on the dose escalation criteria described above. For the purpose of dose escalation decision, these patients were not considered part of the population that could be assessed for DLT. These patients must have a tumor safely accessible and must agree to take a biopsy. To inform pharmacodynamic assessments, patients with tumors expressing PD-L1 and/or TIGIT were enrolled based on prospective testing of tumor tissue during screening or pre-screening. In addition, up to about 12 additional patients may be enrolled in the phase Ia or Ib study at selected dose levels at or below the MTD or MAD to provide additional safety data prior to the initiation of the dose escalation phase.

Only in phase Ia part of the study, patients who developed radiological progression and/or who no longer received clinical benefit from single drug tirayleigh immuzumab might be eligible to receive treatment in phase Ib part of the study, provided they had a tumor safely accessible, consented to biopsy, and met the indicated cohort criteria.

Extended stages of stages Ia and Ib

Patients with locally advanced, recurrent or metastatic incurable malignancies who have progressed after standard therapy is available are included in the extended cohort of studies; or for these patients, standard therapy has proven ineffective or intolerable, or is considered inappropriate; or clinical trials investigating agents are recognized as standard of care for these patients. Only for the phase Ib portion of the study, patients for which clinical trials of study agents in combination with anti-PD-L1/PD-1 antibodies with or without chemotherapy or anti-VEGF antibodies were considered to be acceptable treatment options may be included in the expanded cohort.

This expansion phase consisted of a defined patient cohort to better characterize ibritumomab tiuxetan as a single drug (phase Ia) or with: safety, tolerability, PK variability, pharmacodynamic activity and primary antitumor activity of atelizumab, atelizumab and chemotherapy, atelizumab and bevacizumab, or a parpallizumab combination (stage Ib) in specific cancer settings. Cohort of the expanded cohort was at or below tirayleigh itumumab as single agent (phase Ia) or with: selected dose levels of MAD or MTD for the combination of atlizumab, atlizumab and chemotherapy, atlizumab and bevacizumab, or palboclizumab (phase Ib) were initiated as determined by the investigator of the study based on an assessment of accumulated safety, tolerability, PK, pharmacodynamic and anti-tumor activity data.

In the phase Ia portion of the study, up to about 40 patients were enrolled in a planned expanded cohort that included a variety of tumor indications of PD-L1 selection and/or TIGIT selection, including NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC (including GEJ cancer), UBC, and CRC (including MSS or MSI-Low CRC).

In phase Ib portion of the study (not with chemotherapy), approximately 20 to 40 patients could be included in a variety of tumor indications, including each of the following planned, indication-specific extended cohorts:

NSCLC: primary treatment of Cancer Immunotherapy (CIT) (e.g., no prior treatment with anti-PD-L1/PD-1);

NSCLC: of CIT therapy (e.g. including prior treatment with anti-PD-L1/PD-1)

·RCC

·TNBC

Melanoma (Beech)

·HNSCC

·OC

GC, including GEJ cancer

·UBC

CRC, including MSS or MSI-Low CRC

Biopsy cohort for specific tumor indications (including melanoma, OC, RCC and UBC)

In the phase Ib chemotherapy extension of the study, approximately 20 to 40 patients were enrolled in each of the chemotherapy extension cohorts of the following plans (see fig. 5):

queue A:

-induction phase-alemtuzumab and tirylereuuzumab in combination with cisplatin or carboplatin and pemetrexed

Maintenance phase-alemtuzumab and tirylereuuzumab in combination with pemetrexed

Queue B:

-induction phase-attrituzumab and tirylereuuzumab in combination with carboplatin and paclitaxel

Maintenance phase-attrituzumab and ibritumomab tiuxetan

Queue C:

-induction phase-atlas and ibritumumab in combination with cisplatin or carboplatin and etoposide

Maintenance phase-atelizumab and tirayleigh Euzumab

Queue D:

-atelizumab and tiryleyuuzumab in combination with capecitabine

Approximately 20 to 40 patients may be included in the planned cohort during the Q4W dose chemotherapy extension of the phase Ib of the study (see fig. 4).

Approximately 20 to 40 patients were enrolled in each of the non-chemotherapy expansion cohorts planned below during the non-chemotherapy expansion part of the study in phase Ib (see figure 6).

Queue NC1:

-tirayleigh itumumab and atezumab and bevacizumab

Queue NC2:

-tiryleryitumumab and palboclizumab

Clinical trials of study drugs in combination with anti-PD-L1 antibodies were considered to be acceptable treatment options for CIT naive patients to be eligible only to be eligible for inclusion in the relevant expanded cohort for the phase Ib portion of the study. Otherwise, patients were assigned to available extension sites for phase Ia or Ib portions of the study, as appropriate by the investigator.

Given that the safety of tiryleryitumumab as a single agent (phase Ia) or in combination with atuzumab (phase Ib) may not be fully characterized after assessment of patients in the up-dosing phase, not all potential adverse events or the likelihood of their occurrence may be known at the time of cohort expansion cohort. All available safety data were evaluated continuously to assess tolerance to the dose level studied. To further mitigate the risk of potential unexpected adverse events, the IMC periodically reviews safety data for all patients in an extended cohort into phase Ia and phase Ib portions of the study and makes recommendations for study performance related to patient safety. If the frequency of grade 3 or 4 toxicity or other unacceptable toxicity observed in the extended phase cohort indicates that the dose level has exceeded the MTD during phase Ia or Ib, the accumulation of the dose level is discontinued. Recovery into the group at a lower dose level during the expansion phase will then be considered. Furthermore, if the cumulative safety, tolerability, PK or pharmacodynamic data indicate that the dose levels in the extended cohort are not optimal for assessing primary anti-tumor activity of tirayleigh immuzumab as a single agent (phase Ia) or as a combination of tirayleigh immuzumab with atuzumab (phase Ib), new patients are considered to be included in the cohort at different dose levels. The dose level studied in the extension phase of phase Ia or Ib does not exceed at any time the highest dose level which has been shown to be the MTD not exceeding the corresponding up-dosing phase of phase Ia or Ib.

In the phase Ib chemotherapy extension cohort, the phase Ib Q4W dosing extension cohort, and the phase Ib non-chemotherapy extension cohort, IMC also monitored initial safety after the first 3 patients of each cohort all completed 1 study treatment cycle during the safety introduction period (see fig. 7). The IMC reviews all safety data for the first 3 patients in the cohort to determine whether study treatment can be tolerated, with acceptable assessment of risk by the IMC and investigator allowing the patients to continue dosing. If the study treatment is deemed tolerable in the safety importation of each cohort, the cohorts with equal doses of tiryleiguzumab can be continued in each cohort until a mid-term safety analysis is performed. This occurred after approximately 20 patients were enrolled, including patients in a safety lead.

IMC also monitored efficacy in the extended cohort in the phase Ia and Ib portions of the study by interim analysis after completion of the first tumor assessment in approximately 20 patients in each cohort. If no investigator-determined anti-tumor activity and/or clinical benefit is detected in the expanded cohort, enrollment may be discontinued, as determined after negotiation of the IMC with the investigator. If anti-tumor activity and/or clinical benefit as determined by the investigator is detected in this expanded cohort of patients, IMC may be allowed to continue to cohort up to approximately 40 patients. The sample size of any extended cohort did not increase to more than 40 evaluable patients. Patients who agree to perform serial biopsies without evaluable samples may be replaced with a subset of up to 40 evaluable patients in each expanded cohort.

Phase Ia extended queue

The purpose of the phase Ia extended cohort was to better characterize safety, tolerability, PK and preliminary efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity in patients treated with tiryleauuzumab at dose levels equal to or less than their single drug MTD or MAD. The cohort consisted of approximately 20 to 40 patients with tumors selected for PD-L1 and/or TIGIT. Group entry was initially limited to patients with the following tumor types: NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC (including GEJ carcinoma), UBC, and CRC (including MSS and MSI-Low). If anti-tumor activity and/or clinical benefit as determined by the investigator is observed in patients with other tumor types in the study, cohort may be expanded and/or modified to include other indications.

Of the patients enrolled in this cohort at phase Ia, up to about half of the patients must have tumor lesions safely accessible and agree to receive a biopsy (core needle, punch, clamp or resection/incision) before and during treatment. Other patients may be included to ensure that about half of the patients in the cohort have an evaluable series of biopsies with sufficient live tumor content.

Patients who developed radiological progression and/or patients in this phase Ia extended cohort who no longer received clinical benefit from single drug tegraleigh immuzumab were likely eligible for a subgroup change and receive treatment in phase Ib portion of the study (fig. 8), provided that the patient had a tumor safely accessible, consented for a biopsy, and met the indicated subgroup change criteria.

Extended cohort of stage Ib indication-specific

The purpose of the expanded cohort for phase Ia, which is specific to the indication, was to better characterize safety, tolerability, PK and preliminary efficacy data, and to explore potential tumor biomarkers of pharmacodynamic activity in patients with specific types of cancer treated with tenerriitumumab at dose levels equal to or less than their MTD or MAD in combination with alemtuzumab. Each indication-specific expanded cohort initially included up to about 20 patients with tumors that were PD-L1-selected and/or TIGIT-selected based on prospective testing of tumor tissue during screening or pre-screening, and included a variety of tumor indications, including the following tumor types:

NSCLC: initial treatment of CIT

These patients did not receive prior CIT (studied or approved), including anti-PD-L1/PD-1 and/or anti-CTLA-4, and were only enrolled if the combination of the study agent with the anti-PD-L1 antibody was considered an acceptable treatment option.

NSCLC: of CIT treatment

These patients received prior CIT (either studied or approved), including anti-PD-L1/PD-1.

·TNBC

·RCC

·CRC

Gastric Cancer (GC), including gastroesophageal junction (GEJ) cancer

·HNSCC

·UBC

Melanoma (Beech)

·OC

After 20 patients were enrolled, IMC conferences performed interim analyses to determine whether there was evidence of anti-tumor activity and/or clinical benefit as assessed by the investigator in order to continue enrollment up to approximately 40 patients.

In patients enrolled in phase Ib for each of these indication-specific cohorts, up to about half of the patients must have a tumor lesion safely accessible and agree to receive a biopsy (e.g., core needle, punch, clamp, or excisional/incisional biopsy) before and during treatment. Other patients may be included to ensure that about half of the patients in the cohort have an evaluable series of biopsies with sufficient live tumor content.

Stage Ib series biopsy expansion queue

The purpose of the phase Ib series biopsy expansion cohort was to explore potential tumor biomarkers of pharmacodynamic activity and to better characterize safety, tolerability, PK and preliminary efficacy data in patients with specific types of cancer treated with titrayleigh mab dose levels at or below the MTD or MAD used in combination with atuzumab. This cohort consisted of approximately 20 to 40 patients with tumors that were PD-L1 selected and/or TIGIT selected based on prospective testing of tumor tissue during screening or pre-screening, and may include the following tumor types:

Melanoma (Beech)

·RCC

·OC

·UBC

Patients enrolled in this series of biopsy expansion cohorts must have tumor lesions safely accessible because they need to take two tumor biopsies: 1) Biopsy before treatment: at baseline after all eligibility criteria (except for the requirements on available archival tissues) have been met and prior to administration with study drug, and 2) biopsy during treatment: approximately 2 weeks (days 15 to 21 or between of cycle 1) after the first administration of the combination of tenecteuzumab and atuzumab. RECIST target lesions were not biopsied.

Tissue biopsy methods may include core needle, punch, jaw, or resection/incision biopsy. Patients who provide the required fresh biopsy should also be submitted to an archived tumor specimen (if any).

In this series of biopsy queues, the most recent archival specimen may be used instead of a fresh baseline biopsy, in the following cases:

the specimen meets the sample standard (e.g., core count or punch size).

Specimens were collected within 3 months of day 1 of the proposed 1 st cycle or within time intervals approved by medical monitors.

Specimens were collected following recent systemic therapy and/or any radiotherapy administered to the relevant anatomical region.

The specimen is from the same lesion or organ as the proposed site of the treatment biopsy.

Patients whose baseline biopsy was found to be unevaluable (i.e., due to insufficient material or lack of tumor cells in the sample) were still receiving study treatment and considered for biopsy during treatment. Such patients may be replaced for the purpose of serial biopsy assessment, as well as patients whose on-procedure biopsy cannot be assessed or any patient whose biopsy does not have sufficient live tumor content. Additional optional biopsies may be determined as appropriate by the investigator and with informed patient consent, preferably collected at the time of the imaging response or progression.

Optional biopsies in extended queue

Patients in the cohort expanded cohort were asked to consider optional biopsies (e.g., core needle, punch, clamp, or resection/incision biopsies) to explore pharmacodynamic changes associated with the activity of tirayleigh immuzumab as a single agent or in combination with atuzumab. The grouping of each extended cohort is managed such that up to about half of accrued patients are those with tumor lesions safely accessible and consenting to receive these optional biopsies. In this case, the proposed biopsy time point is the same as described above: baseline after all eligibility criteria (except for the requirements of the available archival organization) have been met, and about 2 weeks (on or between days 15 and 21 of cycle 1) after the first administration of tenecteur.

If the baseline sample is not assessable and no recent archival sample is available for comparison, a during-treatment biopsy need not be performed. Patients with an unevaluable baseline or during-treatment biopsy (i.e., biopsy with insufficient live tumor content) may be replaced for the purpose of serial biopsy assessment.

Patients who provide an optional baseline biopsy should also submit archived tumor specimens (if any).

Phase Ib chemotherapy extended cohort

The purpose of the phase Ib chemotherapy expanded cohort was to better characterize safety, tolerability, pharmacokinetics and preliminary efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity in patients treated with tenecteuzumab in combination with atuzumab and chemotherapy.

Each cohort consisted of approximately 20 to 40 patients with tumors that may be PD-L1 selected and/or TIGIT selected based on prospective testing of tumor tissue during screening or pre-screening. If the medical inspector deems this to be the case based on discussion with the researcher, then patients with insufficient or unavailable archival organization may be eligible for enrollment in the cohort. Patients with tumor types for which clinical trials of study agents in combination with anti-PD-L1 antibodies and chemotherapy are considered acceptable treatment options can be included in these extended cohorts. In each study cohort, the number of patients with a particular tumor type (e.g., NSCLC, SCLC, TNBC) or with a particular treatment history (e.g., CIT treatment) may be limited.

The treatment combinations in each cohort are shown in table 29.

TABLE 29 treatment regimens in chemotherapy extended cohort

^a Patients for cohort a, cohort B with Q3W maintenance (cohort according to scheme GO30103 version 4), and cohort D.

^b Patients with cohort B (grouped according to scheme GO30103 version 5 or later) and cohort D maintained at Q4W.

Each queue had an initial security import of 3 patients (see figure 5). After the first 3 patients in the cohort have completed 21 days of study treatment (i.e., days 1 to 21 of cycle 1), the IMC reviews all safety data for the cohort to determine whether the study treatment can be tolerated, where the presence of acceptable assessments by the IMC and investigator of risk allows the patients to continue administration of atelizumab and tenectereuumab and chemotherapy. Any patient who has not completed the first 21 days of treatment for reasons other than treatment-related toxicity may be replaced by another patient at the same dosage level. If the IMC considers a study treatment to be tolerable in the safety importation of the cohort after a minimum of 3 patients have been enrolled and 21 days of study treatment have been completed, enrollment in the cohort may continue until a total of about 20 patients have been enrolled. The IMC reviews efficacy data for the first approximately 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, then the cohort may continue for a maximum of about 40 patients in total.

If a 600mg dose of tegaserigab is not tolerated during the safety import of any cohort, a lower dose of safety import of tegaserigab can be initiated for the other 3 patients enrolled in the cohort. Safety data for this lower dose group was evaluated after the first 3 patients in the cohort had completed 21 days of study treatment (days 1 to 21 of cycle 1). Approximately 3 additional patients in safety introductions were then included to further assess the safety and tolerability of securititumumab at this lower dose. The dose of only the securitumab can be reduced; the dose of alemtuzumab was not varied. The chemotherapy was dose adjusted, if necessary, following the following guidelines. If such lower dose study treatment can be tolerated, enrollment continues at the lower dose until a total of about 20 patients are enrolled in each cohort, including patients in the lower dose safety lead-in. The IMC reviews data for 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, the cohort may continue to group at lower doses, up to a total of about 40 patients.

If a 600mg dose of ibritumomab tiuxetan was well tolerated during the safety infusion and emerging clinical PK data (e.g., PK data as opposed to chemotherapy) and/or pharmacodynamic data (e.g., receptor occupancy) indicate that a higher dose of ibritumomab tiuxetan is to be used, then the safety infusion of higher doses of ibritumomab tiuxetan was initiated for the next 3 patients in the cohort that were enrolled. This higher dose did not exceed 1200mg every 3 weeks, which is the maximum rated dose of MTG7192A in both phase Ia and Ib of the study, and the maximum concentration observed (C) _max ) Not higher than the maximum concentration observed at a dose level of 1200mg every 3 weeks. If this higher dose of temyleigh immuzumab study treatment is tolerable, the higher dose enrollment into the group safety cohort is continued until at least 6 patients have enrolled and completed the study treatment for 21 days. If IMC considers the higher dose of study treatment to be tolerable in a safety lead, enrollment with the higher dose of Teleliuzumab can continue until a total of approximately 20 patients are enrolled in each cohort. The IMC reviews data for the first 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a favorable benefit-risk profile, the cohort may continue to group at higher doses, up to a total of about 40 patients.

Phase Ib chemotherapy extended cohort: administration and administration

Patients in cohorts a, B and C may receive treatment in 2 phases: an induction phase and a maintenance phase. During the induction phase, patients in a particular chemotherapy extended cohort received the following:

cohort a received atelizumab 1200mg IV on day 1 of each 21 day cycle, followed by tenerayleigh itumumab 600mg IV, followed by pemetrexed 500mg/m ² IV followed by cisplatin 75mg/m ² IV or AUC IV of carboplatin 6 mg/mLmin. Four to six cycles of induction phase therapy are performed without disease progression or unacceptable toxicity.

Queue B at each 21 day cycleDay 1 of (D) received 1200mg IV of atelizumab, followed by 600mg IV of tirayleigh Euzumab, followed by 200mg/m paclitaxel ² IV followed by AUC IV of carboplatin 6 mg/mLmin. Four to six cycles of induction phase therapy were performed without disease progression or unacceptable toxicity.

Cohort C received 1200mg IV of atuzumab, then 600mg IV of ibritumumab tiuxetan, followed by 75mg/m of cisplatin on day 1 of each 21-day cycle ² IV or carboplatin AUC 5mg/mL min IV, then receiving etoposide 100mg/m on days 1 to 3 of each 21 day cycle ² And IV. Four cycles of induction phase therapy were performed without disease progression or unacceptable toxicity.

For cohorts a and C, the choice of cisplatin or carboplatin is at the discretion of the investigator, although the number of patients receiving a particular platinum-based chemotherapeutic agent may be limited. For cohorts a and B, the number of cycles (four to six) applied during the induction period was determined by the investigator as appropriate.

After the induction period, in the absence of unacceptable toxicity, clinically convincing disease progression, and/or loss of clinical benefit, the investigator, as appropriate, can proceed with treatment in the maintenance period after careful evaluation and thorough discussion of potential risk and benefit with the patient.

During maintenance, study treatment was continued every Q3W for cohort a, cohort B and cohort D grouped according to protocol version 4; or for cohorts B and C grouped according to version 5 or later of the protocol, study treatment was continued every Q4W.

During the maintenance phase, patients in a particular chemotherapy extended cohort receive the following:

cohort A received 1200mg IV of atuzumab, then 600mg IV of ibritumumab, and then 500mg/m of pemetrexed on day 1 of each 21-day cycle ² IV

Cohort B received 1680mg IV of atuzumab followed by 840mg IV of ibritumumab tiuxetan on day 1 of each 28 day cycle. If patients were enrolled according to GO30103 version 4, patients in cohort B continued to receive 1200mg IV of atlizumab on day 1 of each 21 day cycle, followed by 600mg IV of ibritumumab tiuxetan

Cohort C received 1680mg IV of atuzumab followed by 840mg IV of ibritumumab tiuxetan on day 1 of each 28 day cycle.

Patients in cohort D were treated with capecitabine, altlizumab, and tirylereuzumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator. The patient took 1250mg/m on days 1 to 14 of each 21-day cycle ² Dose of BID oral capecitabine. On day 1 of cycle 1, the first dose of capecitabine was administered in the clinic prior to infusion of atuzumab and tenectereuzumab. The combination of atezumab and tenecteuzumab was administered by IV infusion over a 21 day period.

If a toxic event occurs without disease progression or loss of therapeutic benefit, the individual chemotherapeutic or immunotherapeutic agents can be discontinued alone. However, treatment with atelizumab alone or with tegraleigh immuzumab alone (with or without chemotherapy) can only be considered after no contraindications and discussion with medical monitors.

Phase Ib Q4W administration extended cohort

The phase Ib Q4W dosing extended cohort was targeted to better characterize safety, tolerability, PK and preliminary efficacy data and explore potential tumor biomarkers of pharmacodynamic activity in patients treated with the tiryleigh itumumab 840mg IV in combination with alemtuzumab 1680mg IV in a 4 week (28 days; Q4W) dosing schedule.

The phase Ib Q4W cohort consisted of approximately 20 to 40 patients with tumors that may be PD-L1 selected and/or TIGIT selected based on prospective testing of tumor tissue during screening or pre-screening. If the medical inspector deems this to be the case based on discussion with the researcher, then patients with insufficient or unavailable archival organization may be eligible for enrollment in the cohort. Patients with tumor types for which clinical trials of study agents in combination with anti-PD-L1 antibodies are considered acceptable treatment options can be included in these extended cohorts. In each study cohort, the number of patients with a particular tumor type (e.g., NSCLC, SCLC) or with a particular treatment history (e.g., CIT treatment) may be limited.

The cohort had an initial security import of 3 patients (see figure 4). After the first 3 patients in the cohort have completed 28 days of study treatment (i.e., days 1 to 28 of cycle 1), the IMC reviews all safety data for the cohort to determine whether study treatment can be tolerated, wherein the presence of an acceptable assessment of risk by the IMC and the investigator allows the patients to continue dosing with both tiyumumab and atuzumab. Any patient who has not completed the first 28 days of treatment for reasons other than treatment-related toxicity may be replaced by another patient at the same dosage level. If the IMC considers the study treatment to be tolerable in the safety importation of the cohort after a minimum of 3 patients have been enrolled and have completed the study treatment for 28 days, enrollment may continue into the cohort until a total of about 20 patients have been enrolled. The IMC reviews efficacy data for the first approximately 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, then the cohort may continue for a maximum of about 40 patients in total.

If a 840mg dose of tenecteuzumab was not tolerated during the safety import of any cohort, a lower dose of the safety import of tenecteuzumab could be initiated for the other 3 patients enrolled in the cohort. Safety data for this lower dose group was evaluated after the first 3 patients in the cohort had completed 28 days of study treatment (days 1 to 28 of cycle 1). Approximately 3 additional patients will be enrolled in a safety study to further assess the safety and tolerability of temrayleigh mab at this lower dose. The dose of only the tegravitumumab can be reduced; the dose of alemtuzumab was not varied. If such lower dose study treatment can be tolerated, enrollment is continued at the lower dose until a total of about 20 patients are enrolled in each cohort, including patients in a lower dose safety lead-in. The IMC reviews the data for 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, the cohort may continue to group at lower doses, up to a total of about 40 patients.

If the dose of the tiryleryuezumab at 840mg is in the safety introducing periodWell tolerated and emerging clinical PK data and/or pharmacodynamic data (e.g., receptor occupancy) indicate that higher doses of ibritumomab are to be used, a safer introduction of higher doses of ibritumomab was initiated for the next 3 patients in each cohort in the group. This higher dose did not exceed 1200mg, which is the maximum rated dose of MTG7192A in both phase Ia and Ib parts of the study, and the maximum concentration observed (C) _max ) Not higher than the maximum concentration observed at a dose level of 1200mg every 3 weeks. If this higher dose of temyleigh immuzumab is tolerated for study treatment, the safety introduction at the higher dose is continued until at least 6 patients have been enrolled and have completed study treatment for 28 days. If IMC considers the higher dose of study treatment to be tolerable in a safety cohort, enrollment with the higher dose of tegaserod may continue until a total of approximately 20 patients are enrolled in the cohort. The IMC reviews data for the first 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, the cohort continues to group at higher doses, amounting to a maximum of about 40 patients.

Phase Ib non-chemotherapy extended cohort

The purpose of the phase Ib non-chemotherapy expanded cohort was to better characterize safety, tolerability and preliminary efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity in patients treated with both tirayleigh itumumab and atelizumab in combination with bevacizumab and tirayleigh itumumab in combination with parbociclizumab.

Each cohort consisted of approximately 20 to 40 patients with tumors that may be PD-L1 selected and/or TIGIT selected based on prospective testing of tumor tissue during screening or pre-screening. If the medical inspector deems this to be the case based on discussion with the researcher, then patients with insufficient or unavailable archival organization may be eligible for enrollment in the cohort. Patients with tumor types for which clinical trials of the study agent in combination with anti-PD-L1/PD-1 with or without bevacizumab are deemed acceptable treatment options (as judged by the investigator) can be included in these extended cohorts. In each study cohort, the number of patients with a particular tumor type (e.g., HCC, melanoma) or with a particular treatment history (e.g., CIT treatment) may be limited.

The treatment combinations in each cohort are shown in table 30.

TABLE 30 treatment combinations by cohort

^a In the order of application

Each queue had an initial security import of approximately 3 patients (see fig. 6). After the first 3 patients in the cohort have completed 3 weeks (21 days) of study treatment (i.e., days 1 to 21 of cycle 1), the IMC reviews all safety data for the cohort to determine whether study treatment can be tolerated, where the presence of an acceptable assessment of risk by the IMC and investigator allows the patients to continue dosing of tirayleigh immuzumab and atuzumab with bevacizumab (cohort NC 1) or tirayleigh immuzumab and palbociclumab (cohort NC 2). Any patient who has not completed the previous 3 weeks of treatment for reasons other than treatment-related toxicity may be replaced by another patient at the same dose level. If the IMC considers the study treatment to be tolerable in the safety importation of the cohort after a minimum of 3 patients have been enrolled and 3 weeks of study treatment have been completed, enrollment may continue into the cohort until a total of about 20 patients have been enrolled. The IMC reviews the efficacy data of the first approximately 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, then the cohort may continue for a maximum of about 40 patients in total.

If a 600mg dose of ibritumomab tiuxetan was not tolerated during the safety import of any cohort, a lower dose of safety import of ibritumomab tiuxetan may be initiated for approximately 3 additional patients enrolled in the cohort. Safety data for this lower dose group was evaluated after the first 3 patients in the cohort had completed 3 weeks of study treatment (days 1 to 21 of cycle 1). Approximately 3 additional patients in safety introductions were then included to further assess the safety and tolerability of securititumumab at this lower dose. The dose of only the securitumab can be reduced; the dosages of either the palbociclumab or the atlizumab and bevacizumab were not changed. If such lower dose study treatment can be tolerated, enrollment continues at the lower dose until a total of about 20 patients are enrolled in each cohort, including patients in the lower dose safety lead-in. The IMC reviews data for 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a beneficial benefit-risk, the cohort may continue to be enrolled at lower doses, up to a total of about 40 patients.

If a 600mg dose of tegaserigab is well tolerated during the safety infusion, a safety infusion of a higher dose of tegaserigab can be initiated for the next approximately 3 patients enrolled in each cohort. This higher dose did not exceed 1200mg every 3 weeks, which is the maximum rated dose of tiryleuimab in both phase Ia and Ib fractions of the study, and the maximum concentration observed (C) _max ) Not higher than the maximum concentration observed at a dose level of 1200mg every 3 weeks. If this higher dose of temleiitumumab is tolerated for study treatment, the safety introduction continues at the higher dose until at least 6 patients have been enrolled and completed the study treatment for 3 weeks. If IMC considers the higher dose of study treatment to be tolerable in a safety lead, enrollment with the higher dose of Teleliuzumab can continue until a total of approximately 20 patients are enrolled in each cohort. The IMC reviews data for the first 20 patients in each cohort to assess safety and efficacy. If the IMC determines that there is a favorable benefit-risk profile, the cohort may continue to group at higher doses, up to a total of about 40 patients.

Dose reduction of tiryleryitumumab and atelizumab and other non-chemotherapeutic agents

Generally, there was no dose reduction for tireyueuzumab in this study. However, if the cumulative safety data available indicates that the dosage level of tirleiuzumab initially selected as the single drug (phase Ia) or used in combination with atuzumab (phase Ib) exceeds the MTD or MAD, the accumulation at that dosage level may be discontinued, and if applicable, further dose escalation may be discontinued.

In this case, the individual patient may choose to reduce the ticagreux dose to the new dose level if the following criteria are met:

the dose initially dispensed by the patient is equal to (or greater than) the dose level that has been turned off for further cohorts

The investigator considered that the overall benefit/risk balance favors continued treatment in phase Ia or Ib

For alemtuzumab, there was no intra-patient dose reduction; astuzumab is to be administered at a fixed dose of 1200mg every 21 days or 1680mg every 28 days (Q4W dose extension cohort).

For bevacizumab, there was no intra-patient dose reduction; bevacizumab is to be administered at a fixed dose of 15mg/kg every 3 weeks.

For palivizumab, there was no intra-patient dose reduction; the palbociclizumab is to be administered at a fixed dose of 200mg every 3 weeks.

Treatment after disease progression

At the discretion of the investigator after discussion with the medical supervisor, patients may continue study treatment in phase Ia or phase Ib portion of the study after RECIST v1.1 criteria that meet criteria for disease progression, provided that the patient meets all of the following criteria (see fig. 7):

absence of symptoms and signs (including laboratory value worsening, e.g., new or worsening hypercalcemia), then a clear indication of disease progression

In vivo status of eastern cooperative tumor group (ECOG)

Critical anatomical sites that cannot be easily managed and stabilized by protocol-allowed medical intervention before repeated dosing are free of tumor progression. Key anatomical sites include the CNS, central airways, large blood vessels and other organs or tissues where impaired function secondary to tumor progression is expected to lead to severe and/or irreversible disability or death.

Patients must agree to confirm a discussion with treatment researchers regarding the benefit-risk balance of continuing study treatment after imaging progress.

If the progress of the imaging disease is confirmed in the subsequent phase Ia or Ib tumor assessments, the investigator may decide, as appropriate, to continue study treatment after discussion with the medical supervisor if the patient continues to meet the above criteria and has sustained clinical benefit as evidenced by at least one of:

tumor shrinkage (reduction in diameter by at least 30% from baseline) of one or more appreciable lesions

Improvement of one or more symptoms or signs caused by the underlying cancer assessed by the investigator (e.g., reduced need for anesthetic against pain, reduced dyspnea associated with pleural effusion, weight gain)

Only in phase Ia of the study, as outlined above, patients treated with single drug telyuromumab and developing disease progression and/or no longer receiving clinical benefit may be eligible for treatment with a combination of telyuromumab and astuzumab in phase Ib of the study, provided that the patients had a safely accessible tumor, consented to biopsy, and met the indicated cohort criteria.

In chemotherapy extension cohorts a, B, C and D, treatment after disease progression must include immunotherapy (atelizumab and/or tenecteuzumab) with or without chemotherapy, and cannot be treated with chemotherapy alone.

Transition from single drug temepruezumab treatment to combinations of temepruezumab with atuzumab at progression

In patients treated with ibritumomab tiuxetan as a single drug in phase Ia portion of the study, patients who developed disease progression and/or no longer achieved clinical benefit may be eligible to receive treatment with ibritumomab tiuxetan in combination with attentizumab in phase Ib portion of the study (see fig. 8), provided that the following conditions are met:

during phase Ia of the study, patients must have imagewise documented disease progression including CT scans of the chest, abdomen and pelvis.

Patients must not experience toxicity that would preclude combination treatment with tirayleigh ecumab and atelizumab in phase Ib studies, requiring termination of treatment with tirayleigh ecumab, and must not experience toxicity during the last dose of study treatment.

Patients must meet all inclusion and exclusion criteria.

Any adverse events associated with tiryleyumumab must have resolved to grade ≦ 1 or baseline on or before the first day of study phase Ib fraction treatment. Exceptions may be allowed after the researcher carefully assesses and discusses the benefit-risk balance with the patient and obtains approval from the medical supervisor.

Treatment with tirayleigh immuzumab and atlizumab after progression during the single drug tirayleigh immitumab period must be considered acceptable as determined after the investigator carefully assesses and discusses the benefit-risk balance with the patient and obtains approval by the medical supervisor.

Patients with safely accessible disease sites need to undergo tumor biopsy. The biopsy may be performed at any time prior to administration of tirayleigh eculizumab and atlizumab in the phase Ib study. An optional treatment session biopsy may also be collected on or between days 15 and 21 of cycle 1 after administration of tirayleigh immuzumab and atlizumab. RECIST target lesions were not biopsied.

In the phase Ib study, the dose and schedule of the group transfer treatment with the combination of tiryleyumab and atuzumab required approval by the medical supervisor. In general, patients transferred to phase Ib portion of the study received the highest dose of tiryleuimab that had been shown to not exceed their MTD when combined with atuzumab (fig. 7). Thus, the dose levels of ibritumomab tiuxetan evaluated in the phase Ib study may be different from those evaluated in the same patient in the phase Ia study. Patients who had been adjusted for dosing and/or schedule of ibritumomab tiuxetan as a single drug in the phase Ia study continued to receive ibritumomab tiuxetan at the same dose and/or schedule during phase Ib, as long as the dose of ibritumomab tiuxetan had previously demonstrated not to exceed the MTD of ibritumomab tiuxetan when used in combination with atuzumab.

Patients who were enrolled from the phase Ia portion of the study to the phase Ib portion of the study were treated as follows:

the assessment obtained at the treatment termination visit in the phase Ia study can be used as a screening assessment for part of the combination treatment in phase Ib of the study. The following rescreening assessments must be repeated/obtained within 2 weeks prior to the first day of initiation of combination regimen treatment in order to reestablish baseline pre-treatment clinical and disease status: targeted physical examination, ECOG status, hematology and serum chemistry laboratory tests, thromboset, amylase, lipase, thyroid function tests, and urinalysis.

There is no need to repeat screening tests for hepatitis b, hepatitis c, HIV, cytomegalovirus (CMV) and EBV unless the clinical suspicion is positive because they were last performed during the screening of the phase Ia study.

Imaging tumor assessments, including CT scans of the chest, abdomen and pelvis, must also be performed within 6 weeks prior to the first day of the start of phase Ib study combination therapy, unless these assessments have been completed to document disease progression, as the assessments become new baseline scans for patients enrolled in the phase Ib study.

In the phase Ib study, patients were treated with a combination of tirayleigh itumumab and atuzumab until a second disease progression event associated with a tumor assessment documenting progressive disease, clinical exacerbation, intolerance to combination therapy and/or loss of clinical benefit of combination therapy during the initial study treatment. As previously noted, patients may continue study treatment after meeting the criteria for RECIST v1.1 disease progression in the phase Ib study, as appropriate by the investigator after discussion with a medical supervisor, provided they meet all of the specified criteria.

Assessment of the safety and efficacy of the patients in the cohort.

Clinical and exploratory data of tumor biopsies obtained prior to treatment of the cohort from phase Ia to phase Ib were continuously monitored.

The cohort shift from phase Ia fraction to phase Ib study may be limited or suspended at any time. Reasons for this may include security, undesirable patient grouping, and/or incomplete data records.

C. Study treatment

Administration and administration

Administration of ibritumumab as a single drug (phase Ia) or in combination with atuzumab (phase Ib) was carried out in an environment with an emergency medical facility that could use intensive care units and staff trained to monitor and respond to medical emergencies.

For study phase Ib fraction treatment (cohort without chemotherapy), on the planned study treatment infusion day, tirayleigh itumumab was administered before atuzumab with an intermediate observation period.

For treatments in the phase Ib chemotherapy extension cohort, atelizumab was used before tenestributumab on the planned study treatment infusion day, with an intermediate observation period. Chemotherapy was administered after alemtuzumab and ibritumomab tiuxetan, with an intermediate observation period for ibritumomab tiuxetan.

For treatment in the phase Ib non-chemotherapy extended Cohort, on the planned study treatment infusion day, securityluzumab was administered before atuzumab (couert NC 1) and bevacizumab (Cohort NC 2), with an intermediate observation period. Bevacizumab was administered after both tirayleigh eculizumab and atlizumab, with one intermediate observation period for bevacizumab.

For detailed information on the instructions for the preparation and administration of the dosages of tirylereumab, atelizumab or bevacizumab, see the corresponding researchers' manual and GO30103 pharmaceutical manual.

For details on the dosage preparation and instructions for administration of cisplatin, carboplatin, pemetrexed, paclitaxel, capecitabine, etoposide, and palbociclizumab, see the package insert or SmPC.

Turayleigh Euzumab in stage Ia and Ib

Approximate dosage levels of tegravitumumab to be evaluated in the phase Ia and Ib portions of the study were 2mg, 8mg, 30mg, 100mg, 400mg and 1200mg administered by IV infusion every 3 weeks. Additional dose levels not exceeding phase Ia or phase Ib MTD, or a new dosing schedule for phase Ia and/or phase Ib, may be assessed after negotiation with the participating investigators based on new non-clinical efficacy, clinical safety and clinical PK data. Assessment of dose levels exceeding 1200mg of ibritumomab tiuxetan required protocol revision with supporting justification. For the phase Ib chemotherapy extension cohort, tirayleigh immuzumab 600mg is the initial dose administered every 3 weeks by IV infusion. For phase Ib chemotherapy cohort B and cohort C with Q4W maintenance, the dose of tiryleauuzumab became 840mg during maintenance. For the phase Ib Q4W dosing cohort, 840mg of tiryleyumumab was the initial dose administered by IV infusion of Q4W. The dose was independent of body weight.

This 840mg Q4W dosing regimen was supported by PK modeling and simulation as well as exposure-safety analysis results. The mean concentration after this 840mg Q4W dosing regimen was comparable to that of the 600mg dosing regimen every 3 weeks, which was evaluated in studies GO30103 and GO 40290. The Cmax of this 840mg Q4W dosing regimen was 28% higher at steady state than the Cmax of the 600mg every 3 weeks dosing regimen, but fell within the exposure range of the highest administered dose observed clinically (1200 mg every 3 weeks in study GO 30103). Preliminary analysis of the exposure-safety relationship for ibritumomab tiuxetan based on data from study GO30103 (dose of ibritumomab tiuxetan 2-1200mg every 3 weeks, administered as monotherapy or in combination with 1200mg of atuzumab every 3 weeks) showed that ibritumomab tiuxetan exhibited a flat exposure-safety relationship. In summary, this 840mg Q4W dosing regimen has safety and efficacy comparable to the 600mg every 3 weeks dosing regimen, given that exposure is within the range of effective exposures observed, and that tiryleiguzumab appears to have a flat exposure-safety relationship.

In phase Ia of the study, the initial dose of tenerriitumumab was delivered over 90 (± 10) minutes (although infusion may be slowed or interrupted for patients experiencing infusion-related symptoms), followed by 240 minutes of observation. In the phase Ib study, the initial dose of tirleiuzumab was delivered over 60 (± 10) minutes, followed by an observation period of 60 minutes. If the initial infusion is tolerated without infusion-related adverse events, the second infusion in phase Ia can be delivered over 60 (+ -10) minutes followed by an observation period of 60 minutes, while the second infusion in phase Ib can be delivered over 30 (+ -10) minutes followed by an observation period of 30 minutes. If the 60 minute infusion of phase Ia is well tolerated, the third infusion of phase Ia may be delivered over 30 (+ -10) minutes followed by a 30 minute observation period. If the third infusion of phase Ia or the second infusion of phase Ib is well tolerated, all subsequent infusions of phase Ia or Ib can be delivered over 30 (. + -. 10) minutes followed by an observation period of 30 minutes. Patients who previously received a single drug, tenecteuzumab, in phase Ia and now received a combination of tenecteuzumab and atuzumab in phase Ib, may receive the fastest initial dose in phase Ib that the patient previously tolerated.

No dose reduction for tegraluretumab in this study (phase Ia or phase Ib) except the indicated subjects. Dosing and treatment discontinuation or termination guidelines for tenerriuzumab are provided. Guidance regarding study drug administration in the context of specific adverse event management is provided.

Adverse events associated with study drug overdose or incorrect administration were recorded.

Abutilizumab in stage Ib

In phase Ib part of the study, the dose of atlizumab administered in combination with tirayleigh eculizumab was 1200mg IV every 3 weeks. For phase Ib chemotherapy cohort B and cohort C with Q4W maintenance, the dose of atzumab was changed to 1680mg during maintenance. In the phase Ib Q4W dosing cohort, atbizumab 1680mg IV Q4W was administered. The dose is fixed and independent of body weight.

In all phase Ib cohorts without chemotherapy, atelizumab was administered after infusion of tegaserod and subsequent observation period. In the phase Ib chemotherapy extension cohort, atelizumab was administered before teneligulizumab.

The initial dose of alemtuzumab is delivered over 60 (± 10) minutes. If a first infusion can be tolerated without adverse events associated with the infusion, a second infusion can be delivered over 30 (± 10) minutes. If a 30 minute infusion is tolerable, all subsequent infusions can be delivered over 30 (± 10) minutes. For cycle 1, the attritumab administration was followed by a 60 minute observation period. All subsequent alemtuzumab infusions may be followed by an observation period of 30 minutes. Patients who have previously received atelizumab in another clinical trial may receive the initial dose at the fastest rate that was previously tolerated.

There was no dose reduction for attrituzumab in this study. Guidance for dose adjustment and treatment discontinuation or termination is provided. Guidance regarding study drug administration in the context of specific adverse event management is provided.

Adverse events associated with study drug overdose or incorrect administration were recorded.

Non-chemotherapy cohort in phase Ib extension

Queue NC1: tirayleigh itumumab and atelizumab and bevacizumab

Patients in the cohort of tirayleigh immuzumab and atlizumab and bevacizumab received treatment as outlined in table 31 until unacceptable toxicity or loss of clinical benefit as determined by the investigator after a comprehensive assessment. It is recommended to initiate treatment no later than 7 days after group entry; however, the first dose of study treatment must not be performed within 7 days after core biopsy or other surgical procedure.

TABLE 31 treatment regimen for cohort NC1

IV = intravenous

^a The drugs are listed in order of administration. All drugs were administered by IV infusion on day 1 of each 21 day cycle.

^b On day 1 of cycle 1, bevacizumab was administered 60 minutes after completing the atuzumab infusion. If the patient experiences an infusion-related reaction during a previous infusion of medication, the interval between subsequent infusions is 60 minutes. If a previous infusion of medication can be tolerated without infusion-related reactions, the interval can be reduced To 30 minutes.

Queue NC2: tirayleigh monoclonal antibody and palivizumab

Patients in the cohort of tirayleigh immuzumab and palbociclumab received treatment as outlined in table 32 until unacceptable toxicity or loss of clinical benefit as determined by the investigator after a comprehensive assessment. It was recommended to initiate treatment no later than 7 days after group entry; however, the first dose of study treatment must not be performed within 7 days after core biopsy or other surgical procedure.

TABLE 32 treatment protocol for cohort NC2

IV = intravenous

^a The drugs are listed in the order of administration. All drugs were administered by IV infusion on day 1 of each 21 day cycle.

^b On day 1 of cycle 1, palbociclumab was administered 60 minutes after completion of the infusion of tiryleiguzumab. If the patient experienced an infusion-related reaction during a previous infusion of ibritumumab, the interval between subsequent infusions was 60 minutes. If a previous infusion of tirayleigh immuzumab was given without prophylactic administration and could be tolerated without infusion-related reactions, the interval could be reduced to 30 minutes.

Phase Ib non-chemotherapy extended cohort: administration and administration

Patients in cohort NC1 received 600mg IV of tirayleigh itumumab on day 1 of every 3 week cycle, followed by 1200mg IV of atelizumab, followed by 15mg/kg IV of bevacizumab. Treatment is administered until unacceptable toxicity or loss of clinical benefit is determined by the investigator.

Patients in cohort NC2 received 600mg IV of ibritumomab tiuxetan on day 1 of every 3 week cycle, followed by 200mg IV of palboceprizumab. Treatment is administered until unacceptable toxicity or loss of clinical benefit is determined by the investigator.

If a toxic event occurs and therapeutic benefit is lost, the immunotherapy agent alone can be terminated. However, treatment with either of the palivizumab or bevacizumab or atuzumab or tiregumab alone is only considered after no contraindications and discussion with medical monitors.

Bevacizumab in phase Ib extended cohort

Bevacizumab was administered at a fixed dose of 15mg/kg by IV infusion on day 1 of each 21-day cycle. The administration of bevacizumab is carried out in a monitored environment where trained personnel and sufficient equipment and medications are immediately available to manage potential critical reactions. Guidance for dose adjustment and discontinuation or termination of treatment due to toxicity is provided.

No prophylactic administration was allowed prior to the first infusion of bevacizumab. If a patient develops IRR as a result of any prior drug infusion, the investigator may decide to administer a prophylactic medication of an antihistamine, antipyretic and/or analgesic as appropriate. Vital signs (pulse rate, respiration rate, blood pressure and body temperature) were measured within 60 minutes prior to infusion. The initial dose of bevacizumab is delivered over 90 (± 10) minutes. If a first infusion can be tolerated without adverse events associated with the infusion, a second infusion can be delivered over 60 (± 10) minutes. If a 60 minute infusion is tolerable, all subsequent infusions can be delivered over 30 (± 10) minutes. For cycle 1, bevacizumab administration was followed by an observation period of 60 minutes. All subsequent infusions of bevacizumab may be followed by an observation period of 30 minutes. Patients who have previously received bevacizumab may receive the initial dose at the fastest rate that was previously tolerated. The patients were informed about the likelihood of post-infusion symptom delay and instructed to contact their investigator when such symptoms occurred. An explanation is provided regarding vital sign measurements.

Pabolizumab in stage Ib extended cohort

In the phase Ib non-chemotherapy extension cohort of the present study, the dose of palbociclizumab administered in combination with tirayleigh itumumab was 200mg IV every 3 weeks. The dose is fixed and independent of body weight.

For guidance on dosage preparation, storage, administration, and instructions for discontinuation or termination of treatment of palbociclizumab, see information on the palbociclizumab formulation.

Chemotherapy in the phase Ib extended cohort

Chemotherapy (except capecitabine) was administered after infusion of atuzumab and tirylereuzumab and subsequent observation periods.

During the induction period, the chemotherapy cycle counts the predetermined number of induction chemotherapy cycles as long as at least one chemotherapy component has been administered at least once during a 21 day cycle. Cycles without administration of the chemotherapy components do not account for the total number of induced chemotherapy cycles.

Patients with evidence of clinical benefit are allowed to continue treatment after RECIST v1.1 criteria for PD are met during treatment (induction or maintenance).

Patients received an antiemetic and IV chemotherapeutic agent hydrated according to local standard of care and manufacturer instructions. However, due to the immunomodulatory effects of steroids, prophylactic use of steroids is minimized within clinical feasibility.

Dose adjustments for chemotherapy and guidance for discontinuation or termination of treatment are provided.

And a queue A: abiralizumab gagatirayleigh eryitumumab plus carboplatin/cisplatin plus pemetrexed

On day 1 of each 21-day cycle, all eligible patients received drug infusions in the following order:

induction: abiralizumab → Tarayleigh Eusumab → Pemetrexed → carboplatin or cisplatin

After 4 to 6 cycles in the induction phase, the patient began maintenance therapy in the following order of administration:

maintaining: abiralizumab → Tarayleigh Eusumab → Pemetrexed

Table 33 lists the suggested prophylactic administration of pemetrexed. Table 7 lists the recommended infusion times for pemetrexed and carboplatin or cisplatin during the induction period and for pemetrexed treatment administration during the maintenance period.

TABLE 33 preoperative medications for pemetrexed

BID = twice daily; IM = intramuscular; PO = oral; Q9W = every 9 weeks.

And a queue B: atelizumab plus titrayleigh itumumab plus carboplatin plus paclitaxel

On day 1 of each 21-day cycle, all eligible patients received drug infusions in the following order:

induction: alemtuzumab → terayleigh immuzumab → paclitaxel → carboplatin

After 4 to 6 cycles in the induction phase, maintenance therapy is started on day 1 of each 21-day cycle if patients are enrolled according to the version 4 protocol, and on day 1 of each 28-day cycle if they are enrolled according to the version 5 or later. All eligible patients received drug infusions in the following order of administration:

Maintaining: abiralizumab → Tarayleigh immuzumab

Table 8 lists the recommended prophylactic medications for induction treatment of patients in cohort B. Table 9 lists the recommended infusion times for paclitaxel and carboplatin treatment administration during the induction period.

And C, queue C: atelizumab plus titrayleigh eryusizumab plus carboplatin or cisplatin

On day 1 of each 21-day cycle, study drug infusions were administered to all eligible patients in the following order:

induction: abiralizumab → Tarayleigh Eusumab → cisplatin or carboplatin → Etoposide

After the induction period, the patient began maintenance therapy on day 1 of each 28-day cycle in the following order of administration:

maintaining: atelizumab → terayleigh immuzumab

Table 10 lists the recommended infusion times for carboplatin or cisplatin and etoposide treatment administration during the induction period.

And a queue D: capecitabine plus atelizumab plus titarelinyluxuuzumab

On day 1 of each 21-day cycle, all eligible patients were administered study medication in the following order:

capecitabine → altuzumab → Ewing Rayleigh

Table 34 lists the recommended length, route of administration, and regimen for capecitabine therapeutic administration.

TABLE 34 cohort treatment regimens for capecitabine and tiryleigh Euzumab and Attuzumab

BID = twice daily; PO = oral.

^a The drugs are listed in the order of administration.

Cis-platinum

Guidelines for cisplatin administration in the different cohorts are shown in table 11.

Carboplatin

Guidelines for administration of carboplatin in the different cohorts are shown in table 12.

Pemetrexed

Guidelines for the administration of pemetrexed in cohort a are shown in table 13.

Paclitaxel

A guideline for paclitaxel administration in cohort B is shown in table 14.

Etoposide

Guidance for the administration of etoposide in cohort C is shown in table 15.

Capecitabine

Capecitabine is provided as 150mg and 500mg gram tablets. Patients received treatments as outlined in table 35 until unacceptable toxicity or loss of clinical benefit occurred as determined by the investigator.

TABLE 35 Capecitabine administration timing and guidelines

BID = twice daily; PO = oral.

Capecitabine is administered with water and within 30 minutes after meals. Patients were instructed to return used and unused medications to the study site.

D. Concomitant therapy

Concomitant therapy includes patients using any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic drugs and/or nutritional supplements) from 7 days prior to screening to the treatment termination visit.

Allowed therapy

Patients who experienced infusion-related symptoms in this study (phase Ia or Ib) may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine and/or ranitidine or another H2 receptor antagonist according to standard practice (for sites outside the united states, local convention may be substituted for the equivalent). Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and are managed with supportive care (e.g., supplemental oxygen and β 2 adrenergic agonists) according to clinical indications. The antihistamine may be used prophylactically in cycle Ia or Ib as appropriate by the attending physician.

Systemic corticosteroids, immunosuppressive drugs and TNF-alpha antagonists may attenuate the potentially beneficial immune effects of treatment with tiryleyumab as a single agent or in combination with anti-PD-L1/PD-1, but may be administered by the attending physician in an emergency as appropriate or after consultation with a medical supervisor. Alternatives to corticosteroids, immunosuppressive drugs or TNF-alpha antagonists are contemplated, if applicable. After consultation with a medical monitor, the attending physician may decide to administer prophylactic medications for tenecteuzumab, atuzumab, bevacizumab, and palboceprizumab at cycle # 2 as appropriate. Inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for orthostatic hypotension or adrenal insufficiency patients) are allowed. Allows the use of physiological doses of corticosteroids for the treatment of adrenal insufficiency. Megestrol is also allowed to be administered as an appetite stimulant. The planned use of other medications is discussed with the medical supervisor.

For patients in the phase Ib chemotherapy extended cohort, antiemetics and systemic steroids may also be administered:

appropriate antiemetic prophylaxis is administered. If feasible, the use of a non-steroidal antiemetic regimen consisting of 5-HT3 receptors and NK1R antagonists was encouraged (Hesketh et al J Clin Oncol 2017.

All patients in cohort a who received pemetrexed may be given a dexamethasone (or equivalent) pretreatment to reduce the incidence and severity of skin reactions. In clinical trials, dexamethasone 4mg was given by oral BID the day before, on and the day after pemetrexed administration.

Dexamethasone (or equivalent) pretreatment can be given to all patients in cohort B who received paclitaxel. In clinical trials, dexamethasone 20mg was given orally 12 and 6 hours prior to paclitaxel administration.

Planned use of prophylactic antibiotics (e.g., after surgical intervention) is discussed with medical monitors. Study drug treatment continued until the end of the course of antibiotics.

Patients using oral contraceptives, hormone replacement therapy, prophylactic or therapeutic anticoagulant therapy (such as low molecular weight heparin or a stable dose level of warfarin), or other maintenance therapy for non-malignant indications should continue to use. Men and women with reproductive potential should use highly effective means of contraception.

For patients in the chemotherapy extended cohort, the following medications were cautiously administered:

cautious administration of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with mild to moderate renal insufficiency (creatinine clearance [ CrCl ] 45 to 79 mL/min) receiving pemetrexed (cohort a). NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) are avoided at 2 days, on the day, and 2 days after pemetrexed administration. In the absence of data regarding potential interactions between pemetrexed and longer half-life NSAIDs (e.g., meloxicam (meloxicam), nabumetone (nabumetone)), patients taking these NSAIDs should discontinue dosing on the first 5 days, the same day, and the next 2 days of pemetrexed. If concomitant administration of NSAIDs is necessary, the patient is closely monitored for toxicity, especially myelosuppression, renal and gastrointestinal toxicity.

Ototoxic drugs such as aminoglycosides and loop diuretics may potentiate ototoxicity in patients receiving cisplatin or carboplatin. Antihistamines have been scrutinized for use with cisplatin because they may mask ototoxic symptoms such as dizziness and tinnitus. The levels of lithium and anticonvulsants, including phenytoin, are closely monitored in patients receiving cisplatin or carboplatin. INR was closely monitored in patients taking oral anticoagulants and cisplatin.

Prolongation of clotting time was reported in patients taking warfarin with etoposide (cohort C), as evidenced by an increase above baseline INR. Patients receiving warfarin and etoposide were closely monitored for INR frequency.

Patients receiving concomitant capecitabine (cohort D) and oral coumarin derivative anticoagulant therapy should be frequently monitored for anticoagulant response (INR or prothrombin time) in order to adjust anticoagulant dose accordingly. In patients who concomitantly take capecitabine with coumarin derivative anticoagulants, such as warfarin and coumarins, altered coagulation parameters and/or bleeding and death have been reported. Additional precautions were taken for capecitabine patients taking the CYP2C9 substrates folinic acid and phenytoin (cohort D).

For patients in the non-chemotherapy extended cohort, the following medications are cautious:

jaw necrosis has been reported in patients receiving bevacizumab, mainly in combination with bisphosphonates. Thus, bevacizumab must be used with caution in patients receiving concomitant bisphosphonates.

Treatment inhibition

The following therapies were prohibited during the study:

any concomitant therapy intended to treat cancer, whether approved by health authorities or experimental, including (but not limited to) the following: chemotherapy, hormone therapy, immunotherapy, radiotherapy, research drug or herbal therapy

If the patient is otherwise benefited, it may be considered to use radiation therapy to relieve pain (e.g., to treat a known bone metastasis). Palliative radiotherapy is postponed for patients in the dose escalation cohort in phase Ia or Ib until the DLT assessment window is completed. Study treatment administration may be suspended during radiation therapy with the consent of the medical supervisor.

Upon approval by a medical supervisor, a patient experiencing a mixed response may undergo local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) to control three or fewer lesions.

According to RECIST v1.1, patients who undergo radiation therapy or ablation of a target lesion may subsequently render the target lesion unevaluable for response determination.

The use of live attenuated vaccines was banned at any time during the study and within 5 months after the last dose of study treatment (e.g.,

influenza vaccine).

Patients were not allowed to receive immunostimulants, including but not limited to IFN-alpha, IFN-gamma or IL-2, throughout the study. These agents in combination with atelizumab may increase the risk of autoimmune disorders.

Traditional herbs, as these drugs are often incompletely characterized and may lead to unexpected drug-drug interactions, leading to or confounding toxicity assessments.

Forbidden therapies specific to patients with HCC considered for cohort NC 1:

the use of currently used full dose anticoagulants, therapeutic doses of thrombolytic therapy, and antiplatelet therapy is prohibited.

Local labeling recommendations for prophylactic use of anticoagulants or thrombolytic therapy are allowed.

Low doses of aspirin (< 325 mg/day) were allowed. It is strongly recommended to administer proton pump inhibitors simultaneously to reduce potential gastrointestinal damage.

If a patient experiences a venous thromboembolic event while still receiving study medication, it is possible for the patient to continue to maintain study medication despite anticoagulation.

Forbidding the use of warfarin or coumarin based products currently in use (including for prophylactic use).

Allowing prophylactic use of low dose anticoagulants, plain heparin or LMWH. According to the ASCO guidelines, the preferred choice of anticoagulant therapy is LMWH (Lyman GH et al J Clin Oncol 2015 33.

Concomitant long-term NSAID use while receiving study medication is prohibited except for long-term low dose aspirin (< 325 mg/day). However, when co-administered with proton pump inhibitors to reduce potential gastrointestinal damage, intermittent or short-term dosing of oral NSAIDs is permitted in order to alleviate symptoms of medical conditions (e.g., headache, fever).

D. Inclusion criteria

Patients must meet the following conditions to enter the study:

general standard

Signing Informed Consent (ICF)

Age ≥ 18 years

Compliance with the study protocol at the discretion of the investigator

Eastern Cooperative Oncology Group (ECOG) physical status of 0 or 1

Expected life ≥ 12 weeks

Sufficient blood and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (cycle 1 day 1):

absolute Neutrophil Count (ANC) ≥ 1,500 cells/. Mu.L

White Blood Cell (WBC) count ≥ 2,500/. Mu.L

Lymphocyte count ≥ 500/. Mu.L

Platelet count ≧ 100,000/μ L (no blood transfusion within 14 days before day 1 of cycle 1)

Hemoglobin. Gtoreq.9 g/dL

Patients may require transfusion or may receive erythropoiesis therapy according to local standard of care.

Total bilirubin ≦ 1.5 × Upper Normal value (ULN)

Patients receiving paclitaxel (cohort B) must have a total bilirubin of ≦ 1.25 × ULN

AST and ALT. Ltoreq.3 × ULN

Alkaline phosphatase. Ltoreq.2.5 XULN, with the following exceptions:

patients with documented liver or bone metastases may have ≦ 5 × ULN alkaline phosphatase

Serum albumin ≥ 2.5g/dL

PT and activated partial thromboplastin time (aPTT) of 1.5 XULN or less

This is only applicable to patients who do not receive therapeutic anticoagulation.

Patients receiving therapeutic anticoagulation are dose-stable.

Measured or calculated creatinine clearance ≧ 50mL/min, estimated based on Cockcroft-Gault glomerular filtration rate:

(140-age) × (body weight in kilograms) × (0.85, if female) 72 × (serum creatinine in mg/dL)

Patients receiving cisplatin (cohort A or cohort C) must have a measured or calculated creatinine clearance of ≧ 60mL/min, based on the Cockcroft-Gault GFR estimate

Fertility women (including those who have undergone tubal ligation) must be tested for serum pregnancy within 14 days prior to day 1 of cycle 1 and recorded as negative.

For fertile women: consent to maintain abstinence (avoidance of sexual intercourse) or use of contraceptive measures, and consent to not donate ova, is defined as follows:

a contraceptive method in which the female has to remain abstinent or with an annual failure rate < 1% during the treatment period and within 90 days after the last administration of ibritumumab, within 5 months after the last administration of atelizumab, within 4 months after the last administration of parbolizumab and within 6 months after the last administration of bevacizumab and chemotherapy (pemetrexed, cisplatin, carboplatin, paclitaxel, etoposide and capecitabine). During this same period, women must avoid donating eggs.

A woman is considered to have fertility potential if, after menarche, he has not reached a postmenopausal state (amenorrhea for a period of > 12 months, no cause other than menopause) and has not been surgically sterilized (ovariectomy, oviduct and/or uterus removal) or for any other reason determined by the investigator (e.g. Mullerian hypoplasia). The definition of fertility potential may be adjusted according to local guidelines or regulations.

Examples of contraceptive methods with annual failure rate < 1% include bilateral tubal ligation, male sterilization, hormonal contraceptives to inhibit ovulation, hormone releasing intrauterine devices and copper intrauterine devices.

Hormonal contraception must be supplemented by barrier methods.

Assessing the reliability of sexual abstinence according to the duration of the clinical trial and the patient's preferred and usual lifestyle. Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

For males: consent to maintain abstinence (avoid sexual intercourse) or to use contraceptive measures, and to not donate sperm, is defined as follows:

with a non-pregnant female partner with fertility, men who are not surgically sterilized must remain on abstinence or use condoms with an additional contraceptive method with an annual failure rate < 1% during the treatment period and within 90 days after the last administration of ibritumomab tiumuliginis, within 3 months after the last administration of capecitabine and within 6 months after the last administration of any other chemotherapy drugs. At this same time, the male must avoid donating sperm

With pregnant female partners, the men must remain abstinent or use condoms during the treatment period and within 90 days after the last administration of tirayleigh immuzumab, within 3 months after the last administration of capecitabine and within 6 months after the last administration of chemotherapy to avoid embryo exposure.

Assessing the reliability of sexual abstinence according to the duration of the clinical trial and the patient's preferred and usual lifestyle. Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

E. Cancer-specific inclusion criteria

Patients with histologic records of locally advanced, recurrent or metastatic incurable malignancies who have progressed following at least one available standard therapy; or for these patients, standard therapy has proven ineffective or intolerable, or is considered inappropriate; or clinical trials investigating agents are recognized as standard of care for these patients.

If a patient who progressed on at least one available standard therapy has additional approved standard treatment regimens available, the researcher must discuss the risks and benefits of those treatments before obtaining informed consent to participate in the study. This discussion must be recorded in the patient record.

For the expanded cohort of phase Ib studies only, patients with histologic records of locally advanced, recurrent or metastatic incurable malignancies, and clinical trials of study agents in combination with anti-PD-L1 antibodies with or without combination with chemotherapy are acceptable treatment options for this patient, who may also be eligible.

Patients have representative tumor specimens confirmed available in formalin fixed, paraffin embedded (FFPE) blocks (preferred) or ≧ 15 unstained slides, with associated pathology reports.

Acceptable samples may also include core needle biopsies (at least three core needles) for deep tumor tissue or for excision, incision, perforation or biopsy forceps biopsies of skin, subcutaneous or mucosal lesions.

No Fine Needle Aspiration (FNA) samples, swabs, cell pellets from effusion or ascites, and lavage samples were received.

Tumor tissue from bone metastases could not assess PD-L1 and/or TIGIT (with Ig and TIG)ITOf the IM domainTCell depletion (I) Epidemic receptors) and is therefore unacceptable.

As sufficient tissue is available from different time points (such as initial diagnosis time and time to disease recurrence) and/or multiple metastatic tumors, the most recently collected tissue is prioritized (preferably after the most recent systemic therapy). Based on availability, multiple samples of a given patient may be collected; however, the requirement for a block or ≧ 15 unstained slides should be met by a single biopsy or resection specimen.

Prior to signing the primary study Informed Consent Form (ICF), patients may sign pre-screening ICF to specifically allow for the collection and testing of archived or fresh tumor specimens.

Archiving a patient with insufficient or unavailable tissue may be eligible after discussion with a medical inspector if the patient satisfies any of the following:

at least 10 unstained consecutive slides can be provided

Core, punch or excise/nick biopsy collection before treatment willing to agree to and receive tumors (see description of acceptable samples above)

Dose escalation cohort to be enrolled

To be included in the chemotherapy extended cohort (stage Ib)

Dose extension cohort to be included in Q4W (stage Ib)

For patients in the fill-in cohort or extended cohort, submitted archived tumor tissues must be evaluated for PD-L1 and/or TIGIT expression prior to enrollment.

Patients with measurable disease according to RECIST v1.1

Previously irradiated lesions are targeted lesions.

Lesions intended for biopsy are not counted as target lesions.

F. Additional inclusion criteria for patients whose cohorts had been cleared in stage Ia and Ib

The recruitment cohort was limited to patients whose tumors had PD-L1 and/or TIGIT expression. Therefore, tumor tissue must be committed and PD-L1 and/or TIGIT expression assessed prior to enrollment. Patients whose tumor tissues were not assessable for PD-L1 and/or TIGIT expression were ineligible. PD-L1 and/or TIGIT expression can be assessed in immune infiltrating cells or tumor cells. If multiple tumor specimens (e.g., archival specimens and tissues from relapsed disease) are submitted, the patient may be eligible if at least one specimen can evaluate PD-L1 and/or TIGIT. The PD-L1 and/or TIGIT score of the patient is the maximum PD-L1 and/or TIGIT score, respectively, in the sample.

Patients must have a tumor of PD-L1 choice and/or TIGIT choice 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 Carcinoma (HNSCC), ovarian Cancer (OC), gastric Cancer (GC), including gastroesophageal junction (GEJ) cancer, urothelial Bladder Cancer (UBC), and colorectal cancer (CRC), including microsatellite stability (MSS) and low microsatellite instability (MSI-low).

The patient must have a lesion in reach, allowing a total of one to two biopsies (pre-treatment and during treatment) or one biopsy (during treatment if archival tissue can be submitted instead of a pre-treatment biopsy) without an unacceptably significant risk of procedural complications.

Acceptable samples include core needle biopsies or lymph nodes for deep tumor tissue, or for excision, incision, perforation or clamp biopsies of skin, subcutaneous or mucosal lesions. FNA, cell pellets from effusion or ascites, lavage samples, and bone biopsies were not accepted. Considering the target lesion for core needle biopsy is considered suitable for retrieving a minimum of three, but ideally five cores (minimum diameter 18 gauge) at a given point in time.

If multiple lesions are available, then if feasible, biopsies of the same tumor lesion are to be performed at all time points to avoid introducing heterogeneity associated with the tumor or metastatic site.

G. Additional inclusion criteria for patients in extended cohort

Cohort expansion cohort is limited to patients whose tumors are selected for PD-L1 and/or TIGIT. Therefore, tumor tissue must be committed and PD-L1 and/or TIGIT expression assessed prior to enrollment. Patients whose tumor tissues were not assessable for PD-L1 and/or TIGIT expression were ineligible. PD-L1 and/or TIGIT expression can be assessed in immune infiltrating cells or tumor cells. If multiple tumor specimens (e.g., archival specimens and tissues from relapsed disease) are submitted, the patient may be eligible if at least one specimen can assess PD-L1 and/or TIGIT expression. The PD-L1 and/or TIGIT score of the patient is the maximum PD-L1 and/or TIGIT score, respectively, in the sample.

Managing the grouping such that approximately up to half of the accrued patients in each extended cohort are patients who agree to receive an optional biopsy.

For patients entering the expanded cohort of stage Ib series biopsies, a biopsy is required.

Additional inclusion criteria for extended cohort of patients in stage Ia

Patients must have tumors selected by PD-L1 and/or TIGIT, including the following tumor types: NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC (including GEJ carcinoma), UBC, and CRC

Additional inclusion criteria for patients in each of the extended, indication-specific cohorts of stage ib

·NSCLC cohort (CIT-first treatment): patients with histologically confirmed incurable advanced NSCLC who were not previously treated with CIT (studied or approved), including anti-PD-L1/PD-1 and/or anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), for which clinical trials of a combination of a study agent and an anti-PD-L1 antibody are considered an acceptable treatment option if CIT (including an anti-PD-L1/PD-1 agent) is approved by the local regulatory agency for use as a treatment for NSCLC.

Patients whose tumors have known sensitizing EGFR mutations must also have undergone disease progression (during or after treatment) or be intolerant to treatment with EGFR tyrosine kinase inhibitors.

Patients whose tumors have a known Anaplastic Lymphoma Kinase (ALK) rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ALK tyrosine kinase inhibitors.

Patients whose tumors have a known ROS1 rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ROS1 tyrosine kinase inhibitors.

The tumors have a known BRAF ^V600E MutationsThe patient of (a) must also have experienced disease progression (during or after treatment) or be intolerant to treatment with a combination of dabrafenib and trametinib.

·NSCLC cohort (CIT treated): patients with histologically confirmed, incurable advanced NSCLC who had been previously treated with CIT (studied or approved), including anti-PD-L1/PD-1.

Patients whose tumors have known sensitizing EGFR mutations must also have undergone disease progression (during or after treatment) or be intolerant to treatment with EGFR tyrosine kinase inhibitors.

Patients whose tumors have a known ALK rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ALK tyrosine kinase inhibitors.

Patients whose tumors have a known ROS1 rearrangement must also have undergone disease progression (during or after treatment) or be intolerant to treatment with ROS1 tyrosine kinase inhibitors.

Its tumor has a known BRAF ^V600E The mutated patient must also have undergone disease progression (during or after treatment) or be intolerant to treatment with a combination of dabrafenib and trametinib.

Patients must have experienced recorded disease progression during CIT monotherapy and/or combination therapy (studied or approved), which must include prior anti-PD-L1/PD-1.

Prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy must represent the latest systemic anti-cancer therapy administered prior to enrollment in this extended cohort.

At least about 10 patients who experienced the best recorded remission of confirmed Partial Remission (PR) or Complete Remission (CR) according to investigator assessment of RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy or combination therapy, may be enrolled.

At least about 10 patients experienced a recorded optimal response to disease Stability (SD) as assessed by investigators of RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy, and these patients could be enrolled.

At least about 10 patients who experienced the best response recorded for disease Progression (PD) assessed by investigators according to RECIST v1.1 at any time while receiving prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy, can be enrolled.

The previous anti-PD-L1/PD-1 as monotherapy and/or as combination therapy must represent the latest systemic anti-cancer therapy administered prior to enrollment in this extended cohort.

Patients who terminated prior anti-PD-L1/PD-1 monotherapy and/or combination therapy, primarily due to toxicity or intolerance, did not meet this extended cohort entry condition.

·TNBC queue: patients with histologically confirmed incurable, advanced Estrogen Receptor (ER) negative, progesterone receptor negative, and human epidermal growth factor receptor 2 (HER 2) negative breast adenocarcinoma (triple negative)

Triple negative status must be recorded as defined by the american academy of clinical oncology american pathologist college of america (ASCO-CAP) guidelines:

< 1% of the tumor cell nuclei are immunoreactive with ER and < 1% of the tumor cell nuclei are immunoreactive with progesterone receptor

And is

The HER2 test showed Immunohistochemistry (IHC) 1+, IHC 0 or In Situ Hybridization (ISH) negative

·CRC queue: patients with histologically confirmed incurable advanced colon or rectal adenocarcinoma

Patients with tumors of appendiceal origin are ineligible.

·GC queue: patients with histologically confirmed inoperable, locally advanced or metastatic or recurrent gastric or GEJ adenocarcinomas who are not amenable to curative therapy

Patients with type 1 GEJ tumors (defined as distal esophageal adenocarcinoma) with tumor centers within 1 to 5cm above the anatomical esophagogastric junction met the criteria of the study

Patients with esophageal cancer (squamous cell carcinoma or adenocarcinoma) may be eligible after discussion with a medical inspector.

Patients whose tumors are HER2 positive must also have undergone disease progression (during or after treatment) or be intolerant to treatment with HER 2-targeting antibodies/HER 2 inhibitors.

HER2 positive is defined as IHC 3+ or IHC 2+/ISH + (where ISH positive is defined as HER2: CEP17 ratio ≧ 2) as assessed by local laboratory testing for primary tumors or metastatic lesions

Patients with tumors of unknown HER2 status may remain eligible after discussion with a medical inspector because HER2 testing was not performed due to insufficient tissue or unavailability (e.g., archiving and/or biopsy).

·HNSCC queue: patients with histologically confirmed inoperable, locally advanced or metastatic, recurrent or persistent squamous cell carcinoma of the head and neck (oral, oropharyngeal, hypopharyngeal or laryngeal), unsuited for curative treatment

Patients with HNSCC of any other primary anatomical site of the head and neck, patients with primary unknown HNSCC, or patients with non-squamous histological tumors are not eligible.

Patients with nasopharyngeal HNSCC may be eligible after discussion with a medical inspector.

The HPV status of HNSCC must be known.

·UBC queue: patients with histologically confirmed incurable advanced urothelial transitional cell carcinoma (including renal pelvis, ureter, bladder and urethra)

Patients with mixed histology need to have a dominant transitional cell pattern.

·Melanoma cohort: patients with histologically confirmed incurable advanced metastatic melanoma

If CIT (including anti-PD-L1/PD-1 and/or anti-CTLA-4 agents) is approved by the local regulatory authority as a treatment for melanoma, then for patients with melanoma, clinical trials of the study agent in combination with anti-PD-L1/PD-1 antibodies are considered acceptable treatment options.

Patients whose tumors have known BRAFV600 mutations must also have undergone disease progression (during or after treatment) or be intolerant to treatment with BRAF inhibitors and/or mitogen-activated kinase (MEK) inhibitors.

Cohort management is performed such that no more than about 20% of patients in the cohort are patients with ocular (uveal) melanoma.

·OC queue: patients with histologically confirmed incurable advanced epithelial ovarian, fallopian tube or primary peritoneal carcinoma

Exclusion of borderline ovarian epithelial tumors (e.g., low malignant potential tumors, atypical proliferative tumors).

·RCC queue: patients with histologically confirmed, incurable advanced RCC comprising clear cell and/or sarcoma-like histological components

If CIT (including anti-PD-L1/PD-1 agent) is approved by local regulatory authorities as a treatment for RCC, then for patients with RCC, a clinical trial of the study agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option.

Additional enrollment criteria for stage Ia series biopsy extended cohort patients

The patient must have a tumor of PD-L1 choice and/or TIGIT choice, which may include the following tumor types: melanoma, OC, RCC and UBC

If CIT (including anti-PD-L1/PD-1 agents) is approved by local regulatory agencies as a treatment for these indications, clinical trials of study agents in combination with anti-PD-L1 antibodies are considered to be an acceptable treatment option for patients with melanoma or RCC.

The patient must have access to the lesion, allowing a total of one to two biopsies (pre-treatment and during treatment) or one biopsy (during treatment if archival tissue can be submitted instead of a pre-treatment biopsy) without an unacceptably significant risk of procedural complications.

Acceptable samples include core needle biopsies or lymph nodes for deep tumor tissue, or for excision, incision, perforation or jaw biopsies of skin, subcutaneous or mucosal lesions. FNA, cell pellet from effusion or ascites, lavage samples, and bone biopsies were not received. Considering the target lesion for core needle biopsy is considered suitable for retrieving a minimum of three, but ideally five cores (minimum diameter 18 gauge) at a given point in time.

If multiple lesions are available, biopsies of the same tumor lesion at all time points are to be taken, if feasible, to avoid introducing heterogeneity associated with tumor or metastatic sites.

K. Exclusion criteria

Patients who met any of the following criteria were excluded:

general exclusion criteria

Failure to comply with the study and follow-up procedure

Pregnancy, lactation or lactation

Significant cardiovascular diseases, such as New York Heart Association heart disease (grade II or higher), myocardial infarction over the past 3 months, unstable arrhythmias and/or unstable angina

Liver diseases known to be of clinical significance, including active virus, alcoholic or other hepatitis, cirrhosis and hereditary liver diseases or alcohol abuse at present

Poorly controlled type 2 diabetes defined as screening for hemoglobin A1 _C Not less than 8 percent or fasting blood sugar not less than 160mg/dL (or 8.8 mmol/L)

Major surgery was received 28 days before day 1 of cycle 1, or was expected to be required during the study

Any other disease, metabolic dysfunction, physical examination findings and/or clinical laboratory findings, from which the presence of a disease is reasonably suspected to contraindicate the use of study medication or a disease or condition that may affect the interpretation of the outcome or may put the patient at high risk for treatment complications.

Cancer-specific exclusion criteria

Within 3 weeks before initiation of study treatment, any anti-cancer therapy, whether studied or approved, including chemotherapy, hormone therapy and/or radiation therapy, is performed, with the following exceptions:

hormone therapy using gonadotropin releasing hormone (GnRH) agonists or antagonists for prostate cancer

Hormone replacement therapy or oral contraceptives

Tyrosine Kinase Inhibitors (TKIs) approved by local regulatory agencies for the treatment of cancer have been terminated > 7 days before day 1 of cycle 1; baseline scans must be obtained after the termination of a prior TKI, and criteria for adverse events due to prior cancer treatments must be met

Herbal therapy > 1 week before day 1 of cycle 1

Palliative radiotherapy for pain metastasis or metastasis to potentially sensitive sites (e.g., epidural space) > 2 weeks before day 1 of cycle 1

Patients enrolled from the phase Ia part of the study to the phase Ib study with ibritumumab and atlizumab were allowed to be treated with ibritumumab as a monotherapy before entering the phase Ib study.

Eligibility based on prior treatment with CIT depends on the mechanistic class of the drug and the cohort in which the patient is considering participation, as described below. Furthermore, all criteria relating to adverse events due to prior cancer treatments must be met.

All cohorts (dose escalation, filling and extension) for stages Ia and Ib：

The use of previous anti-TIGIT drugs was not allowed, except for the following:

patients allowed treatment with tenecteuzumab in phase Ia studies could be included in the phase Ib study, provided that the prescribed criteria were met.

Allow prior treatment with cancer vaccines and/or cytokines, provided that at least 6 or 5 drug half-lives (whichever is shorter) have elapsed between the last administration and the proposed 1 st day of cycle 1.

For any prior systemic cancer treatment, the minimum clearance time was 3 weeks.

Previous cancer immunotherapy not explicitly described in the protocol is to be discussed with a medical inspector to determine potential eligibility.

Dose escalation and padding cohort in phase Ia and phase Ib (group during dose escalation):

allowing prior treatment with immune checkpoint inhibitors (such as anti-PD-L1/PD-1), immunomodulatory mabs and/or MAb-derived therapies, provided that at least 5 elimination half-lives of the drug have passed between the last administration and the proposed 1 st day of cycle 1.

Allowing prior treatment with immune modulators including Toll-like receptor (TLR) agonists, indoleamine 2, 3-dioxygenase or tryptophan-2, 3-dioxygenase (IDO/TDO) inhibitors or OX40 agonists, provided that at least 6 weeks have elapsed between the last administration and the day 1 of the proposed cycle 1.

Dose escalation and padding cohort in phase Ia and phase Ib (grouping during dose extension):

allowing prior treatment with immune checkpoint inhibitors, immunomodulatory mabs and/or MAb-derived therapies, provided that at least 6 weeks have elapsed between the last dose and day 1 of the proposed 1 st cycle, with the following exceptions:

previous anti-PD-L1/PD-1 undergoes a washout period of at least 3 weeks

The previous anti-CTLA-4 undergoes a clearance period of at least 6 weeks

In an expanded cohort of stage Ib NSCLC CIT treatments, the most recent systemic treatment was anti-PD-L1/PD-1 as monotherapy or combination therapy.

In the initial treatment expansion cohort for NSCLC CIT stage Ib, prior treatment with immune checkpoint inhibitors (such as anti-PD-L1/PD-1), immunomodulatory MAb and/or MAb-derived therapies was not allowed.

Previous treatments with immune modulators (including TLR agonists, IDO/TDO inhibitors, or OX40 agonists) were allowed, provided that at least 5 drug half-lives or a minimum of 3 weeks had elapsed between the last dose of the last treatment and day 1 of the proposed cycle 1, with the following exceptions:

in the initial treatment expansion cohort for NSCLC CIT stage Ib, no prior treatment with other immune modulators was allowed.

Any history of immune-mediated adverse events of grade 4 due to previous cancer immunotherapy (except endocrine diseases controlled by replacement therapy or asymptomatic serum amylase or lipase elevation) -

Any history of immune-mediated grade 3 adverse events (other than endocrine disease controlled by replacement therapy or asymptomatic elevation of serum amylase or lipase) due to prior cancer immunotherapy that result in permanent cessation of prior immunotherapeutics and/or occurred < 6 months prior to day 1 of cycle 1.

Adverse events caused by previous anticancer treatments, not yet resolved to grade < 1, except for alopecia, vitiligo or endocrine diseases controlled by replacement therapy

All immune-mediated adverse events associated with previous cancer immunotherapy (except endocrine disease or stable leukoderma controlled by alternative therapy) must have resolved completely to baseline.

Patients receiving corticosteroid therapy for immune-mediated adverse events must demonstrate no associated symptoms or signs for more than 4 weeks after corticosteroid withdrawal.

Patients with a lung lymphoepitheliomatous carcinoma subtype of NSCLC

Primary CNS malignancy, untreated CNS metastasis or active CNS metastasis (progression or need of corticosteroid to control symptoms)

Patients with a history of treated CNS metastases were eligible provided that they met all of the following criteria:

measurable disease outside of the CNS

No sustained requirement for treatment of CNS metastases with corticosteroid, discontinuation of corticosteroid for > 2 weeks prior to addition, and no sustained symptoms attributable to CNS metastases

Allowing the use of stable doses of anticonvulsants.

Radiographies after completion of CNS-directed therapy demonstrate improved disease and there is no evidence of a temporary progression between completion of CNS-directed therapy and screening radiographic studies

Screening for CNS imaging studies greater than or equal to 4 weeks after radiotherapy was completed

Leptomeningeal disease

Uncontrolled tumor-related pain

Symptomatic lesions (e.g. bone metastases or metastases causing nerve entrapment) suitable for palliative radiotherapy should be treated prior to enrollment.

Further growth of asymptomatic metastatic lesions may lead to functional defects or intractable pain (e.g. epidural metastasis which is currently not associated with spinal cord compression), patients are considered for regional treatment, if appropriate, prior to enrollment.

Uncontrolled pleural effusion or ascites requiring repeated drainage procedures (once a month or more frequently)

Patients who indwelling the catheter (e.g., a PleurX catheter) are allowed.

Except for malignancies with negligible risk of metastasis or death (such as well-treated cervical carcinoma in situ, basal cell or squamous cell skin carcinoma, localized prostate cancer or ductal carcinoma in situ) other than the disease under study within 5 years prior to day 1 of cycle 1

Uncontrolled hypercalcemia (> 1.5mmol/L ionized calcium or Ca > 12mg/dL or post-correction serum calcium ≧ ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (denosumab).

Patients receiving bisphosphonate treatment or denosumab for the exclusive use in preventing skeletal events and having no clinically significant history of hypercalcemia met the entry criteria. However, patients who are using denosumab must be willing and eligible to receive bisphosphonate instead of denosumab during the study.

Patients with spinal cord compression that were not treated explicitly by surgery and/or radiation therapy, or previously diagnosed and treated spinal cord compression, but no evidence of clinically stable disease for more than 2 weeks prior to screening.

M. treatment-specific exclusion criteria

A history of autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, wegener's granulomatosis, sjogren's syndrome, bell's palsy (autoimmune etiology only), guillain-barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis, with the following exceptions:

patients with a history of autoimmune hypothyroidism and receiving stable doses of thyroid-substituting hormone may meet inclusion criteria.

Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only dermatological manifestations (e.g., no psoriatic arthritis) may meet the criteria of inclusion, provided they meet the following conditions:

The area of the rash must be less than 10% of the body surface area.

Disease is well controlled at baseline and only low potency topical corticosteroids need be used.

Acute exacerbation of the underlying disease (e.g., no need for psoralen plus ultraviolet a radiation (PUVA), methotrexate, retinoids, biologicals, oral calcineurin inhibitors, high potency or oral corticosteroids) over the past 12 months

Treatment with systemic immunosuppressive drugs (including but not limited to prednisone > 10 mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide and tumor cyclic servoin-alpha [ TNF-alpha ] antagonists) within 2 weeks prior to day 1 of cycle 1

Patients who received acute, low dose, systemic immunosuppressive drugs (e.g., a single-dose dexamethasone for the treatment of nausea) can be enrolled after discussion and approval with a medical inspector.

Inhaled corticosteroids (e.g., fluticasone for the treatment of chronic obstructive pulmonary disease) are permitted.

Oral mineralocorticoids (e.g., fludrocortisone for orthostatic hypotension patients) are allowed.

Allows the use of physiological doses of corticosteroids for the treatment of adrenal insufficiency.

History of idiopathic pulmonary fibrosis, pneumonia (including drug-induced pneumonia), organized pneumonia (i.e., bronchiolitis obliterans, cryptogenic organized pneumonia, etc.), or evidence of active pneumonia when screening chest CT scans

A history of radiation pneumonitis (fibrosis) in the radiation field was allowed.

HIV infection detection Positive

Active hepatitis B (defined as positive test for hepatitis B surface antigen [ HBsAg ] at screening)

Patients with past hepatitis B infection (defined as a negative HBsAg test and positive IgG antibody to hepatitis B core antigen [ anti-HBc ]) who had developed or had resolved are eligible. Hepatitis B Virus (HBV) DNA must be obtained from these patients before day 1 of cycle 1 and no active infection must be demonstrated.

Active hepatitis C

Patients positive for Hepatitis C Virus (HCV) antibodies are eligible only when the Polymerase Chain Reaction (PCR) results for HCV RNA are negative.

Active EBV infection at screening and known or suspected chronic active EBV infection

Patients with EBV IgG and/or EBNA positive are eligible only if the EBV IgM and/or EBV PCR is negative.

Active tuberculosis

Severe infection, including but not limited to hospitalization for complications of infection, bacteremia or severe pneumonia, occurs within 4 weeks prior to day 1 of cycle 1

Infections that do not meet the above serious infection criteria, which occur recently, include the following:

signs or symptoms of infection appear within 2 weeks before day 1 of cycle 1

Receiving oral or IV antibiotics within 2 weeks before day 1 of cycle 1

Patients receiving prophylactic antibiotics (e.g. for preventing urinary tract infection or chronic obstructive pulmonary disease) are eligible.

Previous allogenic bone marrow transplant or previous solid organ transplant

Inoculation of live attenuated vaccines within 4 weeks before day 1 of cycle 1 or expected need of such live attenuated vaccine inoculation during the study

Influenza vaccination was given only during influenza season. Patients must not be vaccinated with live attenuated influenza vaccine (e.g.,

)。

history of severe allergic, allergic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

Known allergy to CHO cell products

Allergic or anaphylactic reaction to the Atlizumab formulation Components

Exclusion criteria specific to chemotherapy extended cohort

Known severe allergic or anaphylactic reactions to platinum or platinum-containing compounds

Exclusion criteria specific for cisplatin

Patients with known hearing impairment (cisplatin only treatment)

Grade 2 peripheral neuropathy as defined according to the NCI CTCAE v4.0 Standard (cisplatin treatment only)

Measured or calculated creatinine clearance ≦ 60mL/min (cisplatin-only treatment), estimated based on Cockcroft-Gault GFR:

o. queue A specific exclusion criteria

Known to have severe allergic or anaphylactic reactions to pemetrexed

P. exclusion criteria specific to queue B

Known to have severe allergic or anaphylactic reactions to paclitaxel

Known to contain

EL products (e.g., cyclosporine concentrate for injection and teniposide concentrate for injection) have a history of severe allergic reactions

Queue C specific exclusion criteria

Known to have severe allergic or anaphylactic reactions to etoposide

R. queue D specific exclusion criteria

Allergy to any component of the capecitabine pharmaceutical preparation

Pill incapable of being swallowed

Malabsorption syndrome, diseases which significantly affect gastrointestinal function, gastroenterotomy or enterotomy, or ulcerative colitis

Known dihydropyrimidine dehydrogenase deficiency or severe and unexpected history of response to fluoropyrimidine therapy

Requiring the concomitant use of the antiviral agent solivudine (antiviral) or a chemically related analog, such as brivudine (brivudine) (these drugs are not allowed within 4 weeks after initiation of study treatment including capecitabine)

S. exclusion criteria specific to queue NC1

Inadequate control of hypertension (defined as systolic > 150mmHg and/or diastolic > 100 mmHg), based on an average of > 2 treatments > 3 blood pressure readings; allowing antihypertensive therapy to achieve these parameters

Hypertensive crisis or hypertensive encephalopathy history

Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recently peripheral arterial thrombosis) within 6 months prior to initiation of study treatment

History of hemoptysis (2.5 mL of bright red blood per episode) within 1 month before initiation of study treatment

Evidence of hemorrhagic diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

Use of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day) currently or recently (10 days before initiation of study treatment)

Remarks: full dose oral or parenteral anticoagulation for therapeutic purposes is allowed as long as INR and/or aPTT are within therapeutic limits (according to institutional standards) within 7 days prior to initiation of study treatment and the patient has received a stable dose of anticoagulant for ≧ 2 weeks prior to initiation of study treatment; allowing prophylactic use of anticoagulants

Core biopsy or other minor surgery performed within 3 days before initiation of study treatment, excluding placement of vascular access devices

Study of history of abdominal or tracheoesophageal fistula, gastrointestinal perforation or intra-abdominal abscess 6 months before initiation of treatment

Clinical signs or symptoms of ileus, including sub-occlusive or occlusive syndromes associated with underlying disease, with a history of ileus and/or gastrointestinal obstruction 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

Patients presenting signs or symptoms of sub-occlusion or occlusion syndrome or ileus at the time of initial diagnosis can be grouped if they have received definitive (surgical) treatment to resolve the symptoms

Evidence of abdominal free air unexplained by abdominocentesis or recent surgery

Critical, non-healing or dehiscent wounds, active ulcers or untreated fractures

Proteinuria grade 2 or greater as demonstrated by protein 2+ in dipstick urinalysis and protein 1.0g in 24 hour urine collection

All patients screened for > 2+ protein in dipstick urinalysis must undergo 24 hours urine collection to obtain protein.

Patients with < 2+ protein in dipstick urinalysis were eligible for study enrollment.

Metastatic disease involving major airways or blood vessels, or centrally located mass mediastinal tumor masses (< 30mm distant knob)

Study of history of intra-abdominal inflammatory processes within 6 months before initiation of treatment, including but not limited to peptic ulcer disease, diverticulitis, or colitis

Radiation therapy within 28 days before initiation of study treatment or abdominal/pelvic radiation therapy within 60 days before initiation of study treatment

Major surgery, open biopsy or significant trauma within 28 days before initiation of study treatment; or abdominal surgery, abdominal intervention or severe abdominal trauma within 60 days prior to initiation of study treatment; or to anticipate the need for major surgery during the course of the study or to recover from the side effects of any such surgery

Evaluation of

Patients were closely monitored for safety and tolerability and toxicity was assessed prior to each dosing of ibritumomab tiuxetan as a single drug (phase Ia) or in combination with the following drugs: astuzumab, astuzumab with chemotherapy, astuzumab with bevacizumab or palboclizumab (stage Ib). Dosing was only performed when clinical assessments and local laboratory test results were acceptable.

All evaluations are performed on the day of the scheduled visit date unless a time window is specified. Unless otherwise indicated, scheduled assessments on the day of study treatment were performed prior to study drug infusion.

Medical history, baseline conditions, concomitant medications, and demographic data

The medical history includes a history of cancer (including but not limited to previous cancer therapy and/or previous CIT and procedures and tumor characteristics such as hormone receptor status or mutational status), other clinically significant diseases, surgery, smoking history, alcohol and/or drug abuse, reproductive status, and screening for all medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic therapies, and nutritional supplements) used by the patient within 7 days of visit.

For those patients who were enrolled from phase Ia to phase Ib of the study, the re-screening history at treatment re-initiation after disease progression included any cancer-related programs that occurred after the termination of the initial treatment or any adverse events associated with study treatment that were not captured during the protocol-specified follow-up period.

Demographic data include age, gender, and self-reported race/ethnicity. Ethnicity/ethnicity was recorded because of the potential contribution of this variable to differences in observed PK, pharmacodynamics, toxicity, and/or response to treatment.

Vital signs

Vital signs include body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure, measured while the patient is seated.

On the study treatment day, vital signs were measured within 60 minutes prior to the first study drug infusion on the day.

For the first infusion of ibritumomab tiuxetan in phase Ia, vital signs were measured every 15 (+ -5) minutes during the infusion, at the end of the infusion (+ -5 minutes), 30 (+ -10) minutes, 120 (+ -15) minutes and 240 (+ -15) minutes after the end of the infusion.

For the first infusion of ibritumomab tiuxetan in phase Ib, vital signs were measured every 15 (+ -5) minutes during infusion, at the end of infusion (+ -5 minutes), and 30 (+ -10) minutes after the end of infusion. For all phase Ib cohorts without chemotherapy, the first infusion of atelizumab or parbolizumab was administered 60 minutes after completion of the infusion of tenecteuzumab; the first infusion of bevacizumab was administered 60 minutes after completion of the attritumab infusion.

For the phase Ib cohort with chemotherapy, the first infusion of tenecteuzumab was administered 60 minutes after completion of the atuzumab infusion.

For the first and subsequent infusions of atuzumab and palboceprizumab, and subsequent infusions of ibritumumab tiuxetan, vital signs were measured during and 30 (± 10) minutes after the infusion if clinically indicated or if symptoms appeared in the previous infusion.

For the first infusion of bevacizumab, vital signs are measured during infusion, at the end of infusion (+ -5 minutes) and 30 (+ -10) minutes after infusion if there is a clinical indication or symptoms appear in previous infusions.

Subsequent infusion intervals between tipletuzumab and atzelizumab or bevacizumab, or between atzelizumab and bevacizumab (for all phase Ib cohorts without chemotherapy), or between atzelizumab and tipleuzumab (for phase Ib cohort with chemotherapy) were 30 minutes if the previous infusion of tipletuzumab or atzelizumab was tolerated without IRR or; or 60 minutes if the patient experienced an IRR upon a previous infusion of either ibritumumab or atelizumab.

In the chemotherapy extension A, B and C cohorts, additional vital signs were measured and recorded at cycle 1 within 30 (+ -10) minutes after completion of the last chemotherapy infusion (e.g., cohort A: after carboplatin or cisplatin; cohort B: after carboplatin; cohort C: after etoposide). In subsequent cycles, additional vital signs are measured and recorded after chemotherapy infusion if clinically indicated.

Vital signs collected at the screening visit were recorded. For each visit thereafter, only those vital signs obtained prior to the first study of the drug infusion on the day or constituting an adverse event (e.g., temperature at fever) or a major manifestation of an adverse event (e.g., blood pressure in response to an infusion or heart rate associated with an arrhythmia) were recorded. All vital signs collected by protocol are recorded in the patient's medical record.

The blood oxygen saturation is measured at baseline by a pulse oximeter.

Physical examination

The overall physical examination performed at screening includes assessment of the head, eye, ear, nose and throat, as well as cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, genitourinary and nervous systems.

The ECOG performance status was assessed.

In subsequent visits (or clinical indications), limited physical examinations for symptoms were performed. Changes from baseline abnormalities are recorded in the patient's medical record. New or worsening clinically significant abnormalities are recorded as adverse events.

Physical examination also includes the assessment of lymphadenopathy, splenomegaly, hepatomegaly and skin tumors or metastases as part of the tumor assessment. All patients were monitored for symptoms of CNS metastases and reported symptoms were followed by a global nervous system examination. A brain Magnetic Resonance Imaging (MRI) scan or a contrast-enhanced head CT scan is performed according to clinical indications to confirm or deny new or worsening brain involvement.

Tumor and response assessment

Screening

All known disease sites must be recorded at screening and re-assessed in each subsequent tumor assessment.

Screening and subsequent tumor assessment must include CT scans of the chest, abdomen and pelvis (using IV contrast agents (unless contraindicated) and oral contrast agents as per institutional standards, if appropriate) or MRI scans. If a CT scan for tumor assessment is performed in a Positron Emission Tomography (PET)/CT scanner, a CT acquisition must be performed to meet the criteria of a full contrast CT scan.

Brain imaging (MRI or contrast enhanced CT) is required in screening patients with treated brain metastases and is clinically indicated based on symptoms or signs suggestive of new or worsening CNS metastases. In the case of ambiguous head CT, brain MRI is required to identify the presence or extent of suspected brain metastases.

Further studies such as bone scans and head and neck CT scans (e.g., head and neck CT scans are appropriate for patients with HNSCC) are performed based on indications of underlying disease, and should be performed if there is clinical suspicion of disease at any site that the above-described minimum assessment schedule may not justify. Other methods of assessing measurable disease according to RECIST v1.1 may be used as appropriate by the investigator.

The same imaging procedure used to assess disease sites at screening (e.g., same imaging protocol for CT scans) was used throughout the study. A stable assessment of brain metastases must be performed for each tumor assessment using the same imaging program as the baseline study. Patients without brain metastases do not need to take a brain scan to assess the tumor unless clinically warranted. Researchers used RECIST v1.1 to assess responses based on the physical examination and imaging modalities described above. The investigator's assessment of overall tumor response at all time points was based only on RECIST v1.1. The assessment is made by the same evaluator, if possible, to ensure internal consistency between visits.

Tumor assessment was performed. If PD is suspected, the investigator can decide to scan at any time as appropriate.

Follow-up tumor assessments were performed after termination of the initial study treatment (if terminated due to a reason other than disease progression) until death, disease progression, initiation of another systemic anti-cancer treatment, missed visits, withdrawal of consent, or study termination, whichever occurred first.

Patients who continued treatment after imaging disease progression according to RECIST v1.1 were monitored for follow-up scans (i.e., when the scan frequency was every 2 cycles, at the next planned tumor assessment; when the scan frequency was every 4 cycles, as an unplanned tumor assessment) within 6 (± 2) weeks, or earlier if clinically indicated. Tumor assessment continues every 2 cycles thereafter until two consecutive scans show stability or improvement relative to the first scan showing imaging disease progression, at which point the scan frequency reverts or shifts to every 4 cycles (if applicable). The investigator's assessment of overall tumor response at all time points was based only on RECIST 1.1.

Laboratory, biomarker and other biological samples

Local laboratory testing of stages Ia and Ib

The following laboratory tests were conducted at the local laboratory of the research site:

hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count [ neutrophils, eosinophils, lymphocytes, monocytes, basophils and other cells ] and platelet count respectively)

Serum/plasma chemistry (sodium, potassium, chloride, bicarbonate, BUN or urea, creatinine, glucose, calcium, magnesium, phosphorus, total bilirubin, ALT, AST, alkaline phosphatase, LDH, total protein and albumin)

Serum ferritin and C Reactive Protein (CRP)

Coagulation (PT, aPTT and INR)

Amylase and Lipase

Pregnancy test: all fertility women (including those who received tubal ligation) were tested for serum pregnancy at screening. Urine pregnancy tests were performed periodically during the duration of study treatment. If the urine pregnancy test result is positive, the administration is delayed until the status of the patient is determined by the serum pregnancy test.

Urinalysis (specific gravity, pH, glucose, protein, ketone and blood)

Thyroid function test (thyroid stimulating hormone [ TSH ], free T3 and free T4)

EBV serology (EBV IgM, EBV IgG and/or EBNA ]) and/or EBV PCR

If the patient is serologically positive for EBV IgG and/or EBNA, the EBV IgM test and/or the EBV PCR test need to be performed before day 1 of cycle 1 to consider compliance.

CMV serology (CMV IgG)

HBV serology (HBsAg, HBsAg antibody and hepatitis B core antigen)

If the patient is serologically positive for anti-HBc, then the HBV DNA test should be obtained before day 1 of cycle 1.

HCV serology (anti-HCV)

If the patient is serologically positive for anti-HCV, an HCV RNA test is required before day 1 of cycle 1 to consider compliance.

All patients were tested for HIV prior to enrollment in the study, HIV positive patients were excluded from the study

Tumor markers (if applicable and informative), including but not limited to CA-125, CA19-9, carcinoembryonic antigen (CEA), prostate Specific Antigen (PSA), beta-hCG, AFP, CA15-3 and CA27.29

Central laboratory test for stages Ia and Ib

The tests listed below were performed at a central laboratory. Additional immunogenicity characterization, PK, biomarker and/or immunogenicity assay development and validation of samples collected for PK or ADA analysis may be required; thus, these samples will be destroyed within 5 years after the final clinical study report is completed, or earlier according to local regulations.

Evaluation of blood samples

ADA assay

Serum samples were obtained to measure ADA (phase Ia and Ib) to ibritumomab using a validated assay

Obtaining serum samples validated assay was used to measure ADA (stage Ib only) to Atlizumab

PK assay

Serum samples were obtained to measure tirayleigh itumumab concentrations (stage Ia and stage Ib) using validated assays

Serum samples were obtained to measure atelizumab concentrations using a validated assay (stage Ib only)

Plasma samples were obtained to measure cisplatin, carboplatin, pemetrexed, paclitaxel, capecitabine, and etoposide concentrations using validated assays (phase Ib chemotherapy extension cohort only).

Autoantibody testing

Serum samples are obtained for autoantibody testing, including but not necessarily limited to antinuclear antibodies, anti-double-stranded DNA, anti-neutrophil cytoplasmic antibodies, and thyroid peroxidase antibodies, to be performed based on clinical events during the study, whether in individual patients or across study populations.

Measurement of biomarkers in blood

Blood samples were taken from all eligible patients at screening visit and during treatment for biomarker assessment.

Whole Genome Sequencing (WGS)

One blood sample is collected for WGS and may be sent to one or more laboratories for analysis. WGS data and related clinical data may be shared with researchers not participating in the study, or may be submitted to a government or other health study database for widespread sharing with other researchers for human health and disease studies. The study participants were not identified by name or any other personal identity information.

The WGS depends on the IRB/EC of each site and (if applicable) the review and approval of the appropriate regulatory authorities. If the site has not been approved for WGS, the assessment is not applicable to the site.

WGS data were analyzed in the context of this study and explored along with other studies to better understand disease pathobiology and guide the development of new therapeutics. Given the complexity and exploratory nature of these analyses, WGS data and analyses were used only for research purposes and were not shared with researchers or research participants.

These samples are stored indefinitely until used up, or until the patient requires that their sample be destroyed.

Assessment of tumor samples

The status of immune-related and tumor-related biomarkers (including but not limited to the expression of PD-L1, TIGIT, PVR, and/or CD226 on specific cell types; and the prevalence and/or activation of infiltrating T cells) in archived and fresh tumor samples can be assessed 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. Other exploratory biomarkers can also be assessed if guided by clinical and non-clinical data.

Archiving tumor tissue: all patients for the study enrolled

Archived tumor tissue samples obtained outside of the study for other purposes (preferably paraffin blocks; at least 15 unstained slides are acceptable) were collected from all patients if available. For all patients in stage Ia or Ib, the availability of archived tumor tissue must be confirmed prior to entry into the study. Fine needle aspirates, cell pellets from effusion or ascites, lavage samples, and bone biopsies do not meet the requirements of archived tissues.

As sufficient tissue is available from different time points (such as time of initial diagnosis and time of disease recurrence) and/or multiple metastatic tumors, the most recently collected tissue is prioritized (preferably after the most recent systemic therapy).

Patients with insufficient or unavailable archived tissue may still be eligible.

Archived tumor tissues are used to evaluate potential predictive biomarkers, using characterized assays to analyze protein, RNA, and DNA.

Required tumor biopsy: patients on an extended cohort for group-entry stage Ib series biopsies

Time point: serial biopsies were obtained at two time points: 1) Pre-treatment biopsies were taken at baseline after meeting all eligibility criteria, and 2) during treatment biopsies were taken approximately 2 weeks after the first administration of both tirayleigh immuzumab and atlizumab (i.e., on days 15 to 21 or between cycles 1).

Additional optional biopsies may be collected at the discretion of the researcher, preferably at the time of imaging progression (especially when false progression is suspected) or at the time of response.

Serial tumor biopsies are used to assess tumor pharmacodynamic and potential predictive biomarkers, using characterized assays to analyze protein, RNA, and DNA.

Tumor tissue biopsy at progression for transition from stage Ia to stage Ib: for patients considered to be in phase Ia to Ib cohort in the study after the investigator assessed progression of imaging disease

If the investigator believes that sample collection is clinically viable and the patient has provided written informed consent, a biopsy may be required at the time of progression. Tumor tissue samples consisting of core needle biopsies or lymph nodes for deep tumor tissue, or excisions, incisions, perforations or clamp biopsies for skin, subcutaneous or mucosal lesions can be obtained.

Biopsies at progression are used to assess tumor pharmacodynamic biomarkers and potential predictive biomarkers, using characterized assays to analyze protein, RNA, and DNA.

Optional tumor biopsy: for patients who provide specific informed consent for optional biopsy, especially up to half of patients in the group's expanded cohort phase Ia or Ib

Patients who consented to optional biopsy provided a tumor biopsy at baseline after meeting all eligibility criteria, and either about 2 weeks after the first administration of ibritumomab tiuxetan as a single drug (phase Ia) or about 2 weeks after the first administration of ibritumomab tiuxetan and atzumab (phase Ib) (i.e., on days 15 to 21 or between cycles 1).

For patients with established, prolonged CR and/or PR (e.g., about 1 year in duration) and accessible residual tumor mass, it is recommended that the residual tumor mass be biopsied to assess surviving tumor cells (as compared to fibrotic or necrotic tissue).

Tumor tissue samples may be collected using a core needle, punch, excisional biopsy (as described above), or jaw biopsy. For further guidance on the biopsy technique chosen, see the above sample specifications for mandatory tumor biopsies.

Optional tumor biopsy for assessment of tumor pharmacodynamic biomarkers and potential predictive biomarkers, using characterized assays to analyze protein, RNA and DNA.

Sample specification: for all patients in stages Ia and Ib, the required and optional biopsy should meet the following sample requirements

Tumor tissue samples consisting of core needle biopsies or lymph nodes of deep tumor tissue, or excisions, incisions, perforations or clamp biopsies for skin, subcutaneous or mucosal lesions can be obtained. No fine needle aspirates, cell pellets from effusion or ascites, lavage samples, and bone biopsies were received. The target lesion considered for core needle biopsy is considered suitable for retrieving at least three cores (minimum diameter 18 gauge) at a given point in time. If possible, the distance between successive passages through the same lesion should be 1 cm or more.

If multiple lesions are available, it is preferable to obtain a during-treatment biopsy (if feasible) from the same lesion (or organ) as the pre-treatment biopsy to avoid introducing heterogeneity associated with metastatic sites.

RECIST target lesions were not biopsied.

Tissue samples and their derivatives (such as DNA and RNA) are stored indefinitely, or until used up or the patient requests that their sample be destroyed.

Residual samples from all patients using stages Ia and Ib

If the patient is undergoing a medically indicated procedure at any time during the study (i.e., bronchoscopy, esophagogastroduodenoscopy, colonoscopy, etc.), which results in tumor tissue or other tissue that may provide information about the activity of tiryluzumab as a single drug (phase Ia) or in combination with atelizumab (phase Ib) with or without chemotherapy (phase Ib), any remaining sample or portion of sample (body fluid sample or remaining tumor tissue) that is not necessary for medical diagnosis may be obtained for exploratory analysis. The patient must provide specific informed consent in order to collect and evaluate these samples.

The remaining tumor samples were used to evaluate tumor pharmacodynamic biomarkers and potential predictive biomarkers, using characterized assays to analyze protein, RNA, and DNA.

Electrocardiogram

Triplicate ECG recordings were obtained at specific time points for the dose escalation and padding cohorts of tegraleigh immuzumab (phase Ia) alone; and for all other patients a single ECG recording is obtained. The ECGs acquired on different dates match as closely as possible in time. Three interpretable ECG recordings (e.g., without artifacts) must be obtained at each time point (+ -5 minutes). The average of the three readings is used to determine the ECG interval (e.g., PR, QRS, QT). Additional ECGs can be obtained at unplanned time points according to clinical indications.

All ECG recordings must be made using a standard high quality, high fidelity digital electrocardiograph equipped with computer-based interval measurements. The lead placement is as consistent as possible. ECG recordings must be made after the patient has rested in the supine position for at least 10 minutes. All ECGs should be obtained before other procedures (e.g. vital sign measurements, blood draws) within the same time plan and must not be obtained within any 3 hours after meal. If following the guidelines may be challenging for the patient, the time between meals and ECG recordings may be shortened to 2.5 hours or to institutional standards, as long as the same minimum time is maintained for all time points. During pre-ECG rest and during ECG recording, conditions that may cause heart rate changes, including environmental disturbances (e.g., television, radio, talk) should be avoided.

For safety monitoring purposes, researchers must review, sign all ECG tracings and date. The overall assessment of the ECG is recorded as normal or abnormal, with or without clinical significance. A paper or electronic copy of the ECG tracing is saved at the site as part of the patient's permanent study file.

If the average QT interval corrected by using the Fridericia formula (QTcF) at a particular post-administration time point is > 500ms and/or > 60ms longer than the baseline value, another ECG must be recorded, ideally for the next 5 minutes, and ECG monitoring continued until the QTcF stabilizes on two consecutive ECGs. Standard of care treatment may be administered as appropriate by the investigator. If no PK samples were scheduled at this time point, an unplanned PK sample was obtained. The investigator evaluated the patient for potential complications risk factors (e.g., electrolyte abnormalities, drugs known to prolong QT interval, severe bradycardia).

Cancer-related procedures

The collection of medical, surgical and radiological procedures associated with cancer began on day 1 and was performed throughout the treatment and survival follow-up period for both phase Ia and Ib portions of the study.

Anti-drug antibody testing

The ibritumomab tiuxetan and/or atelizumab may elicit an immune response against itself. Validated screens, confirmations and titer determinations are used to detect ADA at multiple time points before, during and after treatment with tirayleigh immuzumab as a single agent in phase Ia, or with a combination of tirayleigh immuzumab and atuzumab in phase Ib with or without chemotherapy. ADA responses were correlated with relevant clinical endpoints to understand their clinical significance. Additional ADA assays (e.g., neutralizing antibody assays) can be used to further characterize the ADA response.

Patient and study treatment termination

Patient termination

Patient termination of the study is different from study treatment termination, which occurs when the patient dies, loses visit, or withdraws consent to follow-up.

Patients were given the right to voluntarily withdraw from the study for any reason at any time. In addition, the investigator has the right to leave the patient from the study at any time. Reasons for exiting the study may include, but are not limited to, the following:

patient withdraw consent at any time

If the patient continues to participate in the study, any medical condition determined by the researcher may jeopardize his or her safety

The researcher determines this as the greatest benefit to the patient

All efforts were made to obtain information about patients who exited the study. The main reason for withdrawal from the study or follow-up was recorded. However, after withdrawal of consent, the patient is not tracked for any reason. Patients who exited the study will not be replaced.

Study termination of treatment

Study treatment must be terminated if the patient experiences any of the following conditions:

worsening of symptoms due to disease progression as determined by the investigator after a comprehensive assessment of all imaging data, biopsy results and clinical status (i.e. uncontrolled pain secondary to the disease or uncontrolled ascites, etc.).

Intolerable toxicity (including the development of immune-mediated adverse events) associated with study treatment, which the investigator determines is unacceptable in view of the potential response of the individual patient to therapy and the severity of the event

If the patient continues with the study treatment, any medical condition determined by the researcher may jeopardize his or her safety

Use of non-regimen systemic anti-cancer therapy

Pregnancy

Patients were given the right to voluntarily withdraw from study treatment for any reason at any time. In addition, the investigator has the right to withdraw the patient from study treatment at any time. Reasons for withdrawal from study treatment may include, but are not limited to, the following:

The researcher determines this as the greatest benefit for the patient

Patient independence

Patients who terminated study treatment primarily for reasons other than disease progression continued to be tumor assessed, and all patients who terminated study treatment continued to be survival followed every 3 months unless consent was withdrawn.

Patients who terminated study treatment were required to return to the clinic for study treatment termination visit no more than 30 days after the last study treatment administration.

Response assessments showed that the visit of PD (which resulted in the termination of tirayleigh immuzumab (phase Ia) or the termination of tirayleigh immuzumab and atuzumab, tirayleigh immuzumab and atuzumab with bevacizumab or the combination of tirayleigh immuzumab and parilizumab (phase Ib)) could be used as a treatment termination visit (as applicable), in which case all assessments related to the treatment termination visit were performed at that time.

After study treatment was terminated, survival and subsequent anti-cancer therapy was followed for all patients. Survival and follow-up anti-cancer therapy follow-up information is collected approximately every 3 months via telephone, patient history and/or outpatient visits until death, missed visits or study termination unless the patient requires withdrawal from follow-up. Information on subsequent anti-cancer therapies includes systemic therapy (e.g., chemotherapy, targeted therapy, hormonal therapy, or CIT), surgery (e.g., removal of metastatic disease), and radiation procedures (e.g., radiation therapy of tumor lesions).

If the patient exits the study, the site staff may use a common information source (e.g., household records) to obtain only information about the survival status.

V. analysis

Target and endpoint

This study evaluated the safety, PK, pharmacodynamics, and primary anti-tumor activity of tenectelomab in patients with locally advanced or metastatic tumors when administered as a single drug (phase Ia) or in combination with atuzumab or other anti-cancer therapies (phase Ib). The specific goals of the study and the corresponding endpoints are summarized in table 36 below.

TABLE 36 targets and corresponding endpoints for periods Ia and Ib

Pharmacokinetic objectives:

activity target:

activity assay

The following analysis is based on the definition of objective remission according to RECIST v 1.1.

All treated patients were listed by dose level or tumor type for response piece assessment data, objective remission duration, PFS and OS, as appropriate.

Objective remission rate

Analysis of ORR included patients who received any number of study treatments in phase Ia or Ib studies and had measurable disease at baseline. Objective remission is defined as CR or PR as determined by investigator rating and confirmed by repeated ratings ≧ 4 weeks after initial recording. Patients with missing baseline or no-response assessments were classified as non-responders. Objective remission rates were estimated and summarized by tumor type and dose, if applicable.

Duration of mitigation

In patients with objective remission, the duration of objective remission is defined as the time from initial complete or partial remission to disease progression or death, whichever occurs first. For patients who did not die or have disease progression or missed visits prior to the end of the study, the duration of objective remission was censored on the day of the last tumor assessment.

Progression free survival

Analysis of PFS included patients who had received any amount of study treatment. PFS was defined as the time from the first day of study treatment until recorded disease progression or death, whichever occurred first. For patients who had not recorded PD or died or missed visits before the end of the study, PFS was missed on the day of last tumor assessment. For patients without any post-baseline tumor assessment, PFS was missed on the first day of study treatment.

Overall life cycle

Analysis of OS included patients who had received any amount of study treatment. OS was defined as the time from the first dose of any study treatment to death during the study for any reason. For patients who did not die before the end of the study or were missed, OS was missed on the last known day of survival.

Security analysis

Safety was assessed by summarizing DLT, adverse events, changes in laboratory test results, changes in vital signs and ECG, and exposure to any study treatment (tiryleavizumab, altuzumab, bevacizumab, palboceprizumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine, etoposide). All patients receiving any amount of study treatment were included in the safety analysis.

The verbatim description of the adverse event maps to a thesaurus term. Adverse event data are listed by study site, dose cohort or appropriate tumor type, number of patients and study day. Events occurring on or after day 1 of treatment were summarized by mapped terminology, appropriate synonym library levels, and NCI CTCAE v4.0 scale. In addition, critical adverse events, including death, were listed and summarized separately.

Adverse events leading to termination of treatment are listed. Patients who exited the study for reasons other than DLT prior to completion of the DLT assessment window were deemed to be unevaluable for DLT and MTD assessments.

The relevant laboratory, vital signs and ECG data were summarized over time and, when appropriate, NCI CTCAE grade 3 and 4 values were determined. The incidence of ADA responses (presence of serum anti-rayleigh eculizumab or anti-atlizumab) and potential correlations with PK, pharmacodynamic and safety parameters can be assessed.

Pharmacokinetic analysis

In the phase Ia study, individual and mean serum concentrations of ibritumomab tiuxetan versus time were tabulated and plotted as dose levels. Pharmacokinetics of temeaux _max 、C _min Total CL and V _ss And terminal half-life (as appropriate for the data collected). The estimates of these parameters are tabulated and summarized (mean, standard deviation and coefficient of variation). Inter-patient variability and drug accumulation were assessed.

In phase Ib studies, serum concentration data for tegraleigh itumumab and atelizumab (C) _max And C _min ) Tabulated and summarized by dose level for each cycle at which collection occurred. Descriptive statistics include mean, median, standard deviation, and range, as appropriate. If the data is warranted, other PK parameters may be determined and summarized. The data can be compared to historical data, as these results provide preliminary information regarding whether the tirleiuzumab or atlizumab PK will change due to co-administration of other drugs.

In the phase Ib chemotherapy extension cohort, the serum concentrations of tirayleigh immuzumab and atelizumab were collected, as well as the plasma concentrations of carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine, and etoposide. The concentrations of tirayleigh immumab, atezumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine, and etoposide were summarized using descriptive statistics as described above. The data were compared to historical data as these results provide preliminary information on whether tirayleigh mab, atelizumab, carboplatin, cisplatin, pemetrexed, paclitaxel, capecitabine, and etoposide PK were altered by co-administration of other drugs.

The pharmacodynamic analysis includes assessing pharmacodynamic biomarkers (if available) in tumor tissue and blood. Additional PK and pharmacodynamic analyses were performed, if appropriate. The biomarker sampling time may be potentially adjusted, if desired, based on biomarker responses observed in early patients.

Immunogenicity assays

A patient is considered to have a treatment-induced ADA response if the patient is ADA negative at baseline and then develops an ADA response following study drug administration. A patient is considered to have a therapeutically enhanced ADA response if the patient is ADA positive at baseline and the titer of the post-baseline sample or samples is at least 4-fold higher than the titer of the baseline sample (i.e., > 0.60 titer units). A patient is considered ADA negative if the patient is ADA negative at all time points. A patient is considered to be unaffected by treatment if the patient is ADA positive at baseline but the titer of the post-baseline sample is at least 4-fold higher than the titer of the baseline sample without any baseline.

ADA results for tenellulomuzumab and atelizumab were summarized and listed by patient and cycle for phase Ia and phase Ib portions of the study.

Metaphase analysis of phase Ia and Ib extended cohorts

Interim analysis was performed by IMC on each extended cohort for phase Ia and Ib to guide possible early withdrawal into cohorts in the absence of evidence of activity. After approximately 20 patients in the cohort extension cohort completed 1 to 2 tumor assessments, the IMC conference performed interim analysis. If the interim analysis indicates that the activity as exhibited by the objective tumor response using tegaserod immumab (phase Ia) or tegaserod immumab with or without chemotherapy in combination with atelizumab or in combination with atelizumab and bevacizumab or in combination with tegaserod and parilizumab (phase Ib) is below the threshold of interest for this patient group (e.g., if no response was observed in the first 20 patients), the IMC may suggest to stop the expansion cohort.

For example, if the true ORR is 5%, the probability of no response observed in the first 20 patients is about 35%, and if the true ORR is 10%, the probability of no response observed in the first 20 patients is about 12%.

IMC may also recommend continued enrollment into the expanded cohort if there is evidence of activity or if there are not enough patients enrolled for adequate assessment (e.g., patients with a particular tumor type, a particular tumor PD-L1 and/or TIGIT expression status, and/or a particular CIT history).

In all cases, the decision to stop the extension queuing was made based on invalidity, according to IMC recommendations after medical supervisors and research investigators have negotiated. The medical supervisor may also require the IMC to hold additional ad hoc meetings to review the persistence data in each extended cohort for phase Ia or phase Ib.

Summary of clinical studies on W, terayleumab

This ongoing study (GO 30103) provides preliminary clinical data, which assesses tiryleiguzumab in patients with locally advanced or metastatic tumors. By the clinical expiration date of 12/2 days in 2019, study GO30103 had a total of 190 patients enrolled, where 42 patients entered phase Ia fraction and 171 patients entered phase Ib fraction, including 23 patients who transitioned from phase Ia to group after disease progression.

An ongoing phase II study (GO 40290, also known as CITYSCAPE) is evaluating the efficacy and safety of tirayleigh immuzumab and atelizumab with placebo plus atelizumab in chemotherapy naive patients with locally advanced unresectable or metastatic PD-L1 selected NSCLC, excluding patients with sensitizing Epidermal Growth Factor Receptor (EGFR) mutations or ALK translocations.

Clinical pharmacokinetics and immunogenicity

As of the data cutoff date of 12 month 2 day 2019, preliminary PK analyses were performed using standard non-compartmental PK methods based on available data (2 to 1200mg tirayleigh immuzumab administered every 3 weeks in phase Ia portion of study GO30103 and 2 to 1200mg tirayleigh immuzumab administered every 3 weeks in phase Ib portion in combination with 1200mg atelizumab administered every 3 weeks). The pharmacokinetics of the combination of securititumumab and astuzumab appeared to be consistent with the pharmacokinetics of administration of securititumumab as a single drug. Preliminary population PK analysis showed that after IV administration at a dose ranging from 100mg to 1200mg every 3 weeks as monotherapy or in combination with 1200mg of atuzumab every 3 weeks, the tiryleigh ewuzumab exposure increased approximately by dose. Preliminary population PK analysis estimated the tirayleigh itumumab clearance rate to be 0.28L/day with a linear drug elimination half-life of about 15 days. In the study of stage Ib portion of GO30103, 3 of 154 evaluable patients (1.9%) developed anti-drug antibodies (ADA) against tiryleiguzumab. Preliminary data indicate that there was no significant effect of tirayleigh eculizumab ADA on PK. However, the number of ADA-positive patients was low and insufficient to assess the effect of ADA on the pharmacokinetics of tenecteuzumab.

Safety in clinic

Safety data was available for 42 patients on the study GO30103 phase Ia part by the data expiration date of 12 months and 2 days in 2019. Regardless of the relationship to tiryleiguzumab, common adverse events in phase Ia (reported in > 10% of all patients) include fatigue, constipation, vomiting, decreased appetite, anemia, cough, dyspnea, headache, infusion-related reactions (IRR), malignancy progression, nausea, and itching. Common adverse events associated with tiryleiguzumab (reported in > 10% of patients) include fatigue and IRR.

Grade 3 adverse events (based on the national cancer institute adverse event general terminology standard version 4.0 [ NCI CTCAE v4.0 ]) were reported in 16 patients (38.1%) in phase Ia section of study GO30103, whether or not due to study drug, of which 3 patients (7.1%) experienced treatment-related grade 3 adverse events. The investigators considered grade 3 or greater adverse events associated with tiryleiguzumab included elevated amylase, elevated blood creatinine, liver failure (as described below), IRR, and skin rash.

By the data expiration date of 12, 2 and 2019, 171 patients were enrolled in the phase Ib portion of study GO30103, including 23 patients who transferred from phase Ia to the group after disease progression. Of the 171 patients treated in phase Ib, 163 patients (95.9%) experienced at least one adverse event, including 110 patients (64.7%) who experienced at least one treatment-related adverse event. Common adverse events in stage Ib (reported in > 10% of all patients), regardless of relationship to tiryleiguzumab, include pruritus, fever, anemia, rash, malignancy progression, constipation, decreased appetite, diarrhea, cough, weakness, vomiting, and fatigue. Common adverse events associated with tiryleigh ewuzumab and/or atlizumab (reported in > 10% of patients) include itching and rash.

Grade 3 adverse events (based on NCI CTCAE v 4.0), whether or not due to study drug, were reported in 91 patients (53.5%) in the Ib phase part of study GO30103, of which 21 patients (12.4%) experienced treatment-related grade 3 adverse events. Grade 3 or more adverse events associated with tirayleigh immuzumab and/or atelizumab are considered by researchers to include decreased lymphocyte count, increased lipase, decreased lymphocytes, increased amylase, adrenal insufficiency, weakness, cardiac tamponade, headache, hyperglycemia, hyperlipidemia, hyper-transaminase, pneumonia, rash pruritus, rhabdomyolysis, diabetes, diabetic ketoacidosis, and lipase.

Cohort study patients with a phase Ia monotherapy extended cohort of GO30103 developed fatal hepatotoxic cases that ultimately led to fulminant hepatic failure. At the time of screening, patients had transaminases within the normal range. C1D1, AST and ALT had risen to grade 1 prior to dosing. During C1D1 tirayleigh immuzumab administration, patients develop infusion responses responsive to dose discontinuation and standard therapy; the patient received about 733mg of the expected 1200mg dose of tenectereumab. On study day 8, ALT/AST rose to grade 3, correlating with grade 3 rash; the patient was treated with prednisone 60mg daily. By study day 12, the rash improved, but AST and ALT were grade 4 (bilirubin and PT-International Normalized Ratio (INR) normal) and a second immunosuppressive agent (azathioprine) was added. Despite the use of both immunosuppressive agents, the patient continued to progress and developed significant liver failure with elevated bilirubin and progressive hepatic encephalopathy, ultimately leading to death on study day 30. Various alternative causes of hepatitis are excluded, including viral (HBV, HCV), concomitant medication or anatomical abnormalities. Liver biopsies performed on study day 16 showed confluent sub-massive necrosis with a small inflammatory infiltrate, interpreted as toxic hepatitis.

Following this event, analysis of safety data indicates that no significant change in adverse event findings, and no new significant adverse events were found in subjects administered study phase Ia and Ib portions of GO 30103.

As of the data cutoff date of 2019, 6 months and 30 days, 135 patients with evaluable safety were administered either tirayleigh itumumab (600 mg every 3 weeks) in combination with atuzumab or placebo in combination with atuzumab in a phase II blinded study GO 40290. The safety of tiryleigh ewolizumab and atzelizumab was similar to that of placebo and atzelizumab for all grades of adverse events (98.5% and 95.6%), > 3 grades of AEs (41.8% and 44.1%), critical AEs (34.3% and 35.3%) and AEs that led to treatment termination (7.5% and 10.3%). Adverse events of particular interest were reported in 47.8% of patients in the arm of securityluzumab and atuzumab and 32.4% of patients in the arm of placebo plus atuzumab. The 12-month 2019 update data shows similar security.

Taiwan, a 69 year old male with the metastatic lymphoepitheliomatous subtype NSCLC (PD-L1 positive) reported a fatal case of EBV reactivation and possible secondary Hemophagocytic Lymphohistiocytosis (HLH), which may be associated with EBV infection in asian patients. At the time of screening, the patient's serum Epstein-Barr nuclear antigen (EBNA) antibody tests positive, but the treatment investigators demonstrated no clinical symptoms of active EBV infection. On day 1 of cycle 1, patients received both the study drugs atelizumab and tegraluezumab, and were well tolerated for treatment. On day 10, the patient developed a fever, believed to be due to an upper respiratory infection, treated with antibiotics. On cycle 2 day 1, the patient received atelizumab and developed a grade 2 fever 20 minutes after infusion. Since fever was presumed to be atuzumab IRR, no tenerayleigh was administered in cycle 2. The patient was hospitalized for fever, but the examination of the cause of infection was negative. After the fever had subsided, the patient was discharged on day 8 of cycle 2. On cycle 2 day 15, the patient was again hospitalized with intermittent fever and transferred to an intensive care unit as he developed shock with hypotension, metabolic acidosis, acute kidney injury, pancytopenia, blood coagulation disorders, hemorrhage, mental state changes, elevated transaminases, hyperbilirubinemia and respiratory failure. EBV titers were higher in the patient's blood and bone marrow biopsies were consistent with HLH. The culture results were negative for other infectious etiologies. Despite treatment with steroids and various immunosuppressive agents (tositumumab, hydroxychloroquine, and etanercept), patients worsened and died on cycle 2 day 31. In general, the patient had received one dose of tenecteuzumab (at cycle 1) and two doses of atelizumab (at cycles 1 and 2). Although the exact reason for the event at this revision is not clear and investigations are still ongoing, the current information suggests that the patient has a rare histological subtype of NSCLC and a suspected chronic active EBV infection that is reactivated after the use of tiryleigh ewuzumab and atuzumab. In view of the temporal relationship between study drug exposure and patient clinical course, patients appear to develop secondary HLH. Since the occurrence of an indicative case of EBV reactivation in this patient with pulmonary lymphoepithelioid cancer, safety data have been scrutinized, with no other cases of viral reactivation observed in phase II studies (GO 40290) or current phase I studies (GO 30103).

By the data cutoff date of 2019, 12 months and 2 days, 42 patients were treated with the only drug of securititumumab. Patients receiving the single drug, ibritumomab tiuxetan, experienced IRR. In phase Ia, 5 patients (12%) experienced IRR. Signs and symptoms associated with IRR are usually mild and include fever, chills, hot flashes, hypertension, lymphadenopathy, nausea, myalgia and skin lesions. All IRR cases were successfully treated by supportive measures. Since 12% of patients develop IRR during and after infusion of single drug tirayleuzumab, IRR shifts from potential to established risk. Although there are no other established risks for tegravitumumab, the involvement of the TIGIT co-inhibitory route may increase the risk of autoimmune inflammation when tegravitumumab is administered as a single drug. Thus, tegralyluzumab as a single drug may cause similar adverse events as atelizumab. This immune-mediated adverse event has been well characterized by other immune checkpoint inhibitors (such as anti-CTLA-4 and anti-PD-L1/PD-1).

This is the first clinical assessment of combinations of tirylereumab with anti-PD-L1/PD-1 drugs. Although clinical assessments of the combination of tenecteuzumab and atuzumab are limited and not all risks are known, by 12/2 in 2019, over 200 patients have been treated with tenecteuzumab in combination with atuzumab. While the unique risk of combined administration of tenecteuzumab and adzuzumab has not been identified at present, when tenecteuzumab is administered in combination with adzuzumab, the involvement of the TIGIT co-inhibitory pathway may increase the risk of some immune responses, including HLH and MAS. Thus, when administered with atuzumab, tirayleigh may exacerbate the atuzumab-related adverse events or may have non-overlapping toxicity with atuzumab.

To date, the greatest clinical experience with complementary modulator combinations of adaptive immunity has been from trials of ipilimumab in combination with nivolumab. Another anti-TIGIT antibody, MK-7684 (viburnumab), when combined with pertuzumab, showed acceptable safety and promising anti-tumor activity in patients with advanced tumors. Based on these data, it is expected that combined immune-mediated adverse events will be amenable to monitoring and manageable in a clinical setting, although frequency and severity may be increased compared to either single-drug inhibitor.

Clinical curative effect

As of the data expiration date of 12 months and 2 days 2019, no objective remission has been reported for patients enrolled in the phase Ia portion of the study GO 30103; the best response was disease Stability (SD), with 8 out of 42 patients undergoing tumor assessment during the study. Objective remission was observed in patients with multiple tumor types (including NSCLC, HNSCC, and triple negative breast cancer) who had not received Cancer Immunotherapy (CIT), including 4 of 171 patients with Complete Remission (CR) and 23 of 171 patients with Partial Remission (PR), in the phase Ib portion of the study.

By the data cutoff date of 2019, 30 days 6, data from the blinded, randomized, phase II study GO40290 showed that the combination of tirayleigh immuzumab and atuzumab improved ORR and PFS in the ITT population compared to placebo and atuzumab. The ORR for both tiryleuyuzumab and atlizumab was 31.3% (95% ci.

Phase Ib Using Triraleyuzumab and Attuzumab with chemotherapy

In multiple large randomized phase III trials of advanced solid tumors, addition of anti-PD-L1/PD-1 to standard chemotherapy improved both OS and PFS in patients compared to chemotherapy alone. These experiments investigated the addition of anti-PD-1 to pemetrexed and platinum-based chemotherapy in non-squamous NSCLC (Gandhi et al N Engl J Med 2018, 378) and to carboplatin and paclitaxel or nab-paclitaxel in squamous NSCLC (Paz-Ares et al N Engl J Med 201379. These experiments also investigated the addition of anti-PD-L1 to carboplatin and etoposide in extensive SCLC (Horn et al N Engl J Med 20137379, 2220-9) and to nab-paclitaxel in TNBC (Schmid et al N Engl J Med 20137379. As a result of these trials, anti-PD-L1/PD-1 in combination with chemotherapy has been approved by the FDA and EMA for patients with advanced cancer. Since non-clinical data suggests that concomitant anti-TIGIT and anti-PD-L1/PD-1 enhanced anti-tumor immune responses more than single agent anti-PD-L1/PD-1 alone, it is hypothesized that adding anti-TIGIT to anti-PD-L1/PD-1 in combination with chemotherapy may be more effective than adding anti-PD-L1/PD-1 to chemotherapy.

The safety resulting from combining anti-PD-L1/PD-1 with chemotherapy is generally consistent with the known toxic effects observed in clinical trials of multiple advanced solid tumors for each agent (Gandhi et al N Engl J Med 2018. Given the similarity in mechanism of action between securititumumab and astuzumab, it is expected that the safety of combined administration of securititumumab with astuzumab and chemotherapy may be consistent with the immune-related toxicity of combining anti-TIGIT and anti-PD-L1 and the toxicity of individual chemotherapeutic agents. Thus, the design and safety management plan of the phase Ib chemotherapy extended cohort incorporates extensive chemotherapy clinical experience and the considerations described for combining anti-TIGIT with anti-PD-L1 to reduce the potential risk of participation in patients.

Stage Ib Using Trileiumuzumab and Attuzumab with Bevacizumab

Strong scientific evidence and emerging clinical data suggest that combined PD-L1, VEGF and TIGIT inhibition may have clinical benefit for multiple tumor types.

In patients with stage IV NSCLC who were initially treated with chemotherapy, the results of studies GO29436 (IMpower 150) showed that alemtuzumab plus bevacizumab and chemotherapy can significantly prolong OS compared to bevacizumab and chemotherapy alone (Socinski et al N Engl J Med 2018. For patients with inoperable, locally advanced or metastatic RCC, the results of the study WO29637 (imotion 151) indicate an improvement in PFS following treatment with a combination of atelizumab and bevacizumab compared to sunitinib in the treatment naive patient population (Motzer et al J Clin Oncol 20136 (6_supl): 578, rini et al Lancet 2019. First line HCC stage Ib study GO30140 found that 23 evaluable patients had 65% ORR, with involvement of etiology, geography, baseline alpha-fetoprotein levels and hepatic spread (Stein et al J Clin Oncol 2018 (Suppl 15): 4074, lee et al Lancet Oncol.2020 Jun;21 (6): 808-820). Based on these results, the treatment was awarded breakthrough accreditation and confirmed in the randomized phase III study YO40245 (IMbrave 150) study. Study YO40245 (IMbrave 150) was aimed at assessing the efficacy and safety of atlizumab and bevacizumab compared to sorafenib in patients with advanced or metastatic HCC who did not receive prior systemic treatment. The study was performed as 2: a ratio of 1 was randomly included in 501 patients. Recent study results indicate statistically significant and clinically significant improvements in PFS and OS. The risk of mortality for the atzumab plus bevacizumab arm was reduced by 42% compared to the sorafenib arm (stratified HR =0.58 (95% ci. PFS assessed by the independent examination agency according to the solid tumor efficacy assessment criteria (RECIST) v1.1 showed improvement in favor of combination therapy (stratified HR =0.59 (95% ci from 0.47 to 0.76); median PFS,6.83 and 4.27 months) (Cheng et al Ann Oncol 2019.

These are examples of potential synergy between atelizumab and bevacizumab in different tumor types, supporting further exploration of combinations with telitemizumab.

Example 5 pharmacokinetics, pharmacodynamics, safety and efficacy in a phase Ia/Ib up-dosing study with the anti-TIGIT antibody, TIRAYURUUzumab, as a single agent and in combination with atuzumab in patients with advanced solid tumors

A. Patient characteristics

Baseline characteristics of patients in phase Ia and phase Ib fractions of the study are shown in table 37. Patients in both phase Ia and phase Ib included a population undergoing severe pretreatment, with 42% of patients in phase Ia and 37% of patients in phase Ib having undergone greater than or equal to four prior cancer therapies. Patients in stage Ia and Ib share similar baseline characteristics.

TABLE 37 Baseline characteristics

Most patients in phase Ia and Ib fractions of the study were discontinued from treatment as the disease progressed (42% in phase Ia and 76% in phase Ib). None of the patients in stage Ib were responsive. The patient treatment is shown in table 38.

TABLE 38 patient treatment

B. Pharmacokinetics and pharmacodynamics of tegretaitumomab

Pharmacokinetics of tirayleigh immuzumab as a single agent (phase Ia) and in combination with atuzumab (phase Ib) were measured. Exposure to tirleiitumumab increased with the dose as a single agent and in combination with atuzumab (figure 9). Combination with atelizumab did not alter pharmacokinetics of tenelluzumab

The pharmacodynamics of ibritumomab tiuxetan as single drug (phase Ia) was measured (fig. 10). CD8 measurements at doses of 2mg, 8mg, 30mg, 100mg, 400mg, 600mg and 1200mg every three weeks ⁺ Occupancy of peripheral TIGIT receptors on T cells and NK cells. Complete and sustained occupancy of peripheral TIGIT receptors after the next day (C1D 2) was observed at dosages of greater than or equal to 30mg of tegralueumab.

C. Safety feature

A summary of the adverse events is shown in table 39. The overall incidence of grade 3 to 5 adverse events was low for phase Ia and phase Ib fractions, and there were no grade 5 adverse events. No dose-limiting toxicity was observed with tiryleuyuzumab as a single agent or in combination with atuzumab. All adverse events present in greater than or equal to 10% of patients in phase Ia and Ib are shown in figures 11 and 12, respectively. All immune-mediated adverse events are shown in table 40. The tiryleryitumumab has good tolerance as a single drug and in combination with the atelizumab.

TABLE 39 safety summary of adverse events

TABLE 40 all immune-mediated adverse events

D. Efficacy of

Initial efficacy analysis was performed for the phase Ia and Ib dose escalation studies. In phase Ia fraction, a reduction in tumor size was observed in neuroendocrine, ovarian and rectal cancers (fig. 13). Although there was no objective remission in the phase Ia part of the study, most patients had tumor types that were generally not responsive to Cancer Immunotherapy (CIT), had tumors with low PD-L1 expression, or received a heavy pretreatment. Objective remission was observed in the stage Ib part of the study of NSCLC, TNBC, HNSCC and esophageal cancer types (fig. 14).

The size of PD-L1 positive NSCLC tumors, including CIT naive tumors, was greatly reduced in patients treated with tirayleigh mab in combination with atuzumab (fig. 14). CIT naive PD-L1 positive NSCLC treated with tirayleigh mab in combination with atuzumab had an overall response rate of 46%, including two complete remissions and several responses showing persistence (fig. 15 and 16).

Example 6: application of atelizumab, ibritumomuzumab and bevacizumab in combination on advanced liver cancer

Liver cancer is the fifth most common cancer worldwide and the second most common cause of cancer-related death, with 854,000 new cases and 810,000 deaths per year. Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting for approximately 90% of all primary hepatic malignant tumors. Less common primary liver cancers include intrahepatic cholangiocarcinoma (iCCA), angiosarcoma, and hepatoblastoma.

Study YO40245 (IMbrave 150) is an ongoing randomized phase III study evaluating the comparison of atelizumab plus bevacizumab as first line therapy to sorafenib in patients with advanced or metastatic HCC. This study demonstrated for the first time that a novel therapeutic combination has a statistically and clinically significant improvement in OS and Progression Free Survival (PFS) in head-to-head comparison with sorafenib. At preliminary analysis, the risk of mortality for the alemtuzumab plus bevacizumab arm was reduced by 42% (stratified hazard ratio [ HR ] =0.58[ 0.42 to 0.79]; p =0.0006; median OS, unexstimable [ NE ] vs 13.24 months). Independent investigator-PFS assessed according to RECIST v1.1 also demonstrated statistically and clinically significant improvements in favor of combination therapy (stratified HR =0.59, [95% ci from 0.47 to 0.76]; p < 0.0001; median PFS,6.83 and 4.27 months). Overall, the alemtuzumab plus Bevacizumab combination in HCC generally has good tolerability and manageable toxicity, and Safety is consistent With the known risk of individual Study treatments and With the underlying disease (Cheng et al IMbrave150: effective and Safety Results From a Ph 3 Study Evaluating atteolizumab (atezo) + Bevacizumab (bv) vs Sorafenib (Sor) First Treatment (tx) for properties (pts) With Unresectable hepatocellullus carcioma (HCC). ESMO Asia 2019 meeting notes: 22 to 24 days 11-2019 [ quote: 27 days 11-2019 ]; singapore).

This is a phase Ib/II, open label, multicenter, randomized, umbrella study, performed in patients with locally advanced or metastatic hepatocellular carcinoma (HCC) who had not received prior systemic therapy for their disease.

Patients were randomly assigned to either the control arm (atezumab plus bevacizumab [ Atezo + Bev ]) or the treatment arm consisting of atezumab and bevacizumab in combination with teleyuezumab (Atezo + Bev + Tira).

Contrast arm (Atezo + Bev)

Patients in the atlizumab plus bevacizumab (Atezo + Bev) arm received treatment as outlined in the table below.

TABLE 41 treatment regimens for Atezo + Bev arm

Atezo + Bev = atelizumab plus bevacizumab.

Atezo+Bev+Tira

Patients in the atbizumab plus bevacizumab plus rayleigh itumumab (Atezo + Bev + Tira) arm received treatment as outlined in the table below.

TABLE 42 treatment regimen for arm Atezo + Bev + Tira

Atezo + Bev + Tir = attlizumab plus bevacizumab plus rayleigh immitumumab; IRR = infusion related response.

^a On day 1 of cycle 1, tegaserod was administered 60 minutes after completing the bevacizumab infusion. The interval between subsequent infusions would be 30 minutes if the previous infusion of bevacizumab was administered without prophylactic administration and tolerated without IRR, or 60 minutes if the patient experienced IRR in the previous infusion of bevacizumab.

B. Inclusion criteria

The patient must meet all of the following criteria:

age ≥ 18 years.

ECOG physical performance status was 0 or 1 within 7 days before treatment.

Locally advanced or metastatic and/or unresectable HCC in cirrhosis patients as confirmed by histological/cytological or clinical AASLD criteria

For cirrhosis patients who have not been histologically confirmed, clinical confirmation according to AASLD standards is required.

Child-Pugh grade A within 7 days before randomization

Diseases unsuitable for radical surgery and/or regional local therapy

Patients with disease progression after surgery and/or regional therapy are eligible.

No previous systemic treatment (including systemic study agents) for HCC was performed

Previous treatments with herbal therapies (including traditional chinese medicine) with anti-cancer activity noted in the label were allowed, provided these drugs were terminated prior to randomization.

The expected life is more than or equal to 3 months.

The following table describes efficacy and safety goals and endpoints. It is expected that patients treated with the Atezo + Bev + Tira triple combination herein will achieve one or more of the therapeutic endpoints (ORR, PFS, OS, DOR, and/or disease control) while having acceptable toxicity compared to placebo Atezo + Bev (i.e., no Tira).

TABLE 44 targets and corresponding endpoints

ADA = anti-drug antibody; DOR = duration of remission; HCC = hepatocellular carcinoma; HCC mRECIST = HCC modified RECIST specific; irrecist = RECIST v1.1 modified for an immune-based therapeutic; NCI CTCAE v5.0= american national cancer institute adverse event general term standard version 5.0; ORR = objective remission rate; OS = overall lifetime; PFS = progression-free survival; PK = pharmacokinetics; RECIST = evaluation of efficacy of solid tumors.

TABLE 45 targets and corresponding endpoints

ADA = anti-drug antibody; DOR = duration of remission; HCC = hepatocellular carcinoma; HCC mRECIST = HCC modified RECIST specific; iRECIST = RECIST v1.1 modified for an immune-based therapeutic; NCI CTCAE v5.0= american national cancer institute adverse event general term standard version 5.0; ORR = objective remission rate; OS = overall lifetime; PFS = progression-free survival; PK = pharmacokinetics; RECIST = evaluation of efficacy of solid tumors.

Example 7A phase III, randomized, double-blind, placebo-controlled study of atezumab plus carboplatin and etoposide with or without combination with tegravitumumab in patients with untreated extensive-stage small cell lung cancer

This example describes a randomized, phase III, global, multicenter, double-blind, placebo-controlled study aimed at assessing whether the anti-tumor effect of astuzumab plus chemotherapy in ES-SCLC patients, as measured by OS, PFS, ORR, and DOR, could be improved by the addition of anti-TIGIT antibody, tiryllylauzumab, to both attuzumab and chemotherapy. The safety and efficacy of the combination of tenectereuptab with atuzumab and CE was compared to treatment with placebo in combination with atuzumab and CE in patients with ES-SCLC and who were naive to chemotherapy for their widespread disease.

A. Design of research

The details of a randomized, phase III, multicenter, double-blind, placebo-controlled study for evaluating the safety and efficacy of treatment with tipleuyuzumab in combination with atuzumab and CE compared to treatment with placebo in combination with atuzumab and CE in patients with ES-SCLC and who were naive to chemotherapy for their wide-term disease are described below. Fig. 17 illustrates the study design.

Eligible patients were stratified by eastern cooperative tumor cohort (ECOG) performance status (0 vs 1), LDH ≦ Upper Limit of Normal (ULN) vs > ULN), and presence or history of brain metastases (yes vs no) and scored at 1: ratio of 1 was randomized to receive one of the following treatment regimens as shown in table 46. Further details on ECOG performance status are provided in Oken et al, am.j. Clin oncol.1982,5: 649-655.

A total of approximately 470 patients will be randomized. The main population (PP) included approximately 400 patients, assuming the presence of brain metastases at baseline with a prevalence of 15% or a history of brain metastases. The intent-to-treat (ITT) population included all patients.

TABLE 46 investigational treatment groups

The induction treatment was carried out for four cycles with 21 days as one cycle. After the induction period, the patient continued on maintenance therapy with atelizumab plus rayleigh eculizumab (arm a) or atelizumab plus placebo (arm B). During the maintenance period, preventive Craniocerebral Irradiation (PCI) was allowed according to local standards of care and reported on the preventive craniocerebral irradiation electronic case report form (eCRF). Allowing palliative irradiation for symptomatic management. Table 47 below provides dosing and administration schedules for the treatment regimens in table 46.

TABLE 47 dosing and administration schedules for treatment regimens

On day 1 of each cycle, study drug was administered to all eligible patients in the following order:

an arm A: abiralizumab, tiryleiguzumab, carboplatin and etoposide

And (B) arm: atelizumab, placebo, carboplatin and etoposide

Patients may receive an antiemetic and IV carboplatin and etoposide hydration according to local standard of care and manufacturer instructions. Prophylactic use of corticosteroids is minimized to the extent clinically feasible. All medications were recorded in the appropriate concomitant medication eCRF.

During the induction period, study treatment should be performed in the following manner

On day 1:

1. atlizumab 1200mg was administered intravenously over 60 (+ -15) minutes (shortened to 30[ + -10 ] minutes for the first infusion and then for subsequent infusions) (see Table 48), followed by

2. 600mg of tirayleigh itumumab/placebo was administered intravenously over 60 (. + -. 15) minutes (shortened to 30[ + -. 10] minutes for the first infusion and for subsequent infusions) (see Table 48), followed by

3. Carboplatin over 30 to 60 minutes intravenous administration to achieve an initial target concentration-time area under the curve (AUC) (Calvert formula dosing) of 5mg/mL/min followed by-

4. Etoposide (100 mg/m) ² ) Intravenous administration was over 60 minutes. During the induction period etoposide (100 mg/m) ² ) Intravenous administration will also be over 60 minutes on days 2 and 3.

Cycles without chemotherapy administration do not count the total number of cycles induced by chemotherapy. After the induction period, patients began maintenance therapy with atelizumab plus rayleigh eculizumab/placebo. The recommended infusion times for carboplatin and etoposide were adjusted according to local standard of care. The administration of atelizumab and tirayleigh immuzumab/placebo is performed in a monitored environment where trained personnel as well as sufficient equipment and medications can be immediately accessed to manage potential critical reactions.

Treatment is continued until the imaging disease progression according to RECIST v1.1, or treatment is continued as long as the patient is experiencing clinical benefit as assessed by the investigator, after a combined assessment of imaging data, biopsy results (if available), and clinical status, there is no unacceptable toxicity or worsening of symptoms due to disease progression. Patients meeting the criteria for disease progression according to RECIST v1.1 are allowed to proceed with study entry treatment (tirayleigh eculizumab plus atelizumab or placebo plus atelizumab) if all inclusion criteria are met.

Abiralizumab

The patient received 1200mg of alemtuzumab administered by IV infusion on day 1 of each 21-day cycle. The dose of alemtuzumab is fixed and independent of body weight. The attritumab infusions were administered according to the instructions summarized in table 48. The attrituzumab dose was not adjusted. For more details on the instructions for the preparation, storage and administration of the doses of atuzumab, see pharmacy manuals and/or atuzumab researcher manuals.

Tirayleigh immuzumab/placebo

Following the alemtuzumab administration and observation period (see table 48), patients received 600mg of tirayleigh eculizumab/placebo administered by IV infusion on day 1 of each 21-day cycle. The tirayleigh mab/placebo dose was fixed and independent of body weight. The tegralyleitumumab/placebo infusion was administered according to the instructions outlined in table 48. The tiryleigh ewuzumab/placebo dose was not adjusted. For further details on the instructions for dose preparation, storage and administration of tirayleigh immuzumab/placebo, see pharmacy manual and/or tirayleigh immuzumab researcher manual.

TABLE 48 administration of the first and subsequent alemtuzumab and TELELELEUYUMAB/placebo infusions

Carboplatin

During the induction period, carboplatin was administered over 30 to 60 minutes by IV infusion after completion of the tiryleigh ulizumab/placebo to achieve an initial target AUC of 5mg/mL/min (Calvert formula dosing) and standard antiemetics were used according to local practice guidelines. Prophylactic use of corticosteroids may be minimized to the extent clinically feasible. The carboplatin infusion time was adjusted according to local standard of care.

Carboplatin doses for AUC 5 can be calculated using the Calvert formula (Calvert et al, j. Clin. Oncol.1989,7:

calvert formula:

total dose (mg) = (target AUC) x (glomerular filtration rate [ GFR ] + 25)

Remarking: the GFR used in Calvert's formula to calculate AUC-based dosing should not exceed 125mL/min.

As used herein, GFR is considered equivalent to creatinine clearance (CRCL). According to institutional guidelines or by Cockcroft and Gault, nephron 1976, 16:31-41, calculating the CRCL using the following formula:

CRCL = (140-age) × (wt)

(. Times.0.85, if female)

72×Scr

Wherein: CRCL = creatinine clearance in mL/min

Age = patient age in years

Wt = patient body weight in kg

Scr = serum creatinine in mg/dL

Remarking: for patients with abnormally low serum creatinine levels, GFR is estimated by using a minimum creatinine level of 0.8mg/dL or is limited to 125mL/min.

If the patient's GFR is estimated by isotope dilution mass spectrometry based on serum creatinine measurements, the physician considers limiting the dose of carboplatin to achieve the desired exposure (AUC) to avoid potential toxicity due to overdosing. The maximum dose can be calculated according to the Calvert formula described in the carboplatin label as follows:

maximum carboplatin dose (mg) = target AUC (mg × min/mL) × (GFR +25 mL/min)

For patients with normal renal function, the maximum dose is based on an estimated GFR with a cap of 125mL/min. Higher estimated GFR values should not be used.

For target AUC =5, the maximum dose is 5x (125 + 25) = 5x 150=750mg.

For target AUC =4, the maximum dose is 4x (125 + 25) =4 × 150=600mg.

Etoposide

Etoposide (100 mg/m) on day 1 of each cycle during the induction phase ² ) Administration by IV infusion took 60 minutes after carboplatin administration. Etoposide (100 mg/m) on days 2 and 3 of each cycle ² ) Administration by IV infusion took 60 minutes. Prophylactic administration was performed according to local standards of care. Prophylactic use of corticosteroids may be minimized to the extent clinically feasible. The etoposide infusion time can be adjusted according to local standard of care.

Rationale for evaluating patients without brain metastases at baseline (main population for statistical analysis)

The brain is a common site of metastasis in ES-SCLC patients, some studies show brain metastasis in up to 18% of patients at diagnosis, and up to 80% of patients are predicted to develop brain disease within the first 2 years after diagnosis (Seute et al, cancer,100, 801-806, 2004, pacheco and Bunn, clin Lung Cancer, 20. In general, the benefits of a combination of immunotherapy and chemotherapy have been demonstrated in patients with ES-SCLC. However, as seen in the IMpower133 trial, this benefit may be diminished in patients with brain metastases at baseline, with a Hazard Ratio (HR) of 1.07 for this subgroup of patients, and 0.68 for patients without brain metastases (Horn et al, new Engl J Med, 379.

KEYNOTE-604 is another phase 3 trial that shows that ES-SCLC patients with brain metastases may receive less or no overall survival benefit at diagnosis compared to patients who did not receive first-line immunotherapy plus chemotherapy. In fact, patients with brain metastases had an OS HR of 1.32, compared to 0.75 for patients without brain metastases (Rudin et al, J Clin Oncology,38 2369-2379, 2020). The CASPIAN study initially reported that patients with brain metastases had an OS HR of 0.69, however, in the more recent analysis, HR became 0.79. Patients with no brain metastases in the initial and updated reports had OS HRs of 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, abstrate 9002, 2020.

Understanding the benefit of the study protocol in both patient subgroups is crucial, therefore, a test statistical test hierarchy is implemented to test PP first, then ITT.

B. Evaluation of

Patients were assessed for tumors at baseline and every 6 weeks (+ -7 days) within 48 weeks after day 1 of cycle 1. Pre-treatment tumor tissue (archived or newly acquired) samples were submitted before randomization or within four weeks after randomization. The specimen is accompanied by a relevant pathology report. While any available tumor tissue sample can be submitted, submission of representative tumor samples in paraffin blocks (first choice) or 10 (or more) consecutive, freshly cut, unstained sections is encouraged for biomarker analysis (e.g., PD-L1 status, markers associated with immunobiology or SCLC biology, such as T cell markers or non-genetic biomarkers identified by NGS on extracted DNA, RNA or other biomolecules). Exemplary sample types include formalin-fixed paraffin-embedded (FFPE) samples prepared from resection, core needle, resection, incision, perforation, jaw biopsy, fine needle aspiration, and cell pellet samples (e.g., from pleural effusion and lavage samples). Based on the total and viable tumor content, the tumor tissue should be of good quality. Tumor tissue from bone metastases that were decalcified was not available.

After completion of the 48-week tumor assessment, tumor assessments were performed every 9 weeks (+ -7 days). Patients who continued treatment after the occurrence of disease progression according to RECIST v1.1 underwent tumor assessment until treatment ceased. Patients who terminate therapy for reasons other than progression of the radiological disease according to RECIST v1.1 (e.g., toxicity, worsening of symptoms) will continue to undergo planned tumor assessments every 6 weeks (+ -7 days) for 48 weeks after cycle 1 day, and then every 9 weeks (+ -7 days), regardless of whether the patient has begun a new anti-cancer therapy.

Serum samples were collected to monitor the pharmacokinetics of ibritumomab tiuxetan and atelizumab. In selected patients, plasma samples were collected for chemotherapy pharmacokinetics. Safety assessments include the incidence, nature and severity of adverse events, protocol-specific vital signs, and laboratory abnormalities.

Tumor biopsies were performed as the imaging progressed. Exemplary sample types include FFPE samples prepared from resection, core needle, resection, incision, perforation, jaw biopsy, fine needle aspiration, and cell pellet samples (e.g., from pleural effusion and lavage samples). DNA and/or RNA may be extracted from the tissue.

C. Results reported by the patient

Patient Reported Outcome (PRO) data was collected to record the therapeutic benefit and more fully normalize the clinical profile of tirayleigh plus attentizumab. PRO data were collected using the following questionnaire: EORTC QLQ-C30, single term EORTC IL46, selects items from PRO-CTCAE and EQ-5D-5L.

EORTC QLQ-C30 is a validated and reliable self-reporting questionnaire (Aaronson et al, j. Natl. Cancer inst.1993, 85-365-76, fitzsimmons et al, eur. J. Cancer 1999, 35 939-41), consisting of 30 questions assessing five aspects of patient function (physical, emotional, role, cognition and social), three symptom scales (fatigue, nausea and vomiting, pain), global health/quality of life, and six singles (dyspnea, insomnia, anorexia, constipation, diarrhea, and economic difficulties). A scale score may be obtained for the multi-item scale.

The EORTC QLQ-C30 module takes approximately 15 minutes to complete. In addition, a single term EORTC IL46 is also collected. This validated single-item problem assesses the overall side-effect impact.

PRO-CTCAE is a validated project library used to characterize the presence, frequency, severity and interference with daily function of 78 patient reportable symptomatic treatments toxicities (Basch et al, j. Natl Cancer inst.2014, 106, dueck et al, JAMA oncol.2015, 1. PROCTCAE contains 124 questions, rated on a 5 point Likert scale (frequency, severity and interference) or dichotomy (presence/absence). Included terms of therapeutic toxicity may be subjective, with or without observable components (e.g., emesis and nausea, respectively), or primarily observable subjective components (e.g., rash). The standard PRO-CTCAE recall period is "7 days past". A subset of the three symptoms considered most suitable for current treatment was selected for this study.

EQ-5D-5L is a general, preference-based health utility questionnaire that contains questions about motility, self-care, daily activities, pain/discomfort and anxiety/depression to build up a composite of the patient's health status. EQ-5D-5L takes about 2 minutes to complete. EQ-5D-5L will be used for economic modeling in this study.

The paper version of the PRO questionnaire is self-administered during the treatment visit and field personnel investigate the patient by phone during the visit, so that data can be collected without requiring the patient to go to the clinical site. The PRO data is entered into the research database by field personnel.

To ensure questionnaire validity and data criteria are in compliance with health authorities' requirements, unless otherwise stated, questionnaires scheduled to be conducted during an outpatient visit are completed by the patient entirely before any information regarding the disease state is received, before non-PRO assessments that may have deviating patient responses are conducted, and before study treatment administration.

Questionnaires (EORTC QLQ-C30, EORTC IL46, PRO-CTCAE (selection item) and EQ-5D-5L) were completed on cycle 1 day 1 (baseline) during the induction period prior to study drug administration; and then completed prior to study drug administration at each study treatment cycle (i.e., cycle 2 day 1; cycle 3 day 1; and cycle 4 day 1). During the maintenance period, the questionnaire was completed prior to study drug administration for every two study treatment cycles (i.e., cycle 5 day 1; cycle 7 day 1; cycle 9 day 1, etc.) and at the study treatment termination visit. During the survival follow-up period, PRO was collected at the first survival follow-up at 3 months (+ -30 days) and the second survival follow-up at 6 months (+ -30 days). Patients who terminate study treatment for any reason other than imaging disease progression according to RECIST v1.1 (e.g., toxicity, worsening of symptoms) will complete the EORTC QLQ-C30, PRO-CTCAE (selection item), and EQ-5D-5L tumor assessment visits until imaging disease progression, death, missed visits, consenting withdrawal or sponsor termination of the study, whichever occurred first. Patients who fail to provide their native language questionnaires are free to complete all PRO assessments.

Adverse event reports not derived from PRO data.

D. Endpoint

PFS (assessed by the inventors according to RECIST v 1.1) and OS in PP as assessed by the investigator are common primary endpoints of the study. Objective remission rates in PP and ITT populations, duration of remission 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 date of first recorded disease progression (assessed by investigator according to RECIST v 1.1) or death, whichever occurred first. Patients who did not experience disease progression or did not die before the data expiration date were scored at the last tumor assessment. Patients who did not have a post-baseline tumor assessment were missed at randomization.

PFS as an endpoint may reflect tumor growth and may be assessed prior to determining survival benefit; furthermore, its determination is not usually confounded by subsequent therapy. Whether improvement in PFS represents a direct clinical benefit or a clinical benefit surrogate depends on the magnitude of the effect and the benefit-risk of the new treatment compared to existing therapies (U.S. food and drug administration (2007) guidelines for industry. Clinical Trial ingredients for the approach of Cancer Drugs and Biologics).

To ensure that researchers assess the effectiveness of PFS as a primary endpoint, a number of measures have been implemented: significant target benefit magnitude and study assessment, which would allow robust assessment of benefit-risk (conventional RECIST v1.1 criteria to define imaging disease progression with the same fixed assessment interval in both treatment arms, and robust definition of PFS and methods for assessing, quantifying, and analyzing prospective definition of PFS, including sensitivity analysis).

When approximately 300 PFS events (75% of 400 patients) have been observed in PP, a preliminary analysis was performed on the common primary endpoint of PFS. This provided 96% efficacy to detect PFS with a target HR of 0.56 and a bilateral significance level of 0.001 based on: PFS curves following an exponential distribution; median PFS for placebo + atezumab + EC arm was 5.2 months, and for the tirayleigh itumumab + atezumab + EC arm group was 9.2 months (corresponding to a target HR of 0.56); the withdrawal rate of PFS in 12 months is 5%; and there was no interim analysis of PFS.

HR observed for PFS was 0.68 or higher, corresponding to statistically significant differences between treatment arms. That is, an HR of 0.68 is the smallest detectable difference for this assay; this corresponds to an improvement in median PFS of 2.4 months, from 5.2 months for placebo + atuzumab + CE arm to 7.6 months for tirayleigh immuzumab + atuzumab + CE arm.

The Kaplan-Meier method was used to estimate the median PFS for each treatment arm, and a Kaplan-Meier curve was constructed to provide a visual depiction of the differences between treatment arms. Brookmeyer-Crowley method 95% CI of the median PFS used to construct each treatment arm (Brookmeyer and Crowley, biometrics 1982, 38-41.

PFS rates at 6 months and 1 year after randomization for each treatment arm were estimated using the Kaplan-Meier method, and 95% ci was calculated using the standard error derived from the Greenwood equation. 95% of the difference in PFS rate between the two treatment arms CI was estimated using a normal approximation method.

Overall life cycle

OS is the common primary endpoint of this study. OS is the time between the randomized date and death for any reason. Improvement in OS is generally considered to be the best measure of clinical benefit in patients with advanced/unresectable or metastatic lung cancer.

PFS and OS between treatment arms were compared using a hierarchical log-rank test. The HR of PFS and OS was estimated using a hierarchical Cox proportional hazards model. Providing 95% of HR CI. Stratification factors are those used to randomize from IxRS (i.e., ECOG performance status and Lactate Dehydrogenase (LDH)). If there is a risk of excessive stratification, the stratification factor may be removed from the stratification analysis. Analysis based on the stratification factor of records on an electronic case report form (eCRF) will also be provided if substantial differences are observed between IxRS and eCRF records. Results of the non-stratified analysis are also provided.

When about 288 deaths (72% of 400 patients) have been observed in PP, a final analysis was performed on the common primary endpoint of OS. This provides 85% efficacy to detect OS with a target HR of 0.70 and a bilateral significance level of 0.049 based on: an OS curve following an exponential distribution; median OS of placebo + attentizumab + EC arm was 12.3 months, and terayleigh itumumab + attentizumab + EC arm was 17.6 months (corresponding to target HR of 0.70); the withdrawal rate of OS in 24 months is 5%; and a planned mid-OS analysis, accounting for approximately 70% of the information portion, where the mid-boundary of statistical significance is determined based on the Lan-demons approximation of the O' Brien-Fleming function.

HR observed for OS in PP was 0.789 or higher, corresponding to statistically significant differences between treatment arms. That is, an HR of 0.789 is the smallest detectable difference for this assay; this corresponds to a 3.3 month improvement in median OS, from 12.3 months for placebo + atuzumab + CE arm to 15.6 months for tirayleigh itumumab + atuzumab + CE arm.

Table 49 below summarizes the timing of the interim and final analyses of the OS, along with additional accrued assumptions.

TABLE 49 analysis timing of Total Life time

FPI = first patient; IA = medium term analysis; PP = major population; OS = overall lifetime

^a Efficacy was calculated using a bilateral alpha of 0.049

mid-OS analysis is performed at the time of final PFS analysis. The Kaplan-Meier method was used to estimate the median OS for each treatment arm and a Kaplan-Meier curve was constructed to provide a visual depiction of the differences between treatment arms. Brookmeyer-Crowley method 95% CI of the median OS used to construct each treatment arm (Brookmeyer and Crowley, biometrics 1982, 38-41.

The OS rate at 1 and 2 years after randomization was estimated for each treatment arm using the Kaplan-Meier method, and 95% CI was calculated using the standard error given by the Greenwood equation. The 95% CI of the difference in OS rate between the two treatment arms was estimated using a normal approximation method.

Secondary efficacy endpoints

Progression-free survival and overall survival in intent-to-treat populations

If the OS differences in PP were statistically significant, PFS and OS were tested in the ITT population, following the same alpha distribution ratio (1. PFS and OS in the ITT population will be analysed simultaneously with PP, using the same method as described above, but all three stratification factors for randomization from IxRS (i.e. ECOG physical status, LDH and presence or history of brain metastases) are included in the stratified analysis of the ITT population. If there is a risk of excessive stratification, the stratification factor may be removed from the stratification analysis.

Confirmed objective remission rate

Confirmed objective remission may be confirmed CR or PR 2 consecutive times ≧ 4 weeks apart, as determined by the investigator using RECIST v 1.1. Patients who did not meet these criteria (including patients who did not have any post-baseline tumor assessments) were considered non-responders.

The confirmed ORR is defined as the proportion of patients with confirmed objective remission. The analytical population for confirmed ORR was the PP and ITT populations with measurable disease at baseline. The estimated value of the confirmed ORR for each treatment arm and its 95% ci were calculated using the capper Pearson method. The CI of the identified ORR difference between the two treatment arms was determined using a normal approximation of the binomial distribution.

Duration of remission

The DOR of confirmed responses was assessed in patients with confirmed objective remission as determined by investigators using RECIST v1.1 in PP and ITT populations. The DOR of confirmed response is the time interval from the date of the first appearance of confirmed objective remission until the date of the first recording of disease progression or death as determined by the investigator according to RECIST v1.1, whichever occurs first. Patients who did not develop progression at the time of analysis and did not die will be missed at the last tumor assessment date. DOR is based on a non-randomized subset of patients (specifically, patients achieving objective remission), and therefore no formal hypothesis testing is performed for this endpoint. Comparisons between treatment arms are made for descriptive purposes. DOR analysis was performed using the methods detailed for PFS analysis.

Factor of stratification

Stratification factors are the factors used to randomize from IxRS (i.e. ECOG physical status, LDH, and presence or history of brain metastases). If at least one level (i.e., a combination of the stratification factor levels by IxRS across ECOG fitness status [0 and 1], LDH ≦ ULN and > ULN ], and the presence or history of brain metastases [ yes or no ] has less than 10 events (PFS or OS events), the stratification factor (one of the 3 stratification factors: ECOG fitness status, LDH, and brain metastases presence or history, by IxRS) containing the level of the minimum number of patients is removed from the stratification analysis. The removal of the stratification factor continues until there are no layers of less than 10 events (PFS or OS events). The final set of stratification factors used in the stratified analysis applies to all endpoints for which the stratified analysis is planned. Analysis based on stratification factors recorded on an electronic case report form (eCRF) is also provided if substantial differences are observed between IxRS and eCRF recordings.

E. Qualification

A patient is eligible if the patient is naive to chemotherapy for their ES-SCLC and meets eligibility criteria, which includes the following: age 18 years or older; the ability to follow the study protocol at the discretion of the investigator; the physical ability state of ECOG is 0 or 1; histologically or cytologically confirmed ES-SCLC (according to the modified phase staging System of the refuge military administration Lung research group (VALG) (Micke et al, lung Cancer 2002, 37 271-6)); no prior systemic treatment for ES-SCLC; patients who have received prior chemoradiotherapy for limited-phase SCLC must have received treatment for curative purposes and have a no-treatment interval of at least 6 months between the last dose/last cycle of chemotherapy, chest radiotherapy or chemoradiotherapy and the diagnosis of ES-SCLC; measurable disease, as defined by RECIST v1.1 (if (1) disease progression at that site has been recently documented since radiation therapy and (2) the previously irradiated lesion is not the only measurable disease site, the previously irradiated lesion may only be considered a treatable disease); submitting a pre-treatment tumor tissue sample; for patients receiving therapeutic anticoagulation: a stable anticoagulant regimen; HIV test is negative during screening; hepatitis B surface antigen (HBsAg) test is negative during screening; adequate hematologic and end organ function, as defined by the following laboratory test results, was obtained within 14 days prior to initiation of study treatment (day 1 of cycle 1) : absolute Neutrophil Count (ANC) ≥ 1.5 × 10 in the absence of granulocyte colony-stimulating factor support ⁹ L (1500/μ L); lymphocyte count is not less than 0.5X 10 ⁹ L (500/. Mu.l); in the case of no blood transfusion, the platelet count is greater than or equal to 100X 10 ⁹ L (100,000/. Mu.L); hemoglobin > 90g/L (9 g/dL) (patients can be transfused or receive erythropoiesis therapy to meet local standard of care); INR or aPTT ≦ 1.5 × ULN (INR or aPTT ≦ 1.5 × ULN for patients not receiving therapeutic anticoagulation); AST, ALT and ALP ≦ 2.5 × ULN, except for: (patients recorded with liver metastasis: AST and/or ALT ≦ 5 × ULN; patients recorded with liver or bone metastasis: ALP ≦ 5 × ULN); bilirubin is less than or equal to 1.5 × ULN (except in patients with known Gilbert disease: bilirubin is less than or equal to 3 × ULN); creatinine is less than or equal to 1.5 multiplied by ULN; albumin is more than or equal to 25g/L (2.5 g/dL).

Exclusion criteria included: symptomatic or actively progressing CNS metastasis (note: asymptomatic patients with treated (i.e. local CNS directed therapy) or untreated CNS foci are eligible if all criteria are met: measurable disease, according to RECIST v1.1, must be present outside the CNS; patients have no history of intracranial or myelogenous bleeding due to CNS disease; metastasis is limited to the cerebellum or supratentorial region (i.e. no metastasis to the midbrain, pons, medulla or spinal cord; patients have no symptoms due to CNS disease (i.e. no headache, nausea, vomiting, convulsions, paralysis, etc.); patients have no continuing need for anticonvulsants for CNS disease; patients have no continuing need for dexamethasone/corticosteroid for CNS disease (nor have any need for or receive dexamethasone/corticosteroid for CNS disease for previous untreated patients), patients have no CNS metastasis with previous treated before completion of CNS directed therapy and no CNS progression between CNS directed therapy and randomized mid-course imaging; for patients without prior brain directed therapy related disease (for example, no history of vascular edema for screening for CNS disease; and for magnetic resonance imaging if all evidence of CNS metastasis is met with follow-up MRI scan for mid-up and if the following MRI scan is the first-up for the patient's for CNS metastasis Standard, computed Tomography (CT) scans using contrast agents may be acceptable for follow-up tumor assessment within all follow-up plans: both brain MRI and CT scans with contrast agents must be performed at screening to assess untreated CNS disorders; CT scans using contrast agents can be used to reliably assess lesions identified in screening MRI using contrast agents; if a CT scan using a contrast agent cannot be used to reliably assess a lesion identified in a screening MRI using a contrast agent, an MRI scan using a contrast agent must be performed in a follow-up tumor assessment within all follow-up plans; and the same pattern was used at each tumor assessment; spinal cord compression without definitive treatment with surgery and/or radiation, or spinal cord compression previously diagnosed and treated, there is no evidence that the disease has been clinically stable for > 1 week prior to randomization; leptomeningeal disease; uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (once a month or more frequently); irrespective of the frequency of drainage, indwelling catheters are used (e.g. for

) Is allowed for the patient; uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5mmol/L, total serum calcium > 12mg/dL, or corrected calcium > ULN); clinically significant liver disease is known, including active viral, alcoholic or other hepatitis, cirrhosis and hereditary liver disease, or current alcohol abuse; other malignancies, other than SCLC, within 5 years prior to randomization, except for those with negligible risk of metastasis or death (e.g., 5 years OS > 90% is expected) and treated to have a curative outcome with them (such as adequately treated carcinoma of the cervical in situ, basal cell or squamous cell skin cancer, localized prostate cancer treated with surgery for curative purposes, ductal breast cancer in situ treated with surgery for curative purposes); activity or history of autoimmune disease or immunodeficiency, except for: (patients with a history of autoimmune-related hypothyroidism who are undergoing thyroid replacement hormone therapy meet the study criteria; patients with controlled type 1 diabetes who are undergoing insulin regimen or who meet the study criteria (ii) a Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with only dermatological manifestations (e.g. excluding patients with psoriatic arthritis) met the conditions of the study, provided that all of the following conditions were met: rash must cover < 10% of the body surface area; the disease must be adequately controlled at baseline and only low potency topical corticosteroids are required; within the previous 12 months, no acute exacerbation of the underlying disease requiring psoralen plus ultraviolet a radiation, methotrexate, tretinoin, biopharmaceuticals, oral calcineurin inhibitors or high potency or oral corticosteroids occurred; idiopathic pulmonary fibrosis, organized pneumonia (e.g., bronchiolitis obliterans), a history of drug-induced pneumonia or idiopathic pneumonia, or screening for evidence of active pneumonia on chest CT scans; the history of radiation pneumonitis (fibrosis) in the field of radiation is allowed; active EBV infection at screening or chronic active EBV infection known or suspected; patients positive for EBV IgG and/or EBV nuclear antigen (EBNA) are eligible only if EBV IgM and/or EBV Polymerase Chain Reaction (PCR) is negative; active tuberculosis; severe infections at randomization, including but not limited to hospitalization for infection, bacteremia, or severe pneumonia; significant cardiovascular diseases such as new york heart association heart disease (grade II or higher), myocardial infarction or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmia or unstable angina; patients with known coronary artery disease, congestive heart failure or left ventricular ejection fraction < 50% who do not meet the above criteria must receive a stable medical regimen that the treating physician deems optimal and consult the cardiologist as appropriate; major surgery was performed within 28 days prior to randomization, except for targeting or expected to be required during the course of the study; previous allogeneic bone marrow transplantation or solid organ transplantation; any other disease, metabolic dysfunction, physical examination findings, or clinical laboratory findings, that may reasonably suspect the presence of a disease or condition that is contrary to the use of study drugs, or that may affect outcome interpretation or place the patient at high risk for treatment complications; patients with diseases or disorders that interfere with their ability to understand, follow, and/or comply with research procedures; in the research and treatment Treatment with any other study agent within 28 days prior to mobilization; current treatments with antiviral therapies against HBV or HCV; administration of live attenuated vaccines within 4 weeks prior to randomization, or it is expected that such live attenuated vaccines will be needed during the study; within 4 weeks prior to randomization, during treatment, and within 5 months after the last dose of study treatment, patients must receive live attenuated influenza vaccine (e.g.,

) (ii) a Prior treatment with CDl 37 antagonist 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)) within 4 weeks or 5 drug clearance half-lives (whichever is longer) prior to randomization; treatment with systemic immunosuppressive drugs (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents) within 1 prior to randomization, or it is expected that systemic immunosuppressive drugs will be required during study treatment, except: patients receiving acute, low dose systemic immunosuppressant administration or one-time pulse dose systemic immunosuppressant administration (e.g., 48 hours corticosteroid for contrast agent allergy) were eligible for the study after medical supervisor confirmation; patients receiving mineralocorticoids (e.g., fludrocortisone), corticosteroids for Chronic Obstructive Pulmonary Disease (COPD) or asthma, or low doses of corticosteroids for treatment of orthostatic hypotension or adrenal insufficiency meet the criteria of this study; a history of severe allergic reactions to the chimeric or humanized antibody or fusion protein; known to be allergic to chinese hamster ovary cell products or to any component of the attritumab or tenecteuzumab formulations; (ii) has a history of allergy to carboplatin or etoposide; pregnancy or lactation, or intended pregnancy during study treatment, within 90 days after the last administration of tireyuezumab or placebo, within 5 months after the last administration of atuzumab, or within 6 months after the last administration of carboplatin or etoposide; the fertile woman must be started before study treatment is initiated The result of the serum pregnancy test within 14 days was negative.

F. Cytokine release syndrome

No prophylactic dosing was indicated for administration of tirayleigh mab/placebo or atelizumab on cycle 1. However, patients experiencing Cytokine Release Syndrome (CRS) with tirayleigh itumumab/placebo or atelizumab may receive prophylactic administration of antihistamines, antipyretics and/or analgesics (e.g., acetaminophen) for subsequent infusions. CRS is defined as a supraphysiological response that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells following administration of any immunotherapy. Symptoms may be progressive, always including fever from the outset, and may include hypotension, capillary leakage (hypoxia), and end organ dysfunction (Lee et al, biol Blood Marrow Transplant,25 (4): 625-638, 2019). CRS has been well documented in chimeric antigen receptor T cell therapy and bispecific T cell conjugated antibody therapy, but also in immunotherapy targeting PD-1 or PD-L1 (Rotz et al, pediatr Blood Cancer,64 e26642, 2017, adaschek and feldman, j Oncol practice,15, 502-504, 2019), including astuzumab.

Example 8A phase II, randomized, double-blind, placebo-controlled study on tipleiuzumab in combination with atuzumab plus pemetrexed and carboplatin/cisplatin versus Pabolilizumab plus pemetrexed and carboplatin/cisplatin in patients with previously untreated advanced non-squamous non-small cell lung cancer

This example describes a randomized, phase II, global, multicenter, double-blind study aimed at assessing efficacy and safety of tipleiuzumab in combination with atuzumab plus pemetrexed and carboplatin/cisplatin compared to placebo in patients with locally advanced non-resectable or metastatic non-squamous non-small cell lung cancer (NSCLC) who had not previously been treated.

A. Design of research

Patients eligible for this study included previously untreated male and female patients aged 18 years and older, with eastern cooperative tumor group (ECOG) performance status (0 and 1), with locally advanced unresectable or metastatic non-squamous NSCLC, without EGFR or ALK genomic aberrations.

Patients whose tumors had known EGFR or ALK rearrangements were excluded from the study. Patients with tumors with unknown EGFR or ALK mutation status need to be tested prior to enrollment. Eligible patients were stratified by PD-L1 expression (tumor proportion score (TPS)/Tumor Cells (TC) < 1% and 1% -49% to ≧ 50%, by local or central assay), geographic region (Asia vs. non-Asia), and ECOG physical status (0 vs. 1), and randomized in a 1: 1 ratio to receive the following treatment regimen:

An arm A: (ii) a combination of tireylauzumab and atuzumab plus pemetrexed and cisplatin/carboplatin;

and (B) arm: placebo combined with palbocicluzumab plus pemetrexed and cisplatin/carboplatin.

The selection of carboplatin or cisplatin was according to the choice of the investigator. The selection of carboplatin or cisplatin was made prior to randomization and could not be altered after day 1 of cycle 1.

The randomization protocol was intended to ensure that an approximately equal number of patients were enrolled, representing well all PD-L1 expression subgroups (TPS/TC < 1%, 1% -49%, and ≧ 50%). To reflect the natural distribution of PD-L1 expression observed in first-line NSCLC patients, the proportion of patients enrolled in each PD-L1 subgroup capped approximately 80 patients (approximately 40% of the total number of enrolled groups) at each central test using the investigational VENTANA PD-L1 (SP 263) companion diagnostic (CDx) assay. Given the difference between the local and central results, if the subgroup grouping (as defined by the central result) is on a trajectory that exceeds the upper bound, then selective grouping based on the local PD-L1 status is implemented.

Induction therapy of arm a and arm B was administered for 4 cycles in a 21 day cycle. After the induction period, the patient will continue with maintenance therapy as outlined below.

Arm A: combinations of tireylaumazumab and atezumab plus pemetrexed

Arm B: combination of placebo and palbociclizumab plus pemetrexed

Within 48 weeks after cycle 1 day 1, patients received tumor assessments at baseline and every 6 weeks (+ -7 days), regardless of whether the treatment dose was delayed or not. After completion of week 48 tumor assessments, tumor assessments are required every 9 weeks (+ -7 days) thereafter, whether dose-delayed or not, until imaging disease progression, consent to withdrawal, study termination or death according to RECIST v1.1, whichever occurs first. Patients who continue treatment after disease progression according to RECIST v1.1 will receive tumor assessments at the above-described frequency until study treatment is terminated. Patients who have discontinued treatment for reasons other than imaging disease progression according to RECIST v1.1 (e.g., toxicity, worsening of symptoms), whether or not the patient initiates a new anti-cancer therapy, will continue on-schedule tumor assessment at the same frequency as if the patient maintained investigational therapy (i.e., once every 6 weeks [ ± 7 days ] for 48 weeks after day 1 of cycle 1 and then once every 9 weeks [ ± 7 days ]) until imaging disease progression according to RECIST v1.1 occurs, withdrawal consent, study termination, or death, whichever occurs first.

Patients were asked to complete patient reported outcome questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13, and EORTC IL 46) during treatment, at study treatment termination, and at study treatment termination visit.

Safety assessments at study visit included the incidence, nature and severity of adverse events, protocol-specific vital signs, laboratory abnormalities and other protocol-specific tests deemed critical to the safety assessment of the study.

During the study, serum samples were collected to monitor the pharmacokinetics of tirayleigh immuzumab and atuzumab and to detect the presence of antibodies directed against tirayleigh immuzumab and atuzumab.

Patient samples, including archived and fresh tumor tissue, serum, plasma, and blood samples, were collected for exploratory biomarker assessment.

During the study, patients who met the criteria for disease progression according to RECIST v1.1 and showed evidence of clinical benefit may continue to be treated with tirayleigh unizumab/placebo and atuzumab/palboceprizumab as appropriate by the investigator, provided that the patients met all of the following criteria:

evidence of clinical benefit assessed by the investigator

Absence of symptoms and signs (including laboratory value worsening (e.g., new or worsening hypercalcemia)), then a clear indication of disease progression

No decline in ECOG Performance status attributable to disease progression

No tumor progression at critical anatomical sites (e.g. leptomeningeal disease) that are not addressed by the medical intervention allowed by the protocol

Patients must provide written consent to acknowledge the postponement of other treatment options in support of continuing study treatment at the initial imaging progression according to RECIST v1.1.

The investigator's assessment of overall tumor response at all time points was based only on RECIST v1.1. Objective remission according to irrecist is calculated programmatically based on the investigator's assessment of individual lesions at each specified time point.

B. Administration and administration

The treatment protocol is summarized in figure 18.

Atelizumab and pabulilizumab

On day 1 of each 21-day cycle, the patient received a fixed dose of 20mL (1200 mg) of atuzumab in the a arm or 8mL (200 mg) of pertuzumab in the B arm. The alemtuzumab/palbociclumab infusion was administered according to the instructions outlined in table 50.

TABLE 50 administration of first and subsequent attrituzumab, pabolilizumab, trirayleigh Euzumab, and placebo infusion

Tirayleigh immuzumab and placebo

On day 1 of each 21-day cycle, patients received a fixed dose of 10mL (600 mg) of tiyleitumumab in the a arm or 10mL of placebo in the B arm. The tegralyleitumumab/placebo infusion was administered according to the instructions outlined in table 50.

Pemetrexed, cisplatin and carboplatin

Table 51 lists the dosages and recommended infusion times for therapeutic administration of pemetrexed, carboplatin, or cisplatin.

TABLE 51 treatment regimens for pemetrexed, carboplatin, or cisplatin

Patients received antiemetics and IV hydration for platinum-pemetrexed treatment according to local standard of care and manufacturer's instructions. However, due to their immunomodulatory effects, pre-operative administration of steroids is limited when clinically feasible. In addition, if pemetrexed-related rashes occur, topical use of steroids as first-line therapy is recommended when clinically feasible.

Table 52 lists the suggested prophylactic administration of pemetrexed.

TABLE 52 preoperative preparation of pemetrexed

The chemotherapy cycle includes four cycles of induced chemotherapy, as long as at least one platinum-based chemotherapy component has been administered at least once during a 21 day period during the induction period. Cycles without chemotherapy administration do not count the total number of cycles induced by chemotherapy.

Dose adjustment

Adjustments to the pemetrexed and cisplatin/carboplatin doses were allowed based on the prescription information and local standard of care.

Dose adjustment guidelines are provided below. Once reduced, the dose cannot be increased back to 100%.

Treatment with pemetrexed or cisplatin/carboplatin is terminated if the patient experiences any hematologic or non-hematologic grade 3 or 4 toxicity after two dose reductions, or delays treatment for more than 63 days due to toxicity.

Hematological toxicity

At the beginning of each cycle, the ANC was ≧ 1500/μ L and the platelet count was ≧ 100,000/μ L. Treatment may be delayed for up to 63 days in order to allow sufficient time for recovery. Growth factors may be used according to the American Society for Clinical Oncology (ASCO) and NCCN guidelines (Smith et al 2015. After recovery, the dose was adjusted at the beginning of the subsequent cycle based on the lowest platelet and neutrophil values of the previous cycle (table 53). If the dose needs to be adjusted for both ANC and platelets, the patient will receive a lower dose.

TABLE 53 adjustment of chemotherapeutic dose due to hematologic toxicity

Researchers remain alert and vigilant to early and overt signs of myelosuppression, infection, or febrile neutropenia in order to timely and properly manage these complications. Patients are made aware of these signs and are encouraged to seek medical advice as early as possible.

If chemotherapy is discontinued due to hematologic toxicity, a complete blood count (including classifying WBCs) is obtained weekly until the count reaches the lower limit of the treatment. The treatment is then resumed.

It is not recommended to reduce the dose due to anemia. Support is provided to the patient according to the guidelines of the investigator's institution.

Non-hematologic toxicity

For non-hematologic toxicities (Table 54), treatment was delayed for a maximum of 63 days until regression to less than or equal to the baseline value for the patient (grade ≦ 1 if the patient did not have the toxicity at baseline). Dose reduction at the beginning of the next cycle was based on non-hematologic toxicity of the dose given in the previous cycle. Table 54 provides recommended dose modifications for non-hematologic toxicity.

TABLE 54 adjustment of chemotherapeutic dose due to hematologic toxicity

Diarrhea is controlled by sufficient anti-diarrhea drugs. Nausea and/or vomiting can be controlled with sufficient antiemetics. For grade 3 or 4 neurotoxicity, chemotherapy is either restored or immediately terminated (based on the clinical judgment of the investigator) at 50% of the previous dose following improvement.

C. Concomitant therapy

Concomitant therapy includes patients using any medication other than the regimen prescribed treatment (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplements) from 7 days prior to study drug initiation to study termination visit. All of these medications were reported to the investigator and recorded.

Allowed therapy

Patients were allowed the following therapies during the study:

oral contraceptives with annual failure rate < 1%

Hormone replacement therapy

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

in patients without a record of imaging disease progression, there is a strong recommendation to maximize supportive care for symptomatic management and avoid radiotherapy that would interfere with tumor target lesion assessment. Treatment with tirayleigh unizumab/placebo and atuzumab/palbociclumab may continue during palliative radiation therapy.

Receptor activators for nuclear factor-B ligand-targeted therapy to increase bone mineral density

Bisphosphonates to slow the progression of bone loss

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or low molecular weight heparin)

Inactivated influenza vaccine

Administration of megestrol acetate as an appetite stimulant

Mineralocorticoids (e.g. fludrocortisone)

Administration of inhaled or Low dose glucocorticoids for Chronic obstructive pulmonary disease or asthma

Low doses of mineralocorticoids for orthostatic hypotension or low doses of mineralocorticoids and corticosteroids for adrenal insufficiency. Allowing prophylactic administration of pemetrexed and cisplatin or carboplatin. Prophylactic administration of antihistamines, antipyretics and/or analgesics may only be administered for the second and subsequent atuzumab/palboclizumab and tirayleigh unizumab/placebo infusions, as appropriate by the researcher.

Generally, researchers manage patient care with other supportive therapies than those clinically defined as cautionary or forbidden therapies (according to local standard practice). Patients presenting with infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalents of local standard practice. Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and are managed with supportive therapy (e.g., supplemental oxygen and β 2-adrenergic agonists) based on clinical indications

Warning therapy

Systemic corticosteroids and TNF- α inhibitors may attenuate the potentially beneficial immune effects of treatment with ibritumomab tiuxetan and/or atelizumab. Thus, where systemic corticosteroids or TNF- α inhibitors are routinely administered, alternatives are contemplated, including antihistamines. If alternatives are not feasible, administration of the systemic corticosteroid and the TNF- α inhibitor may be determined by the researcher as appropriate.

At the discretion of the investigator, the use of systemic corticosteroids is advised to treat specific adverse events associated with ibrinout's and/or atelizumab

Treatment inhibition

The following concomitant therapies were prohibited, as follows:

any trial therapy (outside the study treatment specified in the protocol) was prohibited 28 days before study treatment began and during study treatment.

Concomitant therapies aimed at treating cancer (including but not limited to chemotherapy, hormonal therapy, immunotherapy, radiation therapy and herbal therapy) are prohibited for different periods of time (depending on the agent) before study treatment is initiated and during study treatment until disease progression is documented and the patient has terminated study treatment except palliative radiation therapy in certain settings.

Live attenuated vaccines within 4 weeks before initiation of study treatment, during study treatment and within 5 months after the last dose of study treatment

Systemic immunomodulators (including but not limited to interferon and IL-2) within the elimination half-life (whichever is longer) of 4 weeks or 5 drugs before initiation of study treatment and during study treatment, as these drugs may increase the risk of developing autoimmune disease when administered in combination with study treatment

Systemic immunosuppressive drugs (including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide) during study treatment, as these drugs may alter the efficacy and safety of study treatment

D. Inclusion criteria

Patients must meet the following conditions to enter the study:

sign informed consent

The age at which the informed consent was signed was 18 years old or older

Ability to comply with the study protocol

ECOG physical Performance status of 0 or 1

Locally advanced unresectable or cytologically recorded

Metastatic non-squamous NSCLC

Patients with mixed NSCLC histology tumors must be classified as non-squamous cell carcinoma based on major histology. Patients with mixed NSCLC and small cell lung cancer did not meet the conditions of this study.

Absence of previous systemic treatment against metastatic, non-squamous NSCLC

Patients who have received neoadjuvant, adjuvant chemotherapy, radiotherapy or chemoradiotherapy with curative intent for non-metastatic disease must experience a no treatment interval of at least 12 months after randomization since the last dose of chemotherapy and/or radiotherapy.

Known tumour PD-L1 status, by using an assay approved by local health authorities (SP 263[ preferred ], or 22C3 only when SP263 is not available) or, if a local test for approval is not available, by a central laboratory assay (investigational VENTANA [ SP263] CDx assay)

The availability of representative tumor specimens in formalin-fixed paraffin-embedded (FFPE) blocks (preferred) or at least 15 to 20 unstained serial slides and associated pathology reports were confirmed. If a centralized test for EGFR mutations and/or ALK translocations is required, an additional 5 unstained slides must be provided.

The quality of the tumor tissue is good based on total and viable tumor content (i.e., at least 100 viable tumor cells have preserved cellular environment and tissue architecture). Acceptable samples include samples from resection, core needle biopsy for deep tumor tissue (at least three cores are required for freshly taken biopsies) or resection, incision, punch or clamp biopsy for skin, subcutaneous or mucosal lesions, or endobronchial ultrasound (EBUS) core needle biopsy.

Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA), sometimes referred to as fine needle aspiration, is acceptable (especially if larger gauge needles are used) provided that the tissue is of good quality as described above (i.e., a minimum of 100 viable tumor cells have a preserved cellular background and tissue structure). For needle aspiration, 18 gauge or larger needles are suggested.

Fine needle aspiration, brushing, cell pellet from pleural effusions and lavage samples that do not preserve tissue architecture and produce cell suspensions and/or cell smears are unacceptable.

Tumor tissue from bone metastases could not be assessed by IHC for tumor PD-L1 expression and is therefore unacceptable.

If the archived tissue is insufficient or unavailable, the patient may be biopsied at the time of screening if the biopsy site is safely accessible. If a biopsy cannot be provided, the patient is eligible for discussion with a medical supervisor if more than 10 consecutive slides can be provided without staining.

Measurable disease, as defined by RECIST v1.1

If disease progression is clearly documented at that site, only previously irradiated lesions may be considered measurable disease, since radiation and previously irradiated lesions are not the only sites of measurable disease.

Expected life ≥ 12 weeks

Appropriate blood and end organ function, defined by the following laboratory test results obtained within 14 days before initiation of study treatment (day 1 of cycle 1):

ANC ≥ 1.5X 109/L (≥ 1500/μ L) with the support of granulocyte-free colony stimulating factor

Lymphocyte count ≥ 0.5X 109/L (≥ 500/μ L)

In the case of no blood transfusion, the platelet count is > 100X 109/L (≥ 100,000/. Mu.L)

Hemoglobin ≥ 90g/L (≥ 9 g/dL)

Depending on local standard of care, a patient may need to transfuse or receive erythropoiesis treatment to meet this criterion.

AST, ALT and ALP ≦ 2.5 × upper limit of normal values (ULN), with the following exceptions:

patients with liver metastases were recorded: AST and ALT ≤ 5 × ULN

Patients with liver or bone metastases were recorded: ALP ≤ 5 × ULN

-total bilirubin ≦ 1.5 × ULN, with the following exceptions:

patients with known gilbert disease: bilirubin level is less than or equal to 3 × ULN

Creatinine clearance (CrCl) ≥ 40mL/min (for cisplatin, > 60mL/min is required), calculated using the Cockcroft-Gault equation (Cockcroft and Gault 1976) or used to determine CrCl by 24-hour urine collection

Albumin ≥ 25g/L (≥ 2.5 g/dL)

For patients who do not receive therapeutic anticoagulation: INR and aPTT are less than or equal to 1.5 multiplied by ULN

For patients receiving therapeutic anticoagulation: stabilized anticoagulant regimens

HIV test negative at screening

Negative in the hepatitis B surface antigen (HBsAg) test at screening

Hepatitis B surface antibody (HBsAb) test positive at screening, or HBsAb test negative at screening with either:

total hepatitis B core antibody (HBcAb) negative

Positive in total HBcAb test followed by (according to local laboratory definition) negative in Hepatitis B Virus (HBV) DNA test

Hepatitis C Virus (HCV) antibody test negative at screening; or positive for HCV antibody testing and then negative for HCV RNA testing when screened. Only patients who tested positive for HCV antibodies were tested for HCV RNA.

For fertile women: consent to maintain abstinence (avoidance of sexual intercourse) or use of contraceptive measures, and consent to not donate ova, is defined as follows:

women must maintain either abstinence or a contraceptive regimen with an annual failure rate of < 1% during the treatment period and within 90 days after the last administration of tiregumab or placebo, within 5 months after the last administration of atuzumab or palboclizumab, within 6 months after the last administration of pemetrexed and carboplatin or cisplatin. At this same time, women must avoid donating eggs.

A woman is considered to have fertility potential if, after menarche, the woman does not reach a postmenopausal state (continuous > 12 months of amenorrhea, no established cause other than menopause) and is not permanently infertile by surgery (i.e. removal of ovaries, oviducts and/or uterus) or other causes established by investigators (e.g. Mullerian tube hypoplasia). The definition of fertility potential may be adjusted according to local guidelines or regulations.

Examples of contraceptive methods with annual failure rates of < 1% include bilateral tubal ligation, male sterilization, hormonal contraceptives to inhibit ovulation, hormone releasing intrauterine devices and copper intrauterine devices.

The reliability of sexual abstinence is assessed according to the duration of the clinical trial and the patient's preference and usual lifestyle.

Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are inadequate methods of contraception.

Women who want to be pregnant after termination of the study treatment should seek advice on oocyte preservation before the study treatment is initiated, as carboplatin treatment may lead to irreversible infertility.

For males: consent to maintain abstinence (avoid sexual intercourse) or to use contraceptive methods, and consent to not donate sperm, are defined as follows:

With a non-pregnant female fertile partner, men who are not surgically sterilized must remain on abstinence or use condoms with an annual failure rate < 1% for additional contraception to avoid embryo exposure and/or genetic toxicity during the treatment period and within 90 days after the last administration of tenecteuzumab or placebo, within 4 months after the last administration of alemtuzumab or palivizumab, and within 6 months after the last administration of pemetrexed and carboplatin or cisplatin. During this same period, the male must avoid donation of sperm.

Along with pregnant female partners, men must remain abstinent or use condoms during treatment and within 90 days after the last administration of tireyuezumab or placebo, within 4 months after the last administration of attrituzumab or palboceprizumab, within 6 months after the last administration of carboplatin and paclitaxel, in order to avoid exposure to embryos.

The reliability of sexual abstinence is assessed according to the duration of the clinical trial and the patient's preference and usual lifestyle.

Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are inadequate methods of contraception.

Men who want to live their child after the study treatment has started should seek advice on sperm preservation before the study treatment has started, as treatment with pemetrexed, cisplatin or carboplatin may lead to irreversible infertility.

E. Exclusion criteria

Patients were excluded from the study if they had NSCLC known to have mutations in the EGFR gene or the ALK fusion oncogene. Patients with mixed-oil non-squamous NSCLC of unknown EGFR or ALK status were tested at the time of pre-screening or screening. EGFR and/or ALK status was assessed at local or central laboratories. Local assessment of EGFR status is performed histologically or cytologically using validated tests approved by health authorities to detect mutations in exons 18 to 21. Additional slides are provided if samples are submitted for central EGFR and/or ALK testing.

F. Evaluation of

Patient safety and tolerability were closely monitored throughout the study. The patients were assessed for toxicity prior to each dose; administration is only performed when clinical assessments and local laboratory test values are acceptable.

Medical history, baseline conditions, concomitant medications, and demographic data

Medical history, including clinically significant disease, surgery, cancer history (including previous cancer therapies and procedures) and lung cancer mutational status (e.g., EGFR and ALK), reproductive status, smoking history, and alcohol and drug abuse, was recorded at baseline. In addition, all medications (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplements) used by the patient within 7 days prior to the start of study treatment were recorded. At each follow-up visit, a history of the intervals was obtained and any changes in medication and allergy were recorded.

Demographics include age, gender, and self-reported race/ethnicity.

Physical examination

Comprehensive physical examination was performed at screening and included assessment of the head, eye, ear, nose and throat, as well as cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, genitourinary and nervous systems. Any abnormalities identified at baseline were recorded.

Limited, symptom-directed physical examination is performed at a specific post-baseline visit and clinical indication. Abnormalities in changes from baseline were noted in the patient notes. New or worsening clinically significant abnormalities were recorded.

Vital signs

Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure, as well as body temperature, measured while the patient is sitting.

The abnormalities observed at baseline were recorded on the general medical history and baseline condition eCRF. At subsequent visits, new or worsening clinically significant abnormalities were recorded.

ECOG physical fitness status

Performance status was measured at baseline using ECOG Performance status and assessed periodically throughout the study

Tumor and response assessment

Screening and subsequent tumor assessment must include chest and abdominal CT scans (using IV contrast agents (unless contraindicated) and oral contrast agents, if appropriate, on institutional basis). Screening requires a pelvic CT scan with contrast agent, either on clinical indication or in subsequent assessment of response, according to local standard of care. MRI scans of the chest, abdomen and pelvis with contrast agents and non-contrast CT scans of the chest may be used for patients who are contraindicated for CT scans with contrast agents (i.e. patients who are allergic to iodine-based contrast agents or have impaired renal clearance function).

Screening must be performed on head CT (using contrast agents) or MRI scans using contrast agents (if contraindicated for CT contrast agents) to assess CNS metastases in all patients. If CT with contrast agents is performed and the presence of brain metastases is considered ambiguous, then an MRI scan of the brain is required to confirm or deny the diagnosis of CNS metastases at baseline.

If a CT scan for tumor assessment is performed in a Positron Emission Tomography (PET)/CT scanner, a CT acquisition must be performed to meet the criteria of a full contrast diagnostic CT scan.

If clinically indicated, further studies will be performed, such as bone scans and CT scans of the neck. Other methods of assessing measurable disease according to RECIST v1.1 may be used as appropriate by the investigator.

Tumor assessments were performed at standard care, rather than repeat testing, before obtaining informed consent and within 28 days after cycle 1 day 1. All known disease sites, including measurable and/or unmeasurable disease, must be recorded at screening and re-assessed at each subsequent tumor assessment.

Regardless of treatment delay, patients will be assessed for tumors every 6 weeks (+ -7 days) at baseline and within 48 weeks after cycle 1 day. After completion of the 48 th week tumor assessment, tumor assessments need to be made every 9 weeks (+ -7 days), regardless of treatment delay, until imagewise disease progression according to RECIST v1.1 (or for patients who continue study treatment after disease progression according to RECIST v1.1, loss of clinical benefit, withdrawal of consent, death, or study termination, whichever occurs first).

Researchers used RECIST v1.1 to assess responses based on imaging modalities. The investigator's assessment of overall tumor response at all time points was based only on RECIST v1.1. The assessment is made by the same evaluator, if possible, to ensure internal consistency between visits. Results must be reviewed by investigators before the next cycle of dosing.

Study treatment with tirayleigh mab/placebo and atuzumab/palboclizumab can be continued as long as the patient is experiencing clinical benefit as assessed by the investigator, treatment is continued without unacceptable toxicity or worsening of symptoms due to disease progression after a combined assessment of imaging data, biopsy results (if available), and clinical status. Patients who meet the criteria for disease progression according to RECIST v1.1 are allowed to continue study treatment if all specified criteria are met and written consent is provided.

Patients who terminate treatment for reasons other than imaging disease progression according to RECIST v1.1 (e.g., toxicity, worsening of symptoms) will continue on an ongoing oncology assessment at the above-described frequency until imaging disease progression according to RECIST v1.1, withdrawal consent, death, or termination of the study, whichever occurs first. Patients who start new anti-cancer therapy in the absence of imaging disease progression according to RECIST v1.1 will continue tumor assessment at the above-described frequency until imaging disease progression according to RECIST v1.1, withdrawal consent, death or study termination, whichever comes first.

The investigator's assessment of overall tumor response at all time points was based only on RECIST v1.1. Overall tumor assessments were performed according to irrecist based on entries for all target lesions, non-target lesions, and new lesions. To facilitate evaluation of the response according to nonreist, tumor assessment must be continued following disease progression according to RECIST v1.1 for patients who continue to receive study treatment after progression. This includes continuous measurement of the target lesion, assessment of non-target lesions (including monitoring for further deterioration of any non-target lesion that has shown clear progression), and assessment of any newly identified lesions (including measurements if the lesion is measurable) in all subsequent assessments.

Electrocardiogram

ECG was required at screening and with clinical indications. The ECG of each patient is acquired from the same machine as much as possible. The lead placement is as consistent as possible. ECG recordings must be made after the patient has rested in the supine position for at least 10 minutes.

For safety monitoring purposes, researchers must review all ECG tracings. A copy of the ECG tracing is saved at the site as part of the patient's permanent study file. Any morphological waveform changes or other ECG abnormalities must be recorded.

Assessment of clinical results

The PRO questionnaire was completed to document the therapeutic benefit and more fully characterize the clinical profile of tenerayleigh eculizumab and atelizumab plus carboplatin with paclitaxel/nab-paclitaxel. PRO data were collected using the following questionnaire: EORTC QLQ-C30, EORTC QLQ-LC13, and EORTC IL 46.

Questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13 and EORTC IL 46) were completed on cycle 1 day 1 prior to study drug administration (baseline); and then completed prior to study drug administration at each treatment cycle up to cycle 4 day 1 (i.e., cycle 2 day 1; cycle 3 day 1; and cycle 4 day 1).

At cycle 5, the questionnaire was completed on day 1 of each two study treatment cycles (i.e., cycle 5 day 1; cycle 7 day 1; cycle 9 day 1, and so on) prior to study drug administration until and at the study treatment termination visit.

Blood samples for whole genome sequencing or whole exome sequencing

At the participating sites, blood samples are collected for DNA extraction to enable WGS or WES to identify variants that are predictive of response to the study drug, are associated with progression to a more severe disease state, are associated with acquired resistance to the study drug, are associated with susceptibility to developing adverse events, which may improve adverse event monitoring or investigation, or may increase knowledge and understanding of disease biology and drug safety. DNA extracted from blood can be compared to DNA extracted from tissue to identify somatic variants 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 depends on the IRB/EC of each site and, if applicable, the review and approval of exploratory studies by the appropriate regulatory bodies.

Genomics is increasingly informing researchers of the understanding of the pathobiology of disease. WGS and WES provide a comprehensive characterization of the genome and exome, respectively, and, together with the clinical data collected in this study, may increase the opportunity to develop new therapeutic approaches or new methods to monitor efficacy and safety or predict which patients are more likely to respond to drugs or develop adverse events. The data were analyzed in the context of this study, but could also be explored in combination with data from other studies. The availability of larger data sets will help identify and characterize important biomarkers and pathways to support future drug development.

Blood samples collected for WGS or WES will be preserved until they are no longer needed or used up.

Samples for studying biological sample libraries

Research biological sample pools (RBRs) are a centrally managed group of facilities for long-term storage of human biological samples, including body fluids, solid tissues and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, storage and analysis of RBR samples facilitates rational design of new agents and development of diagnostic tests that may provide personalized drug therapy to patients in the future.

Samples of RBRs were collected from patients who explicitly agreed to participate in this optional study. Analyzing the RBR sample to achieve one or more of the following goals:

study of the association of biomarkers with efficacy or disease progression

Identification of safety biomarkers associated with susceptibility to adverse events or likely to lead to improved adverse event monitoring or investigation

Increased understanding and understanding of disease biology and drug safety

Investigating drug response, including drug effects and the course of drug absorption and disposal

Development of biomarkers or diagnostic assays and determination of performance characteristics of these assays

Sample collection

The following samples were stored in RBRs and used for research purposes, including but not limited to, biomarker studies associated with tenecteuzumab, alemtuzumab, non-squamous NSCLC, or drug safety:

residual blood, serum, plasma and tumor tissue samples (except for residual archived tissue pieces returned to the site) and any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including residual tissue samples from medically indicated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, colonoscopy) performed at the discretion of the investigator during the course of the study

Optional fecal samples taken between dosing on day 1 of cycle 1 and dosing on day 15 of cycle 2 and day 1 of cycle 3. These samples can be collected at home.

The samples can be sent to one or more laboratories for germline or somatic variant analysis via WGS, WES or other genomic analysis methods. Genomics is increasingly informing researchers of the understanding of the pathobiology of disease. WGS and WES provide a comprehensive characterization of the genome and exome, respectively, and, together with the clinical data collected in this study, may increase the opportunity to develop new therapeutic approaches or new methods to monitor efficacy and safety or predict which patients are more likely to respond to drugs or develop adverse events.

The data generated from the RBR samples were analyzed in the context of this study, but could also be aggregated with data from other studies and explored. The availability of larger data sets will help identify and characterize important biomarkers and pathways to support future drug development.

G. Treatment and patient termination

Termination of treatment

Study treatment must be terminated permanently if the patient experiences any of the following conditions:

Intolerable toxicity (including the development of immune-mediated adverse events) associated with study treatment, which the investigator determines is unacceptable in view of the potential response of the individual patient to therapy and the severity of the event

If the patient continues to receive study treatment, any medical condition determined by the researcher may jeopardize his or her safety

Determination of termination of treatment by the investigator in accordance with the subject's greatest benefit

Pregnancy

Use of non-protocol-specific anti-cancer therapies

Imaging disease progression according to RECIST v1.1 (unless study treatment continues after imaging progression)

For patients who continue treatment after progression of the imaging disease, clinical benefit is lost (if treatment with tirayleigh umab/placebo and atlizumab/palboclizumab continues after progression of the imaging disease), as determined by the investigator after comprehensive assessment of imaging and biochemical data, local biopsy results (if available), and clinical status (e.g., worsening of symptoms), for example

The main cause of termination of study treatment was documented in the appropriate eCRF. Patients who terminate study treatment prematurely will not be replaced.

Patients returned to the clinic for study drug termination visit no more than 30 days after the last dose of study treatment. Visits for which response assessments showed disease progression may be used as treatment termination visits. Patients who terminate study treatment for any reason other than disease progression or loss of clinical benefit (for patients who continue treatment after imaging disease progression) will continue to undergo tumor response assessment and PRO assessment.

After termination of study treatment and disease progression according to RECIST v1.1, information on survival follow-up and new anti-cancer therapies was collected by telephone, patient medical records and/or clinic visits approximately every 3 months until death (unless patients withdraw consent)

H. Analysis of

Analysis of efficacy

Efficacy analysis was performed in the ITT population, where patients were grouped according to their randomized treatment. Estimates of ORR and PFS HR differences between the two treatment arms were calculated along with their 95% ci.

Hypothetical testing of common primary efficacy endpoints will also be performed in the ITT population.

All common major analyses of disease progression and objective remission were based on investigator review of tumor assessments using RECIST v 1.1.

End of primary efficacy

The common primary efficacy endpoints were confirmed ORR and PFS.

The confirmed ORR is defined as the proportion of patients who achieve objective remission (characterized by CR or PR) twice consecutively at intervals of > 4 weeks.

Objective remission patients evaluated on the treatment arm, who had not been assessed for post-baseline overall response, were counted as non-responders.

Estimates of ORR difference between the two arms were calculated along with their 95% ci. The Mantel-Haenszel test was used to compare ORR between the two treatment arms at a bilateral significance level of 5%, stratified by the stratification factor defined by the protocol.

PFS is defined as the time between the date of randomization and the date of first recording of disease progression or death, whichever occurs first. Patients who did not experience disease progression or did not die at the time of analysis were scored at the last tumor assessment. Patients who did not have a post-baseline tumor assessment were missed at randomization.

PFS between treatment arms was compared using a tiered log rank test.

The hierarchical Cox proportional hazards model was used to estimate the HR of the PFS and its 95% CI.

The Kaplan-Meier method was used to estimate the median PFS of each treatment arm and a Kaplan-Meier curve was constructed to provide a visual depiction of the differences between treatment arms.

Secondary efficacy endpoints

Overall life cycle

OS is defined as the time from randomization to death from any cause. Data for patients who live at the time of data expiration are lost on the last date they were known to be live. Data from patients without post-baseline information were censored on the day of randomization. The hierarchical Cox proportional hazards model is used to estimate the OS HR and its 95% CI. The Kaplan-Meier method was used to estimate the OS curve and median OS for each treatment arm.

Duration of confirmed mitigation

DOR is defined as the time from the first occurrence of recorded objective remission to the onset of disease progression or death from any cause, whichever occurs first. Analysis of DOR will only include patients achieving objective remission on study treatment. DOR was estimated using the Kaplan-Meier method. Since the determination of DOR is based on a non-random subset of patients, no formal hypothesis testing is performed.

Results reported by the patient

The TTCD of cough, dyspnea and chest pain symptoms with EORTC QLQ-LC13, GHS/QoL and physical function with EORTC QLQ-C30 is defined as the time from the day of randomization to the first confirmed clinically significant exacerbation. A confirmed clinically significant worsening of symptoms is defined as an increase in symptom score of ≧ 10 points from baseline and this increase must be maintained in at least two consecutive assessments, or an initial increase of ≧ 10 points from baseline, followed by death. A proven clinically significant symptomatic deterioration with respect to GHS/QoL and physical function is defined as a decrease in the GHS/QoL or physical function scale score of ≧ 10 points from baseline and this decrease must be maintained in at least two consecutive assessments, or initially a decrease of ≧ 10 points from baseline, followed by death.

For TTCD, if patients do not experience a confirmed clinically significant exacerbation event at the clinical expiration date, their data is deleted when they last completed the assessment. Patients were censored on the day of randomization if baseline or post-baseline assessments were not made.

TTCD using the EORTC scale was analyzed using the same method as PFS.

Summary statistics and average change from baseline linear translation scores are reported for all items and sub-tables of the EORTC QLQ-C30, EORTC QLQ-LC13, and EORTC IL46 (items that plague side effects) questionnaire according to the EORTC scoring manual guidelines.

Security analysis

Safety analysis included all treated patients, defined as randomized patients receiving any amount of study treatment.

Safety analysis was performed per treatment arm and based on the actual treatment received. Specifically, if the patient received any number of tenecteuzumab or atezumab, the patient was included in the safety analysis of arm a regardless of the initial treatment allocation at the time of randomization.

Drug exposure, including duration, dose, and dose intensity, was summarized. The verbatim description of the adverse event maps to the MedDRA synonym library term.

The severity of all adverse events was graded by the investigator according to NCI CTCAE v5.0 and the severity of CRS will also be graded by the investigator according to the ASTCT consensus rating scale. All adverse events were summarized on treatment arm and NCI CTCAE scale. CRS will also be summarized by treatment arm and ASTCT consensus ratings. In addition, critical adverse events and adverse events leading to termination or discontinuation of study treatment were summarized accordingly. Multiple occurrences of the same event are counted once by maximum severity. Laboratory data were identified with values outside the normal range. Selected laboratory data, including ADA results, were also summarized by treatment arm. All and mortality factors were summarized.

Pharmacokinetic analysis

PK samples were collected for PK analysis and exposure in this study was compared to exposure obtained in previous studies. Serum concentrations of tirayleigh immuzumab and atelizumab were reported as individual values and summarized in treatment arms and cycles (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean coefficient of variation) where appropriate and data allowed.

Individual and median serum concentrations of securitylyumumab and atelizumab were plotted on treatment arms and days. The titrayleigh immuzumab and atezumab 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 data is warranted. The potential relevance of relevant PK parameters to safety, efficacy or biomarker outcome can be explored.

Immunogenicity assay

Immunogenicity analysis included patients undergoing any ADA assessment, grouped according to treatment received. The number and proportion of ADA positive and ADA negative patients appearing in both tirayleigh immuzumab and atlizumab treatments are summarized by treatment arm. The relationship between ADA status and safety, efficacy and PK endpoint can be analyzed and reported via descriptive statistics.

Biomarker analysis

Biomarker analysis may be performed in an effort to understand the correlation of relevant markers (e.g., TIGIT) with the efficacy of the study treatment. The therapeutic outcome may be explored in a population of patients whose tumors have high biomarker expression, as determined by IHC and/or RNA analysis. Exploratory analysis of WGS data can be performed in the context of this study and explored with data from other studies to increase the researcher's understanding of disease pathobiology and guide the development of new therapeutic approaches. WGS is not applicable to sites that have not been regulatory approved for WGS sampling.

Exploratory analysis

To assess the consistency of the study results in subgroups defined by demographics (e.g., age, gender, and race/ethnicity) and baseline prognostic characteristics (e.g., PD-L1 expression by central laboratory testing, geographic region, and ECOG), the common primary efficacy endpoints of the identified ORR and PFS in these subgroups were examined. A summary of the confirmed ORR and PFS is generated for each level of categorical variable, respectively, for comparison between the two treatment arms.

Middle term analysis

The study plan performs a periodic analysis of the accumulated safety data. An intermediate efficacy analysis 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 was randomized. When approximately 120 patients have been evaluated at least twice for tumors, an early analysis of ORR will also be performed. This is expected to occur approximately 14 months after the first patient was randomized.

Example 9A phase II, open label, multicenter study to assess the safety and efficacy of neoadjuvant and adjuvant tegraleigh Uatuzumab plus atelizumab with or without platinum chemotherapy in patients with previously untreated locally advanced resectable phase II, IIIA, or elective IIIB non-small cell lung cancer

A. Overview of the study design

GO42501 is a phase II, open label, multicenter study on assessing safety and efficacy of neoadjuvant and adjuvant atelizumab (Atezo) plus rayleigh immuzumab (Tira) with or without use with platinum-based chemotherapy (Chemo) in patients with previously untreated histologically or cytologically confirmed resectable phase II, IIIA or selected IIIB (T3N 2 only) NSCLC. The study was aimed at establishing proof-of-concept clinical data demonstrating that neoadjuvant treatment with Atezo + Tira or Atezo + Tira + Chemo is safe, tolerable, and has no clinically significant negative effect on the outcome of surgery in patients with early resectable NSCLC. The study was also aimed at assessing the potential anti-tumor effects of neoadjuvant Atezo + Tira or Atezo + Tira + Chemo as measured by Major Pathological Remission (MPR). The study design has flexibility to open up new cohorts when new treatment combinations are available.

Study treatments administered are provided in table 55. In this protocol, "study treatment" refers to the combination of treatments (i.e., atezo + Tira + chemio, or chemotherapy) dispensed to the patient as part of the study.

TABLE 55 study treatment administered

Atezo = alemtuzumab; chemi = platinum-based chemical haircut; PD-L1= programmed death ligand 1; tira = tirayleigh zeuzumab.

^a Researchers chose to administer chemotherapy as an adjuvant therapy.

Figure 19 presents an overview of the study design. Patients were assigned to one cohort based on PD-L1 status and received the following treatments:

queue a (PD-L1 high): new auxiliary Atezo + Tira, lasting 4 cycles; surgical resection followed by adjuvant Atezo + Tira for 16 cycles, or adjuvant chemotherapy for 4 cycles.

Queue B (PD-L1 all participants): new auxiliary Atezo + Tira + Chemo, lasting for 4 cycles; surgical resection and adjuvant Atezo + Tira were then performed for 16 cycles.

The choice of platinum-based chemotherapy regimen is determined by the investigator as appropriate based on histological subtype and the recorded circumstances at the time of initiation. This study allowed the following platinum-based chemotherapy regimen.

For non-squamous NSCLC:

-cisplatin + pemetrexed

-carboplatin + pemetrexed

-carboplatin + paclitaxel

For squamous NSCLC:

-cisplatin + gemcitabine

-carboplatin + gemcitabine

-carboplatin + paclitaxel

Pathological remission (MPR and complete pathological remission (pCR)) of surgical specimens was assessed by an independent central pathology laboratory as well as by the pathology laboratory where the investigators were located. In addition, exploratory biomarker analysis can be performed on the remaining surgical specimens (primary tumor tissue and dissected lymph nodes).

For patients with confirmed pathological N2+ disease or tumor margin positivity (ypN 2 and/or R1/R2) at the time of surgical resection, postoperative radiation therapy (PORT) is allowed and must be administered prior to adjuvant Atezo + Tira treatment or after adjuvant platinum chemotherapy.

All patients completed the planned assessment of thoracic and abdominal tumors by both Computed Tomography (CT) and Positron Emission Tomography (PET) at screening, and only by CT after the 2 nd and 4 th cycles of neoadjuvant therapy. Tumor assessment was continued after surgery until recurrence. If the follow-up assessment of the disease shows evidence of disease recurrence, confirmation should be made by definitive imaging evidence in the pathology and/or scan. If the scan shows ambiguous results (e.g., the minor axis length of the mediastinal lymph node is < 1.5cm, and the longest diameter of a lung parenchymal lesion or visceral lesion is < 1 cm), a biopsy should be taken. The biopsy should be performed before the next anticancer therapy is initiated. If a biopsy is taken to confirm disease recurrence, it is strongly recommended that any remaining biopsies be submitted for exploratory biomarker studies. If the biopsy is not feasible or safe, a confirmatory scan must be performed again within 4 to 8 weeks.

If the biopsy does not show evidence of disease recurrence (e.g., non-malignant infiltration), the patient may proceed with planned study treatment, assessment, and/or follow-up. In the absence of disease recurrence, disease follow-up assessment should continue until disease recurrence, withdrawal of consent, death, missed visits, or the sponsor terminates the study, whichever occurred first.

All patients underwent safety, tolerability and exploratory assessments on day 1 of each cycle, both in the neoadjuvant (two cohorts) and in the adjuvant treatment period. After termination of treatment, patients were followed up regularly for survival status and any additional anti-cancer treatments. Safety assessments include the incidence, nature and severity of adverse events, protocol-specific vital signs and laboratory abnormalities, and other protocol-specific tests deemed critical to the safety assessment of the study. Adverse events were ranked by investigators according to the National Cancer Institute (NCI) standard of common terminology for adverse events (CTCAE) version 5.0 (v 5.0).

Patient samples, including archived and fresh tumor and/or lymph node tissue as well as serum, plasma, and blood, were collected for future exploratory biomarker assessment. In addition, the patient is provided with an opportunity to agree to an optional fecal collection for exploratory microbiome studies.

The specific goals of the study and the corresponding endpoints are summarized in table 56 below.

TABLE 56 targets and corresponding endpoints

ADA = anti-drug antibody; ASTCT = american society for transplantation and cell therapy; atezo + Tira = atezumab gazerland eculizumab; atezo + Tira + chemi = atezumab gazettuyitumumab plus platinum chemotherapy; CRS = cytokine release syndrome; ctDNA = circulating tumor DNA; EFS = event-free lifetime; EORTC = european cancer research and treatment organization; GHS/QoL = overall health status and quality of life; IL = list of items; MPR = major pathological remission; NCI CTCAE v5.0= american national cancer institute adverse event general term standard version 5.0; NSCLC = non-small cell lung cancer; PBMC = peripheral blood mononuclear cells; pCR = complete remission of pathology; PK = pharmacokinetics; PRO = patient reported outcome; QLQ-C30= cancer quality of life questionnaire; QLQ-LC13= quality of life questionnaire lung cancer module; RECIST v1.1= solid tumor efficacy assessment criteria version 1.1.

B. Treatment distribution and safety introduction

Patients must meet the conditions for R0 excision with curative intent at the time of screening, and must meet all eligibility criteria specified herein. Patients who do not meet the criteria for participation in the study (screening failure) may be eligible for two re-screening opportunities (a total of three screenings per participant), as determined by the investigator at the discretion.

Treatment assignment and safety introduction based on tumor PD-L1 status

After providing informed consent, patients underwent a screening procedure involving a focused assessment of PD-L1 status by SP263 Immunohistochemistry (IHC), a Tumor Cell (TC) based assay.

The cohort was completed in a stepwise manner as follows (see fig. 20), with approximately 41 patients in each cohort:

1. initially for security import:

six patients with tumors with a PD-L1 Tumor Proportion Score (TPS) of 50% or more at screening were placed in cohort A (PD-L1 high cohort);

cohort B (PD-L1 cohort of all participants) started with 6 patients with tumors with PD-L1 TPS < 50%.

2. The security of each queue is evaluated, and if deemed secure:

only patients were enrolled in cohort B (PD-L1 all participants), including patients with tumors with PD-L1 TPS ≧ 50%, until 8 patients with tumors with PD-L1 TPS ≧ 50% were enrolled in this cohort.

The remaining cohort B patients then included patients with tumors with PD-L1 TPS < 50%.

3. After a total of 8 patients with tumors with PD-L1 TPS ≧ 50% were enrolled in cohort B (all participants to PD-L1), the cohort of cohort A (PD-L1 high) was restored, and all subsequent patients with tumors with PD-L1 TPS ≧ 50% were enrolled in this cohort.

Secure import

Each cohort was suspended for safety assessment after approximately 6 patients completed the neoadjuvant treatment and completed the surgery or had changed the surgical plan, taking into account potential surgical delays, cancellations, or complications associated with study treatment. Queues may not be enqueued at the same speed and each queue is evaluated separately and independently.

The safety assessment is based on safety and surgical data. Based on the review of the data, it is suggested to proceed with grouping the queue or close the queue. During the safety lead-in period, the patient may be replaced if he or she is not performing surgery for reasons other than adverse events of particular concern or disease progression.

Surgery and adjuvant therapy

The patient underwent surgical resection of their tumor after four cycles of neoadjuvant therapy. Before surgery, the attending surgeon and oncologist reassess the patient.

Preoperative visit should be made within 30 days after the last dose of neoadjuvant therapy; repeated lung function tests (PFTs), if clinically indicated, and associated assessments should be performed according to local institutional practices. If both the treating surgeon and oncologist judge to be clinically viable, the procedure should be performed within 30 days after the pre-operative visit.

For patients who found disease progression at planned tumor assessments (after cycles 2 and 4) or at any time during neoadjuvant therapy and were still considered resectable and non-metastatic, surgery was performed if appropriate and still met the conditions for all study treatments and assessments.

If the investigator plans to have the patient perform surgery before completing all four cycles of new adjuvant therapy without disease progression, a medical supervisor must be consulted.

For patients who prematurely terminated neoadjuvant therapy due to disease progression and who were not undergoing surgery, additional clinical study procedures were terminated and continued to receive additional therapy as determined by the investigator. Such patients were left in the study for life-cycle follow-up. For patients who respond to neoadjuvant therapy but are inoperable due to unforeseen medical problems (e.g., pulmonary embolism or myocardial infarction), the patient may continue with regimen-specific therapies, such as chemotherapy (cohort a [ PD-L1 high ]) or Atezo + Tira (cohort a or B) and radiation therapy.

Following surgical resection, patients continue to receive adjuvant Atezo + Tira or adjuvant chemotherapy (cohort a [ PD-L1 high only ]) until one of the following occurs: up to four cycles of adjuvant chemotherapy, 16 cycles of adjuvant Atezo + Tira, unacceptable toxicity, disease recurrence, death, or patient and/or physician decision to terminate study treatment were administered according to local standard of care (SOC).

End of study and duration of study

The end of the study was defined as the date when the last patient was last visited, which would occur approximately 3 years after the last patient had received the last dose of study medication post-operatively.

The total length of the study (from screening of the first patient to the end of the study) will be about 5 to 6 years.

C. Fundamental principles of research design

The present study evaluated the surgical safety and feasibility of Atezo + Tira or Atezo + Tira + chemi as a new adjunctive therapy for patients with previously untreated locally advanced NSCLC. The study also evaluated the efficacy, pharmacokinetics, immunogenicity, and safety of neoadjuvant Atezo + Tira or Atezo + Tira + chemi, followed by adjuvant Atezo + Tira or adjuvant chemotherapy.

Basic principles of attrituzumab + tiryleigh Eusumab dose and schedule

Alemtuzumab was administered at a fixed dose of 1200mg Q3W (1200 mg on day 1 of each 21-day cycle), which is an approved dose of alemtuzumab, as outlined in the prescription information. Antitumor activity was observed in a dose range of 1mg/kg to 20mg/kg Q3W. In the study GO27381 (PCD 4989 g), the maximum tolerated dose of atzumab was not reached, and no dose-limiting toxicity (DLT) was observed at any dose. A fixed dose of 1200mg Q3W (equivalent to a mean body weight-based dose of 15mg/kg Q3W) was selected based on two non-clinical studies (Deng et al, MAbs,8, 593-603, 2016) and available clinical Pharmacokinetic (PK), efficacy, and safety data.

Ibritumomab is administered intravenously at a fixed dose of 600mg Q3W on day 1 of each 21-day cycle. A fixed dose of tirayleigh immuzumab at 600mg IV Q3W was selected based on available clinical pharmacokinetic, efficacy and safety data from study GO30103, in which patients received either single drug tirayleigh immuzumab or tirayleigh immuzumab plus atelizumab. In study GO30103, the maximum tolerated dose was not reached, and DLT was not observed with tenerayleigh umab monotherapy or in combination with attrituzumab 1200mg Q3W (tenerayleigh mab dose range 2 to 1200mg Q3W). Starting from a dose level of tirayleigh uzumab of 30mg Q3W, complete occupancy of peripheral TIGIT receptors on CD4+, CD8+ and NK cells was observed and remained persistent at all higher doses. When given in combination with alemtuzumab 1200mg Q3W, antitumor activity was observed over a dose range of tenecteuzumab from 30 to 600mg Q3W (as assessed by imaging Partial Remission (PR)).

In phase II study GO40290, all patients enrolled in the group of attlizumab plus rayleigh eculizumab arms received 600mg rayleigh eculizumab. At this dose, securityluzumab was tolerated, and the combination of atezumab plus securityluzumab resulted in clinically significant improvement in PFS and higher ORR compared to placebo combined with atezumab. Given the favorable benefit-risk ratio observed at 600mg, the same dose of tiryleiguzumab was used in this study.

Rationale for patient population

The study included patients with resectable stage II, stage IIIA, and selection IIIB (T3N 2 only) NSCLC, as determined at the time of screening. Tumor patients with high PD-L1 expression (TPS > 50%, as determined by immunohistochemistry [ IHC ] at central laboratory via SP 263) were enrolled in cohort a (PD-L1 high) while all participants (regardless of PD-L1 expression level) were enrolled in cohort B (PD-L1 all participants).

Neoadjuvant and adjuvant chemotherapy show significant but modest benefits to patients with early resectable NSCLC, but there is still a great unmet need for improved prognosis in this treatment setting.

Killing of tumor cells by cytotoxic chemotherapy may expose the immune system to high levels of tumor antigens. In this case, enhancement of tumor-specific T cell immunity by blocking the PD-L1 and TIGIT pathways may lead to a deeper, more persistent response than observed with standard chemotherapy alone (Merritt et al, J Thorac Cardiovasc Surg, 126.

Given that strong data from CITISCAPE show magnitude of benefit in the PD-L1 TPS ≧ 50% population, and the need to improve survival and reduce relapse rates in patients with resectable early-stage NSCLC, this study examined the efficacy of the Atezo + Tira combination as an option for chemo-sparing therapy. For patients with resectable NSCLC, the chemo-sparing option would be a milestone improvement for the patient and may protect the patient from early and late toxicities associated with platinum-based chemotherapy.

Rationale for taking major pathological remission as the primary endpoint

The primary efficacy objective of this study was to assess the efficacy of neoadjuvant treatment with Atezo + Tira or Atezo + Tira + chemi in patients with resectable stage II, IIIA or alternative stage IIIB (T3N 2 only) NSCLC as measured by Major Pathological Remission (MPR) assessed by the central pathology laboratory.

While Overall Survival (OS) is a standard for assessing clinical benefit in adjuvant and neoadjuvant NSCLC trials, readings of OS often take years, especially in early stage disease. Therefore, using meaningful surrogate endpoints may speed the evaluation of new therapies and bring new treatments to NSCLC patients more quickly. Pathological responses following surgical resection of NSCLC have been proposed as surrogate endpoints for OS (Hellmann et al, lancet Oncol, 15. Hellmann et al (2014) cited the us Food and Drug Administration (FDA) definition of an alternative endpoint, where the endpoint should be "reasonably likely to predict clinical benefit". They argue that this definition is satisfied using pathological relief in a new auxiliary environment based on the following three findings: 1) Pathological remission is closely related to OS; 2) Pathological remission reflects neoadjuvant chemotherapy; 3) The degree of pathological remission correlates with the degree of OS benefit.

The use of pathological remission as a surrogate endpoint is not without precedent. Complete remission of pathology (pCR) has been used in breast cancer trials to evaluate the efficacy of neoadjuvant therapy. However, pCR rates in the newly assisted NSCLC study varied. Furthermore, the relatively low pCR rates reported in NSCLC may not translate into clinically significant OS benefits, thus limiting the utility of pCR as an alternative survival endpoint in NSCLC trials. In fact, few trials have reported inevitable survival data for pCR in NSCLC due to low pCR rates (4% median rate) (Hellmann et al, lancet Oncol,15, e42-50, 2014).

Hellman et al proposed the use of MPR (defined as ≦ 10% residual viable tumor tissue) instead of pCR as a surrogate marker for survival in patients with resectable NSCLC who received new adjuvant chemotherapy treatment (Hellmann et al, lancet Oncol,15 e42-50, 2014. This is based on the recognition by researchers of the rarity of pCR in NSCLC in the study, and other definitions of pathological remission were considered, including residual surviving tumors as surrogate survival endpoints. Junker et al (J Cancer Res Clin Oncol, 123. The median survival for patients in this group with residual tumor of 10% or less was 36 months, while the median survival for patients with residual > 10% of viable tumor tissue was 14 months.

Two prospective trials reported that the MPR rate of neoadjuvant chemotherapy in NSCLC was approximately 22%. The first study indicated that 90 patients with stage IIIA disease receiving neoadjuvant chemotherapy (cisplatin + docetaxel) had a median pathological remission (amount of tumor necrosis and fibrosis) of 60% and a median OS of 61 months, compared to 22 months in patients with ≦ 60% pathological remission (Betticher et al, br J Cancer,94 (8): 1099-1106, 2006). Another study showed that of 50 patients receiving neoadjuvant chemotherapy (cisplatin + docetaxel) in combination with bevacizumab, the 3-year survival of patients with MPR was significantly prolonged (61 and 22 months, respectively) compared to patients who did not achieve MPR (Chaft et al, J Thorac Oncol, 8. A retrospective study by William and colleagues at the MD anderson cancer center (William et al, J Thorac Oncol, 8.

The sponsor believes that there is an important reason to use MPR as a surrogate endpoint based on the correlation of MPR and OS improvement amplitude. Currently, there are global phase III neoadjuvant enrollment trials of ongoing chemotherapy plus PD-L1/PD-1 inhibitors with chemotherapy alone that evaluate MPR as a primary or secondary target. The use of MPR as a surrogate endpoint has the potential to improve the effectiveness of clinical studies and accelerate new therapies in NSCLC patients.

Example 10 materials and methods of the GO42501 study

Approximately 82 patients in stage II, IIIA or selected IIIB (T3N 2 only) were enrolled in the GO42501 study.

A. Inclusion criteria

Patients must meet the inclusion criteria listed below to be eligible for study entry.

The age at which informed consent was signed was 18 years old or older.

Ability to comply with study protocol.

Histologically or cytologically confirmed stage II, IIIA or non-small cell lung carcinoma (NSCLC) selected from the IIIB (T3N 2 only) squamous or non-squamous histology. Staging should be based on the us cancer joint committee/international anticancer union NSCLC staging system, 8 th edition.

Patients with T4 primary NSCLC were eligible only on a size basis (> 7cm tumor). Patients with an affected diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, and a single tumor nodule on different lobes on the ipsilateral side were inconformity.

Patients with NSCLC of mixed histology (squamous and non-squamous) are eligible and must be classified based on major histology (non-squamous or squamous).

Patients can be screened on a clinical stage basis, but for PET positive N2 lymph nodes, a mandatory preoperative record of N2 lymph node involvement by invasive mediastinal stage (e.g., CT guided biopsy, endobronchial ultrasound, mediastinoscopy) is required. Preoperative staging of grade 5 and grade 6 lymph nodes is optional.

CT scans showed solid or sub-solid appearance of NSCLC without pure ground glass shadows (GGO). For sub-solid lesions, tumor size should be measured based on the solid component alone, without including the GGO component (i.e., clinical T-stage).

The intraoperative surgeons and the oncologists participating in the study confirmed prior to study enrollment as being eligible for R0 resection for curative purposes at the time of screening.

Sufficient lung function to meet the conditions of a curative surgical resection, including lung volume, spirometry and capacity for diffusion, as assessed by a lung function test (PFT) performed within 6 months after the planned resection (and repeated at the time of screening if clinically indicated); and at least one of the following conditions is satisfied:

predicted postoperative (ppo) forced expiratory volume for 1 second (FEV 1) and ppo pulmonary carbon monoxide diffusion capacity (DL) _CO )≥40％。

Maximum oxygen consumption (VO) ₂ max)≥15mL/kg/min。

Omicron if ppoFEV ₁ Or ppoDL _CO To < 40% or plan a total pneumonectomy, cardiopulmonary exercise test must be performed and VO' s ₂ max≥15mL/kg/min。

Omicron must be done within the screening period if PFT is done before 6 months post-planned resection or has not been done previously.

Compliance with the regimen of platinum-based chemotherapy. The warnings and precautions in the prescription information for each individual chemotherapy treatment (i.e., carboplatin, cisplatin, pemetrexed, paclitaxel, or gemcitabine) in the intended regimen for each patient are used in part to determine eligibility.

Measurable disease, as assessed by investigators according to RECIST v 1.1.

Availability of representative tumor samples suitable for determination of PD-L1 status and other exploratory biomarkers by central testing.

Eastern Cooperative Oncology Group (ECOG) physical status is 0 or 1.

Normal life expectancy, excluding the risk of lung cancer death.

Appropriate blood and end organ function, defined by the following laboratory test results obtained within 14 days before the initiation of study treatment:

absolute Neutrophil Count (ANC) ≥ 1.5X 10 with the support of granulocyte-free colony stimulating factor ⁹ /L(1500/μL)。

Lymphocyte count ≥ 0.5X 10 ⁹ /L(500/μL)。

In the case of no blood transfusion, the platelet count is > 100X 10 ⁹ /L(100,000/μL)。

-hemoglobin > 90g/L (9 g/dL). Blood transfusions may be given to patients to meet this criteria.

Aspartate Aminotransferase (AST), alanine Aminotransferase (ALT) and alkaline phosphatase (ALP). Ltoreq.2.5 Xthe Upper Limit of Normal (ULN).

-total bilirubin ≦ 1.5 × ULN, with the following exceptions: patients with known gilbert disease: the total bilirubin is less than or equal to 3 × ULN.

Creatinine clearance ≧ 45mL/min (calculated using the Cockcroft-Gault equation). For patients expected to receive cisplatin: the creatinine clearance is more than or equal to 60mL/min.

Serum albumin ≥ 25g/L (2.5 g/dL)

-for a patient not receiving therapeutic anticoagulation: INR or aPTT is less than or equal to 1.5 multiplied by ULN

For patients receiving therapeutic anticoagulation: a stable anticoagulant regimen.

HIV test negative at screening.

The hepatitis B surface antigen (HBsAg) test was negative at the time of screening.

Hepatitis B surface antibody (HBsAb) test positive at screening, or HBsAb test negative at screening with either:

total hepatitis b core antibody (hbcabs) negative.

Total HBcAb test positive, followed by quantitative Hepatitis B Virus (HBV) DNA < 500IU/mL. HBV DNA testing was performed only on patients who were negative for the HBsAg test, negative for the HBsAb test, and positive for the total HBcAb test.

Hepatitis C Virus (HCV) antibody test negative at screening; or an HCV antibody test is positive and then an HCV RNA test is negative when screened. Only patients who tested positive for HCV antibodies were tested for HCV RNA.

For women with fertility: either abstinence was agreed to be maintained (avoiding sexual intercourse) or contraceptive methods were used and no donation of ova was agreed to.

For males: consent was maintained either to abstinence (avoid sexual intercourse) or to the use of condoms, and to no donation of sperm.

B. Exclusion criteria

Patients who met any of the criteria listed below were excluded from the study.

NSCLC, histologically large-cell neuroendocrine carcinoma, sarcomatoid carcinoma or NSCLC not otherwise specified.

Small Cell Lung Cancer (SCLC) histology or NSCLC with any SCLC component.

Diseases or conditions that may interfere with a patient's ability to understand, follow, and/or comply with a study procedure.

Any prior therapy for lung cancer, including immunotherapy, chemotherapy or radiotherapy.

Autoimmune diseases or immunodeficiency active phases or history, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, wegener's granulomatosis, sjogren's syndrome, guillain-barre syndrome, or multiple sclerosis, with the following exceptions: patients with a history of autoimmune-related hypothyroidism who were taking thyroid-substituting hormone met the criteria of the study. Patients with type 1 diabetes and undergoing an insulin regimen were eligible for this study. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with only signs of skin disease (e.g., psoriatic arthritis patients) qualify for the present study if all of the following conditions are met:

The rash must cover < 10% of the body surface area.

The disease is well controlled at baseline and only low potency topical corticosteroids need to be used.

No acute exacerbation of the underlying condition requiring psoralen plus ultraviolet a radiation, methotrexate, retinoids, biologicals, oral calcineurin inhibitors or high potency or oral corticosteroids occurred within the past 12 months.

There is a history of idiopathic pulmonary fibrosis, organized pneumonia (e.g., bronchiolitis obliterans), drug-induced lung inflammation, or idiopathic lung inflammation, or evidence of active lung inflammation found in chest CT scans.

Active tuberculosis.

Significant cardiovascular disease (such as new york heart association grade II or higher heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable angina was experienced within 3 months prior to initiation of study treatment.

Major surgery was performed within 4 weeks prior to initiation of study treatment or was expected to be required during the study.

NSCLC having an activating EGFR mutation or an ALK fusion oncogene. For patients with non-squamous NSCLC histology: unknown EGFR and/or ALK status needs to be tested at the time of screening. ALK and/or EGFR status may be assessed locally or submitted to a central laboratory test.

The known c-ROS oncogene 1 (ROS 1) rearrangement. For study enrollment, no ROS1 test is required at screening; however, patients with known ROS1 rearrangement are excluded.

Except malignancies with a history of malignancy other than NSCLC within the first 5 years of screening, but with negligible risk of metastasis or death (e.g., 5 year OS rate > 90%), such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.

Severe infections occurred within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization due to infection, bacteremia, or complications of severe pneumonia, or any active infection that researchers believe may affect patient safety.

Treatment with therapeutic oral or IV antibiotics within 2 weeks before initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., for preventing urinary tract infection or exacerbation of chronic obstructive pulmonary disease) are eligible for this study.

Previous allogeneic stem cell or solid organ transplantation.

Any other disease, metabolic dysfunction, physical examination findings or clinical laboratory findings that prohibit the use of research drugs, may affect the interpretation of the results or may place the patient at high risk for treatment complications

Treatment with live attenuated vaccine within 4 weeks prior to initiation of study treatment, or such vaccines are expected to be required during study treatment, within 90 days after the last dose of tenecteumab, or within 5 months after the last dose of atelizumab. Patients being treated with chemotherapy (i.e., carboplatin, cisplatin, pemetrexed, paclitaxel, or gemcitabine) should not receive a live vaccine.

Current treatment with antiviral therapies against HBV.

Epstein-Barr virus (EBV) virus capsid antigen immunoglobulin M (IgM) test positive at screening. EBV PCR tests should be performed for clinical indications to screen for acute infections or suspected chronic active infections. Patients positive for the EBV PCR test were excluded.

Treatment with investigational therapy within 42 days before initiation of study treatment.

Prior treatments with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, anti-TIGIT, and anti-PD-L1 therapeutic antibodies.

Treatment with systemic immune stimulants (including but not limited to interferon and IL-2) within 4 weeks before initiation of study treatment or within 5 drug elimination half-lives (whichever is longer).

Treatment with systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha [ TNF-alpha ] agents) within 2 weeks prior to initiation of study treatment, or it is expected that systemic immunosuppressive drugs will be required during study treatment, except:

Patients receiving acute, low dose systemic immunosuppressant administration or one-time pulsed dose systemic immunosuppressant administration (e.g. 48 hours corticosteroid for contrast agent allergy) met the criteria of the study.

Patients receiving mineralocorticoids (e.g. fludrocortisone), corticosteroids for Chronic Obstructive Pulmonary Disease (COPD) or asthma or low doses of corticosteroids for the treatment of orthostatic hypotension or adrenal insufficiency meet the criteria of this study.

History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins.

Known to be allergic to chinese hamster ovary cell products or to any component of the attritumab or tenecteuzumab formulations.

Known allergic reactions or allergies to any component of the chemotherapy regimen that the patient may receive during the study.

Pregnancy or lactation, or pregnancy intended during study treatment, within 90 days after the last administration of ibritumumab, within 5 months after the last administration of atezumab or within 6 months after the last administration of pemetrexed, gemcitabine, paclitaxel, carboplatin or cisplatin. A female with fertility must be negative for serum pregnancy test results within 14 days before study treatment initiation.

C. Treatment distribution

This study is an open label study.

Patients with high PD-L1 expression (TPS ≧ 50%, as determined by SP263IHC in the central laboratory) were enrolled in cohort A (PD-L1 high) while all participants (regardless of PD-L1 expression level) were enrolled in cohort B (PD-L1 all participants). The cohort was completed in a stepwise manner as follows (see fig. 20), with approximately 41 patients in each cohort:

1. initially for security import:

six patients with tumors with PD-L1 TPS > 50% at screening were enrolled in cohort A (PD-L1 high cohort);

cohort B (PD-L1 cohort of all participants) started with 6 patients with tumors with PD-L1 TPS < 50%.

2. The security of each queue is evaluated, and if deemed secure:

only patients were enrolled in cohort B (all participants in PD-L1), including patients with tumors with PD-L1 TPS ≧ 50%, until 8 patients with tumors with PD-L1 TPS ≧ 50% were enrolled in the cohort.

The remaining cohort B patients then included patients with tumors with PD-L1 TPS < 50%.

3. After a total of 8 patients with tumors with PD-L1 TPS > 50% were enrolled in cohort B (all participants to PD-L1), cohort A (PD-L1 high) was restored, and all subsequent patients with tumors with PD-L1 TPS > 50% were enrolled in this cohort.

D. Study of therapeutic dose, administration and compliance

Each study treatment was administered at the dose and frequency specified in table 57.

TABLE 57 study treatment composition protocol

AUC = area under the concentration-time curve; IV = intravenous.

^a. Carboplatin when given after pemetrexed or gemcitabine should be administered at an initial target AUC of 5 mg/mL/min; and when given post-paclitaxel, was administered at an initial target AUC of 6 mg/mL/min.

^b. Gemcitabine should be administered at 1000mg/m when administered before carboplatin ² Administration; and 1250mg/m when administered before cisplatin ² And (4) application.

^c. For patients of Asian race/ethnic group, paclitaxel should be administered at 175mg/m ² Administration at 200mg/m for patients other than Asian race/ethnic group ² And (4) application.

The neoadjuvant treatment phase includes four cycles of Atezo + Tira or Atezo + Tira + Chemo. Each cycle had a duration of 21 days. On day 1 of each cycle, all eligible patients were administered study medication in the following order:

queue a (PD-L1 high): the preparation method comprises the following steps of (1) atelizumab and (2) tiryleyuzumab.

Queue B (PD-L1 all participants): researchers were given one of the listed protocols for histological subtype and local SOC administration.

- (1) atelizumab, (2) tiryleigh ewolimumab, (3) paclitaxel, (4) carboplatin

- (1) atelizumab, (2) tiryleigh itumumab, (3) pemetrexed, (4) (carboplatin or cisplatin)

- (1) atelizumab, (2) tirayleigh unizumab, (3) gemcitabine, (4) (carboplatin or cisplatin)

Attrituzumab (1200 mg) and tirayleigh itumumab (600 mg) were administered at fixed doses. If applicable, the patient received the first dose of study treatment on the day of enrollment. If treatment is not available on the day of enrollment, the first dose is not later than 5 days post-enrollment.

For cycle 1, no preventive medication against primary prevention (antihistamines, antipyretics and/or analgesics) of alemtuzumab and tenectereuzumab was allowed. The patient should receive an antiemetic and IV hydration for the selected chemotherapy regimen, according to local SOC and manufacturer's instructions. However, due to the immunomodulatory effects of corticosteroids, prophylactic use of corticosteroids should be minimized to the extent clinically feasible.

Adjuvant therapy with Atezo + Tira was initiated within 14 to 60 days post-surgery or within 7 to 42 days post-last PORT treatment. If adjuvant chemotherapy is to be given, the treatment is started within 28 to 72 days after surgery, followed by PORT (if selected) within 21 to 60 days after adjuvant chemotherapy. During the postoperative adjuvant treatment, infusions were administered in the following order (one protocol per patient). The choice of cohort a (PD-L1 high) protocol was decided by the investigator as appropriate for each patient.

Queue a (PD-L1 high): the investigator applied one of the following protocols.

- (1) atelizumab, (2) tirayleigh eculizumab

- (1) paclitaxel, (2) carboplatin

- (1) Pemetrexed, (2) (carboplatin or cisplatin)

- (1) Gemcitabine, (2) (Carboplatin or cisplatin)

Queue B (PD-L1 all participants): (1) Attrituzumab, (2) tirayleigh Uitumumab

Atelizumab and tirylyuxus mab

Alemtuzumab was administered at a fixed dose of 1200mg by IV infusion on day 1 of each 21 day cycle. The dose of alemtuzumab is fixed and independent of body weight. Dose reduction is not allowed.

Following the alemtuzumab administration and observation period, the patient received 600mg of tiryleyuzumab administered by IV infusion on day 1 of each 21-day cycle. The tiryleigh ewuzumab dose was fixed and independent of body weight. Dose reduction is not allowed.

Administration of the study treatment is carried out in a monitored environment where trained personnel and sufficient equipment and medications are immediately available to manage the potential critical response. The alemtuzumab and terayleigh itumumab infusions were administered according to the instructions outlined in table 58.

TABLE 58 study treatment composition protocol

IRR = infusion-related response

Abiralizumab and tirylyulluzumab dose-delay

As long as neither alemtuzumab nor tegraleigh immuzumab have been permanently terminated, the following rule applies:

normally, the treatment cycle begins with the administration of atuzumab and tenectereuzumab on day 1 of each 21-day cycle. If any of the study drugs were delayed by the associated toxicity, it is recommended that the other study drug be delayed because of the similar safety profile of alemtuzumab and tenectereuzumab.

In the case where one study drug is administered with a delay due to drug-related toxicity, but another study drug is administered on a schedule, it is recommended that the delayed study drug be administered at the time of the next intra-schedule infusion (i.e., in the next intra-schedule 21-day period).

Chemotherapy

The site should comply with the following information and local prescription information. Typically, the site should also follow its institutional and local SOC to determine the dose adjustments that will be made as the patient's weight changes. If the treatment cycle is delayed or interrupted due to toxicity caused by either component of the chemotherapy regimen, both chemotherapy components should be retained, and if recovered, both components should be restored to maintain synchronization.

Paclitaxel

Patients of Asian race/ethnic race received a lower initial dose of paclitaxel of 175mg/m ² IV, over 3 hours. The lower starting dose of paclitaxel for asian race/ethnic patients was based on the overall incidence of hematologic toxicity in asian patients over non-asian patients, as observed during safety review by the independent data monitoring committee on the results of the IMpower150 and IMpower131 studies. The term "asian ethnicity" refers to a pan ethnic group, including different populations living in or ancestors originating in east asia, south-east asia, or south asia. The applicability of this term in a particular patient is determined by the treatment researcher as appropriate and should be based on the clinical characteristics of the patient and the country of origin.

Paclitaxel injection must be diluted prior to infusion. Paclitaxel should be in 0.9% sodium chloride USP;5% glucose injection, USP;5% glucose and 0.9% sodium chloride injection, USP; or 5% glucose in ringer's injection at a final concentration of 0.3 to 1.2mg/mL. The infusion site should be closely monitored for the presence of infiltration during drug administration.

It is not recommended to contact the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion. Paclitaxel should be administered through an in-line filter with a microporous membrane no larger than 0.22 μm. Using filter devices such as

Filters (which contain short inlet and outlet PVC coated tubes) do notResulting in significant leaching of di (2-ethylhexyl) phthalate.

The site should follow its institutional SOC guidelines to determine adjustments to the paclitaxel dose as the patient's weight changes. For paclitaxel infusion, exceptions to the 3 hour infusion time are allowed for sites with faster (over 90 minutes) or slower (up to 4 hours for the first infusion) paclitaxel infusion regime.

Pemetrexed

The institution should follow the standard administration procedure for pemetrexed. The administration of pemetrexed should be by IV infusion over at least 10 minutes. The prophylactic dose administered should comply with the prescription information. All patients eligible for pemetrexed therapy should avoid taking non-steroidal anti-inflammatory drugs with long drug elimination half-lives at least 5 days before, on the day of administration, and at least 2 days after pemetrexed administration.

Gemcitabine

Gemcitabine should be administered by IV infusion over 30 minutes prior to carboplatin or cisplatin. Note that the dose of gemcitabine was different when administered before carboplatin than when administered before cisplatin (table 57). Gemcitabine must be diluted prior to infusion. The diluent that would be recommended for reconstitution of gemcitabine is 0.9% sodium chloride injection, USP, without preservatives. Gemcitabine administration should be done according to local practice and prescription information.

Carboplatin

Carboplatin should be administered by IV infusion immediately after completion of paclitaxel or pemetrexed administration over 15 to 30 minutes to achieve an initial target concentration-area under the time curve (AUC) of 6mg/mL/min (Calvert formula dosing) and using standard antiemetics according to local practice guidelines.

Calvert formula was used to calculate the carboplatin dose at AUC 6mg/mL/min (Calvert et al, J Clin Oncol,7:

total dose (mg) = (target AUC) × (glomerular filtration rate [ GFR ] + 25)

The GFR used in the Calvert's equation to calculate AUC-based dosing should not exceed 125mL/min. For the purposes of this study, GFR is considered equivalent to creatinine clearance (CrCl). CrCl is calculated by institutional guidelines or by the method of Cockcroft and Gault (Nephron, 16, 31-41, (1976)) using the following formula:

CrCl = ((140-age) (wt)/(72 × Scr)) 0.85 in case of female

Wherein: crCl = creatinine clearance in mL/min; age = patient age in years; wt = patient body weight in kg;

scr = serum creatinine in mg/dL.

For patients with abnormally low serum creatinine levels, a minimum creatinine level of 0.8mg/dL should be used to estimate GFR or to cap the estimated GFR to 125mL/min. If the patient's GFR is estimated by isotopic dilution mass spectrometry based on serum creatinine measurements, the FDA recommends physicians to consider limiting the dose of carboplatin to achieve the desired exposure (AUC) to avoid potential toxicity due to overdosing.

Based on the Calvert formula described in the carboplatin label, the maximum dose can be calculated as follows:

carboplatin maximum dose (mg) = target AUC (mg min/mL) (GFR × 25 mL/min)

For patients with normal renal function, the maximum dose is based on an estimated GFR with a cap of 125mL/min. Higher estimated GFR values should not be used. For AUC =6, the maximum dose is 6 x (125 + 25) =900mg. For target AUC =5, the maximum dose is 5 x (125 + 25) =750mg. For target AUC =4, the maximum dose is 4 x (125 + 25) =600mg.

Cis-platinum

Cisplatin is administered at 75mg/m over 1 to 2 hours at about 30 minutes after completion of pemetrexed or gemcitabine infusion ² The dose of (a) is administered by IV infusion, or in accordance with the institutional SOC. Patients must receive adequate antiemetic therapy and appropriate hydration before and after receiving cisplatin.

E. Surgical treatment planning

The attending thoracic surgeon, who has experience in early resectable NSCLC, assesses the patient at the time of screening to determine the suitability of the procedure and whether the condition for surgical resection is met. The patient must be screened for conditions for performing R0 excision for curative purposes. The intention of descending for the patient to be operable is not allowed.

At screening, the patient's surgical suitability must be confirmed based on the Pulmonary Function Test (PFT) outlined in the inclusion criteria. PpoFEV ₁ And ppoDL _CO Calculated using the following method (Brunelli et al, chest,143 (5 Suppl): e166S-e190S, 2013):

if a perfusion method (lung ventilation/perfusion scan (VQ scan)) is performed:

ppoFEV ₁ or ppoDL _CO = preoperative FEV ₁ Or DL _CO ×(1-x)

Wherein: x = fraction of total perfusion of resected lung

The dissection method:

ppoFEV ₁ or ppoDL _CO = preoperative FEV ₁ Or DLCO × (1- (y/z))

Wherein: y = number of functional or unobstructed lung segments to be removed; z =19, total number of functional lung segments. Note that the total number of functional lung segments (19) is represented by the following formula for 10 segments in the right lung (3 in the upper lobe, 2 in the middle lobe, 5 in the lower lobe) and 9 segments in the left lung (5 in the upper lobe, 4 in the lower lobe).

The patient is reassessed by the attending surgeon and oncologist after completion of the neoadjuvant therapy and prior to surgery. Preoperative evaluations should be made based on local SOC, including but not limited to blood tests, coagulation, heart tests or PFT (if indicated), anesthesia assessments and other evaluation procedures.

The surgical procedure should be performed as soon as possible within 30 days after the preoperative visit. If surgery cannot be performed within this time window (e.g., due to a long-term adverse event), a medical supervisor should be consulted. If surgery is planned more than 30 days after the preoperative visit, repeated CT scans should be obtained prior to the planned surgery.

Resection should be accomplished via open or minimally invasive surgery (e.g., thoracotomy, sternotomy, clamshell or half clamshell incisions, or video thoracoscopic [ VATS ] or robot-assisted VATS).

Pathological complete resection of the primary tumor and affected lymph nodes (R0) should be performed. A dissection may be performed by segmental resection, lobectomy, bilobalectomy or total lung resection. For all resections, all anatomical partitions (e.g. arteries, bronchi, veins) should be included. Wedge-shaped resection is not allowed. Deep wedge resections, which include segments that do not provide the above-described anatomical details (e.g., apical or superior wedge resections), are not counted as segmental resections.

Pulmonic and mediastinal lymph node clearing or sampling is mandatory. For right side resection, this involves at least lymph nodes of grade 4R, 7, 10R and 11R.

Inclusion of grade 2R lymph nodes was encouraged. For left sided resection, this involves at least grade 5/6, 7, 10L and 11L lymph nodes. For inferior lobe resection, encouragement includes 8 or 9 levels.

F. Postoperative radiation therapy

For patients with confirmed pathological N2+ disease (ypN 2) or tumor margin positive (R1 or R2) at the time of surgical resection, postoperative radiation therapy (PORT) is allowed and must be administered prior to Atezo + Tira adjuvant therapy or after adjuvant platinum chemotherapy.

Conformal 3-dimensional or intensity modulated radiation therapy should be performed according to institutional and/or international guidelines, with recommended doses of 50 to 66 gray (Gy), 1.8 to 2 gray at a time. Strongly recommended limiting conditions include an average lung dose after a lobectomy of 20Gy or less and a V20 (percentage of lung volume receiving a radiation dose of 20Gy or more) of not more than 31%, or an average lung dose after a total lung resection of 8Gy and a V20 of 5 or less.

G. Concomitant therapy

Concomitant therapy included patients using any medication other than the regimen prescribed treatment (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplements) from 7 days prior to study drug initiation to treatment termination visit.

Allowed therapy

Patients were allowed the following therapies during the study:

oral contraceptives with an annual failure rate of < 1%.

Hormone replacement therapy.

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or low molecular weight heparin).

Inactivated influenza vaccines.

Megestrol acetate is administered as an appetite stimulant.

Mineralocorticoids (e.g., fludrocortisone).

Administration of corticosteroids for COPD or asthma.

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency.

Prophylactic administration of antihistamines, antipyretics and/or analgesics may only be administered for the second and subsequent atuzumab infusions, as appropriate by the researcher.

Generally, in accordance with local care practices, researchers should manage patient care (including previous conditions) using supportive therapy rather than therapy defined as prudent or forbidden therapy based on clinical indications.

Patients presenting with infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalents of local standard practice. Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and should be managed with supportive therapy (e.g., supplemental oxygen and β 2 adrenergic agonists) according to clinical indications.

Cautious therapy for patients treated with atelizumab and tirylereuzumab

Corticosteroids and TNF-alpha inhibitors

Systemic corticosteroids and TNF- α inhibitors may attenuate the potentially beneficial immune effects of treatment with atelizumab. Therefore, in the case of conventional administration of systemic corticosteroids or TNF- α inhibitors, alternatives, including antihistamines, should be considered. If alternatives are not feasible, administration of the systemic corticosteroid and the TNF- α inhibitor may be determined by the researcher as appropriate.

Systemic corticosteroids are recommended, as appropriate by the investigator, to treat specific adverse events associated with atelizumab and/or tenecteuzumab.

Treatment inhibition

The following concomitant therapies were prohibited, as follows:

concomitant therapies (including but not limited to chemotherapy, hormone therapy, immunotherapy, radiotherapy and herbal therapy) for the treatment of cancer depending on the agent are banned for different periods of time before the study treatment is started and during the study treatment, whether approved or experimental by health authorities, until disease progression is recorded and the patient has discontinued study treatment.

Investigational therapy within 42 days before initiation of study treatment and during study treatment.

Prohibition of live attenuated vaccine (e.g., for example, within 4 weeks prior to initiation of study treatment, during study treatment, within 90 days after the last administration of ibritumumab, and within 5 months after the last administration of atezumab

). Patients being treated with chemotherapy (i.e., carboplatin, cisplatin, pemetrexed, paclitaxel, or gemcitabine) should not receive a live vaccine.

The use of systemic immune stimulants (including but not limited to interferon and IL-2) was banned within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment, as these drugs may increase the risk of developing autoimmune disease when given in combination with atelizumab and tiryleyuuzumab.

Systemic immunosuppressive drugs (including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide) are administered during study treatment, as these drugs may alter the efficacy and safety of study treatment.

H. Study evaluation

Patient safety and tolerability were closely monitored throughout the study. The toxicity of the patients should be assessed before each administration; dosing was only performed when clinical assessments and local laboratory test values were acceptable.

Unless otherwise stated, all treatment visits must be made ± 3 days after the planned day. All assessments should be made on the day of the specified visit unless a time window is specified. Toxicity assessments must be made on the patient before each dose; dosing was only performed when clinical assessments and local laboratory test values were acceptable. Unless otherwise specified, assessments scheduled to be made on the day of study treatment administration should be made prior to dosing.

The following assessments may be made at day 1 and 4 of each cycle:

limited physical examination

Local laboratory tests

In addition to the tumor assessments, screening assessments performed on day 1 before cycle 1. Ltoreq.4 did not need to be repeated on day 1 of cycle 1.

If a holiday, weekend or other event is encountered precluding planned administration, administration may be postponed to the nearest day thereafter, with subsequent administrations continuing on a 21 day schedule. If treatment is delayed by less than 3 days, the patient may resume the original plan.

I. Follow-up assessment of tumor response and disease status

During the post-operative and adjuvant treatment period, all patients (both cohorts) were assessed for disease status by chest CT (including liver and adrenal glands) administered IV contrast agent every 4 months from the day of surgery in the first year, and then every 6 months in the second year. If there is contraindication for CT scans with contrast agents (e.g. in patients with impaired renal clearance function), a chest non-contrast CT scan may be performed. Patients who have not experienced relapse are assessed for disease status follow-up by chest CT (including liver and adrenal glands) with IV contrast agent every 6 months during 3 to 5 years post-surgery.

The follow-up assessment of the disease state should be made within the allowed time window for the follow-up assessment within the plan. The allowable time window for follow-up assessment of disease status was ± 7 days in year 1, ± 14 days in years 2 to 3, and ± 4 weeks thereafter.

Postoperative disease recurrence should be confirmed by pathological and/or definitive radiographic evidence. If the scan shows ambiguous results (e.g., a mediastinal lymph node short axis length of < 1.5cm, a lung parenchymal lesion or a visceral lesion longest diameter of < 1 cm), a biopsy should be taken. If the biopsy is not feasible or safe, a confirmatory scan should be performed again within 4 to 8 weeks. If a confirmatory scan confirms that the disease has recurred, the suspicious event should be recorded on the confirmatory scan date on which it was previously displayed.

The biopsy should be performed before the next anticancer therapy is initiated. If the biopsy does not show evidence of disease recurrence (e.g., non-malignant infiltration), the patient may proceed with planned study treatment, assessment, and/or follow-up.

Follow-up assessment of tumor or disease status should continue for patients who have prematurely terminated treatment for reasons other than disease progression or recurrence (e.g., due to toxicity). In the absence of disease progression or recurrence, follow-up assessment of tumor or disease status should continue for all patients, regardless of whether they began a new anti-cancer therapy until disease progression or recurrence, withdrawal of consent, death, missed visits, or termination of the study by the host, whichever occurred first.

J. Study termination of treatment

Study treatment must be terminated permanently if the patient experiences any of the following conditions:

intolerable toxicity (including the development of immune-mediated adverse events) associated with astuzumab or tenecteuzumab, which researchers determined to be unacceptable in view of the potential response of the individual patient to therapy and the severity of the event. If the atelizumab and the tiryleyuzumab are terminated within the neoadjuvant treatment period, chemotherapy may continue.

Intolerable toxicity associated with other components of the study treatment. Atezo + Tira should still be used if any or all chemotherapeutic agents are terminated during the neoadjuvant treatment period due to chemotherapy-related toxicity.

Any medical condition may compromise his or her safety if the patient continues with the study treatment.

The investigator or sponsor determines that termination of treatment is in line with the subject's greatest benefit.

Use of another non-protocol-specific anti-cancer therapy.

Pregnancy.

Clear imaging disease progression according to RECIST v1.1 during the neoadjuvant treatment period.

Pathologically confirmed or definitive imaging evidence of disease recurrence during the adjuvant treatment period.

Patients who received at least 2 cycles of neoadjuvant therapy and terminated study therapy prematurely would not be replaced. Patients receiving less than two new cycles of adjuvant therapy may be replaced if the cause of premature termination of therapy is not an adverse event or disease progression of particular concern.

For patients who terminated the neoadjuvant study treatment before receiving four cycles (e.g., due to treatment intolerance or lack of response), surgical resection or non-surgical standard of care treatment (if not appropriate for surgery) was assessed by the treating oncologist and attending surgeon. The planned protocol specifies that the patient undergoing surgery is still eligible for all post-operative study treatments and procedures.

Patients returned to the clinic for study treatment termination visit no more than 30 days after the last dose of study treatment. Visits with disease assessments showing disease progression or confirmation of disease recurrence may be used as treatment termination visits. Patients who terminate study treatment for any reason other than disease progression or recurrence will continue to receive tumor or disease status assessments.

Example 11 safety assessment of the GO42501 study

A. Security plan

The safety program for patients in this study was based on the expected mechanism of action, the results of non-clinical studies, published data for similar molecules, clinical experience using tirayleigh itumumab alone and in combination with atuzumab in phase I and phase II studies, and clinical safety profile of atuzumab.

Measures were taken to ensure the safety of patients participating in the study, including the use of strict inclusion and exclusion criteria and close monitoring of patients during the study. The administration of atezumab and tenecteuzumab is performed in a monitored environment where trained personnel are immediately available as well as sufficient equipment and medications to manage potential critical reactions.

B. Management of adverse events

Dose adjustment

In this study, attritumab or ibritumumab tiuxetan did not have dose adjustments, including dose reductions.

Treatment interruption

Study treatment may be suspended to manage toxicity, if appropriate. Based on existing mechanism of action characteristics, tenecteuzumab may cause adverse events similar to but independent of atuzumab, may exacerbate the frequency or severity of atuzumab-related adverse events, or may have toxicity that does not overlap with atuzumab. Since these conditions may not be distinguishable from each other in a clinical setting, immune-mediated adverse events should generally be attributed to both study drugs, and dose discontinuation or treatment termination in response to immune-mediated adverse events should be applied to both alemtuzumab and tenecteuzumab.

In an adjuvant setting, atuzumab and tiryleyuzumab can be maintained for up to 12 weeks. If tenecteuzumab is discontinued for any reason for > 12 weeks, the patient must permanently terminate tenecteuzumab treatment, but the use of atelizumab may continue if there are no contraindications and after discussing whether toxicity is considered to be associated with tenecteuzumab and/or the combination. An exception may be made if the investigator judges that the patient is likely to recover clinical benefit from using tegraleigh itumumab after > 12 weeks. In this case, the securititumumab may be restarted. If the atuzumab is discontinued for > 12 weeks, the patient must permanently terminate the atuzumab. However, if the investigator determines that the patient is likely to receive clinical benefit from atlizumab after > 12 weeks, then the attlizumab may be restarted. Continued administration of single-drug atlizumab to patients is required to continue to meet all other study eligibility criteria.

Continued administration of the single drug, tiyuetuzumab, after permanent termination of atuzumab, is not allowed.

If the patient must taper off the steroid for treatment of an adverse event, atelizumab and/or tegraleigh immuzumab may be suspended for a period of time more than or equal to 12 weeks since the last dose, while tegraleigh immuzumab may be suspended for a period of time more than or equal to 12 weeks since the last dose until the steroid ceases, or until the steroid is reduced to a prednisone dose (or equivalent dose) of ≦ 10 mg/day. Discontinuation of the dose for reasons other than toxicity may be permitted. After termination of both study treatments, patients were monitored for safety and efficacy.

C. Security parameters and definitions

The security assessment consists of: monitoring and recording adverse events, including critical adverse events and adverse events of particular concern, performing protocol-specific safety laboratory assessments, measuring protocol-specific vital signs, and conducting other protocol-specific tests deemed critical to the safety assessment of the study.

Adverse events

According to good clinical practice guidelines for ICH, an adverse event refers to any adverse medical event that occurs when a drug is used in a clinical study subject, regardless of its causal relationship. Thus, an adverse event may be any of the following:

Any adverse and unexpected signs (including abnormal laboratory test results), symptoms or disease associated with the use of a drug, whether or not considered to be associated with the drug.

Any new disease or worsening of an existing disease (worsening in the characteristics, frequency or severity of a known disease).

Recurrence of intermittent medical conditions (e.g., headache) that did not exist at baseline.

Any worsening of laboratory values or other clinical tests (e.g., ECG, X-ray) associated with the symptoms or resulting in study treatment or concomitant changes in treatment or termination of study treatment.

Adverse events associated with the regimen prescribed intervention, including adverse events that occurred prior to dispensing study treatment (e.g., screening for invasive procedures such as biopsies).

Critical adverse event

A critical adverse event is any adverse event that meets any of the following criteria:

is fatal (i.e., the adverse event actually causes or results in death).

Is life-threatening (i.e., adverse events, in the opinion of the investigator, expose the patient to an immediate risk of death). This does not include any adverse events that could lead to death if they occur in a more severe form or were allowed to continue.

Requiring or extending hospital stay.

Resulting in persistent or significant disability/disability (i.e., adverse events result in substantial disruption of a patient's ability to perform normal life functions).

Congenital abnormalities/birth defects in newborns/infants born to mothers exposed to study treatment.

A significant medical event that is at the discretion of the researcher (e.g., the patient may be compromised or medical/surgical intervention may be required to prevent one of the above outcomes).

The terms "severe" and "critical" are not synonymous. Severity refers to the intensity of an adverse event (e.g., graded as mild, moderate, or severe, or according to NCI CTCAE); the event itself may have relatively little medical significance (such as a severe headache without any further findings)).

Adverse events of particular interest

Adverse events of particular interest for this study are as follows:

potential cases of drug-induced liver injury, including ALT or AST elevation in combination with bilirubin elevation or clinical jaundice (as defined by the hessian Law (Hy's Law)).

Transmission of infectious pathogens suspected of being carried out by study therapy, defined as follows:

any organism, virus or infectious particle (e.g., prion protein that transmits transmissible spongiform encephalopathies), whether pathogenic or non-pathogenic, is considered an infectious pathogen. Transmission of the source of the infection may be suspected based on clinical symptoms or laboratory findings that indicate infection in patients exposed to the drug. The term is only applicable in cases where the study treatment is suspected to be contaminated.

Pneumonia.

Colitis.

Endocrine diseases: diabetes, pancreatitis, adrenal insufficiency, hyperthyroidism, and hypophysitis.

Hepatitis, including AST or ALT > 10 × ULN.

Systemic lupus erythematosus.

Disorders of the nervous system: guillain-Barre syndrome, myasthenia gravis syndrome or myasthenia gravis and meningoencephalitis.

Events suggestive of anaphylaxis, transfusion-related reactions, cytokine release syndrome, hemophagocytic lymphohistiocytosis and macrophage activation syndrome.

Nephritis.

Ocular toxicity (e.g., uveitis, retinitis, optic neuritis).

Myositis.

Myopathy, including rhabdomyolysis.

For heart conditions of grade ≧ 2 (e.g., atrial fibrillation, myocarditis, pericarditis).

Vasculitis.

Autoimmune hemolytic anemia.

Severe skin reactions (e.g., stevens-Johnson syndrome, bullous dermatitis, toxic epidermal necrolysis).

Assessment of severity of adverse events

The adverse event severity rating scale for NCI CTCAE (v 5.0) is used to assess the severity of adverse events. In reporting the severity of CRS, the American Society for Transplantation and Cell Therapy (ASTCT) CRS consensus rating scale should be used in addition to NCI CTCAE v 5.0.

Example 12 statistical consideration and analysis planning for the GO42501 study

All patients enrolled in the GO42501 study, who received at least one dose of study drug in each cohort, were analyzed for efficacy and safety.

Determination of sample amount

The primary efficacy objective of this study was to assess the Major Pathological Remission (MPR) rate. Approximately 41 patients were enrolled in each cohort of the study. Assuming an observed MPR rate of 61%, this sample volume provides sufficient accuracy for point estimation of MPR rate in each cohort, where both sides 95% ci have a lower limit of more than 46%, which ratio may warrant further study of the combination therapy in this case.

Summary of study performance

The number of patients enrolled, terminated or completed the study was aggregated. The reasons for early study withdrawal are listed and summarized. The cohort and main regimen deviations for each treatment cohort are listed.

A. Demographic and baseline feature summarization

Demographic information, such as age and race, is tabulated. Descriptive statistics are presented, including the mean, standard deviation and range of consecutive parameters, as well as the percentage and frequency of classification parameters. Summaries for the overall population and for each treatment cohort are presented. Unless otherwise indicated, the baseline measurement is the last available data obtained before the patient received the first dose of any component of the study drug.

B. Security analysis

For each cohort, the safety analysis included all patients in the cohort receiving at least one dose of study treatment.

Study treatment exposure including treatment duration, dose and dose intensity are summarized.

The incidence and duration of surgical delays, the incidence of surgical and postoperative complications, and/or the number of surgical cancellations associated with study treatment were assessed for each cohort.

The verbatim description of the adverse event maps to the MedDRA synonym library term. The severity of all adverse events was graded by the investigator according to NCI CTCAE v5.0 and the severity of CRS was also graded by the investigator according to the ASTCT consensus rating scale. These summaries are provided as treatment arms. All adverse events were summarized by treatment arm and NCI CTCAE grade. CRS was also summarized by treatment arm and ASTCT consensus grade. In addition, adverse events leading to withdrawal from study treatment, leading to dose reduction or discontinuation, adverse events occurring in treatment associated with study treatment, severe (i.e., > 3 grade) adverse events, fatal (i.e., grade 5) adverse events, and critical adverse events, as well as adverse events of particular concern, were summarized. Multiple occurrences of the same event were counted once with maximum severity. Laboratory data were identified with values outside the normal range. In addition, selected laboratory data, including ADA results and changes in vital signs, were aggregated by treatment arm. All and the causes of death were summarized.

C. Analysis of efficacy

The efficacy analysis population included all patients enrolled to receive at least one dose of study treatment.

End of primary efficacy

The MPR rate is defined as the proportion of patients who have achieved MPR and is estimated for each treatment cohort in the efficacy analysis population. MPR is defined as residual viable tumors with < 10% of the primary tumors surgically removed, as assessed by the central pathology laboratory. Patients who did not undergo surgery were considered non-responders to MPR. Both sides of the MPR rate calculated using the capper-Pearson method are reported as 95% ci.

Secondary efficacy endpoints

The rate of complete remission from pathology (pCR) is defined as the proportion of patients who have achieved pCR. pCR is defined as the lack of any viable primary tumor at the time of surgical resection, as assessed by the central pathology laboratory. pCR rates were analyzed using the same statistical method as MPR rates for each treatment cohort of the therapy analysis population.

Event-free survival (EFS) is defined as the time from the first dose of study drug to any of the following events (whichever occurs first): disease progression excluding surgery as assessed by investigator according to RECIST v 1.1; local or distant disease recurrence (including the development of new primary NSCLC); or die for any reason. Patients who did not experience disease progression leading to surgical disability, local or distant disease recurrence, or death at the time of analysis were scored at the last tumor or disease follow-up assessment. Patients who did not receive a post-baseline tumor assessment were scored on the day of the first dose of study drug. EFS was evaluated for each treatment cohort of the efficacy analysis population using the Kaplan-Meier method.

D. Pharmacokinetic analysis

Samples were collected for PK analysis and exposure in this study was compared to exposure obtained in previous studies. Serum concentrations of alemtuzumab and tenecteuzumab were reported as individual values and summarized by cohort and cycle (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean coefficient of variation) as appropriate and data allowed.

Individual and median serum concentrations for alemtuzumab and tiryleyumab were plotted as cohort and days. The alemtuzumab and tirayleigh mab concentration data may be merged with data from other studies using established population PK models to derive PK parameters such as clearance, volume of distribution, and AUC as data is warranted. The potential relevance of relevant PK parameters to safety, efficacy, or biomarker outcome can be explored.

E. Immunogenicity assays

Immunogenicity analysis included patients with any anti-drug antibody (ADA) assessments, grouped according to the treatment received. The number and proportion of ADA positive and ADA negative patients presented in both alemtuzumab and tenecteuzumab treatments were summarized in cohorts. The relationship between ADA status and safety, efficacy and PK endpoint can be analyzed and reported via descriptive statistics.

F. Biomarker analysis

Exploratory biomarker analyses were performed in order to explore the relationship between various pathological, immunological and genomic features of cancer and clinical outcomes of these patients. These assays include, but are not limited to, characterization of immune cells and ctDNA in the tumor microenvironment and/or periphery. Clinical efficacy outcomes including MPR, pCR and EFS were analyzed in biomarker subgroups (e.g., based on PD-L1 and TIGIT status) to assess therapeutic benefit where feasible.

Example 13 therapeutic efficacy of anti-TIGIT antagonist antibodies in combination with PD-1 axis binding antagonists in patients with cervical cancer

Assessing the efficacy and safety of treatment with an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., ibritumomab tiuxetan) in combination with a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., altlizumab)) and an altlizumab monotherapy in a patient having metastatic and/or recurrent PD-L1 positive (tumor cells and tumor-associated immune cells [ TIC ] ≧ 5%) cervical cancer, the assessment being performed after the patient has progressed or relapsed with at least one platinoid but no more than two prior systemic therapies. To be eligible, patients must have an Eastern Cooperative Oncology Group (ECOG) physical status of 0 or 1 and have metastatic and/or recurrent PD-L1 positive cervical cancer.

The clinical trial consisted of a single phase, as described in detail below and shown in fig. 21.

Randomization

In this study, approximately 160 patients were enrolled and assigned to either treatment arm of both tenecteuzumab and atuzumab or atuzumab monotherapy. Randomization was performed at a 3: 1 ratio by using the permutation zone randomization method to ensure balanced distribution for each treatment arm. Randomization was stratified by ECOG performance status (0 vs. 1), previous use of chemo-or radiotherapy (yes or no), and treatment history (persistent versus recurrent disease).

Qualification of

The study included female patients with a minimum age of 18 years according to the following inclusion criteria:

-squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix, histologically confirmed to be recurrent or persistent after 1 to 2 lines of previous systemic chemotherapy (neuroendocrine, clear cell and sarcoma histology is not allowed), not amenable to curative treatment with systemic chemotherapy, surgery and/or radiotherapy.

At least one prior line platinum based systemic chemotherapy. The administration of radiosensitizing cisplatin in radiotherapy is not considered systemic chemotherapy.

-radiologically measurable disease

Eastern Cooperative Oncology Group (ECOG) physical condition 0 or 1

Cervical cancer tissue (archival or fresh biopsy specimen) for research and analysis

Life expectancy of at least 12 weeks

Adequate hematology and organ function

Fertility women must be willing to comply with appropriate contraceptive measures

Patients were excluded from the cohort based on the following criteria:

treatment with investigational therapy with therapeutic intent within 28 days prior to randomization and during study treatment

Any Central Nervous System (CNS) or brain metastases

Active autoimmune disease or immunodeficiency or history

Active tuberculosis

Known, clinically significant liver disease

Severe infection at randomization as judged by the investigator

Previous 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 before randomization or within 5 drug elimination half-lives (whichever is longer)

Use of systemic immunosuppressive medication within 1 week before randomization or anticipated need for systemic immunosuppressive medication during the study period

-pregnant or lactating women.

Known allergy to any component of the preparation of securititumumab or atelizumab

A. Study of therapeutic dose and administration

During treatment, patients received 1200mg fixed dose of alemtuzumab or 1200mg fixed dose of alemtuzumab and 600mg fixed dose of tenecteuzumab. Alemtuzumab was administered at a fixed dose of 1200mg Q3W (1200 mg on day 1 of each 21-day cycle). On day 1 of each 21-day cycle, all patients in the experimental arm were administered a fixed dose of 600mg IV Q3W of tirayleumab in combination with atuzumab.

In an alternative trial, on the day of administration, atlizumab was administered as a monotherapy according to the instructions outlined in table 59. Prior to the first infusion, the patient's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) were recorded for 60 minutes prior to the start of the infusion. The first atlas infusion was administered over 60 (+ -15) minutes, while vital signs of the patient were recorded every 15 (+ -5) minutes during the infusion and 30 (+ -10) minutes after the infusion. Subsequent infusions can be administered over 30 (+ 10) minutes if no infusion related adverse event is experienced during the first infusion. Pre-infusion recording of vital signs should continue to be recorded within 60 minutes prior to the start of the atlizumab infusion.

TABLE 59 administration of the first and subsequent alemtuzumab monotherapy infusions

In an alternative experiment, on the day of administration, attentizumab was administered prior to ibrinout itumumab according to the instructions outlined in table 60. Prior to the first infusion, the patient's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) were recorded for 60 minutes prior to the start of the infusion. The first attritumab infusion was administered over a period of 60 (+ -15) minutes, while patient vital signs were recorded every 15 (+ -5) minutes during the infusion and 30 (+ -10) minutes after the infusion. The first infusion of anti-TIGIT antibody (e.g., an anti-TIGIT antibody disclosed herein, e.g., ibritumomab tiuxetan) was administered over 60 (+ 10) minutes while patient vital signs were recorded every 15 (+ 5) minutes during the infusion and 30 (+ 10) minutes after the infusion. Subsequent infusions can be administered over 30 (+ 10) minutes if no infusion related adverse event is experienced during the first infusion. Pre-infusion recording of vital signs should continue to be recorded within 60 minutes prior to the start of the atlizumab infusion.

Treatment can continue as long as the patient is experiencing clinical benefit, with no unacceptable toxicity or worsening of symptoms due to disease progression after a combined assessment of imaging data, biopsy results, and clinical status. Patients who meet the criteria for uncertain disease progression of RECIST v1.1 as determined by the independent review board (IRC) will be allowed to continue treatment if all specified criteria are met (either tenecteuzumab in combination with atuzumab or atuzumab alone).

TABLE 60 administration of the first and subsequent infusions of Uluzumab and Attuzumab

B. Concomitant therapy

Some concomitant therapies are allowed. Concomitant therapy includes patients using any medication other than the study treatment prescribed by the regimen (e.g., oral contraceptives, hormone replacement therapy, prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic, nutritional supplements) from seven days prior to the start of study treatment to the treatment discontinuation visit. Patients were allowed the following concomitant therapy during the study.

Systemic corticosteroids and TNF- α inhibitors may attenuate the potentially beneficial immune effects of treatment with atelizumab. Therefore, in the case of conventional administration of systemic corticosteroids or TNF- α inhibitors, alternatives, including antihistamines, should be considered. If alternatives are not feasible, administration of the systemic corticosteroid and the TNF- α inhibitor may be determined by the researcher as appropriate.

Prophylactic administration of antihistamines, antipyretics and/or analgesics may only be administered for the second and subsequent study treatment infusions, as appropriate by the investigator.

C. End of therapeutic effect

To evaluate the efficacy of the combination of tirleivuzumab and atuzumab compared to the effect of atuzumab monotherapy, objective Remission Rate (ORR) was measured as the primary endpoint, where ORR is defined as the percentage of patients who experienced Complete Remission (CR) or Partial Remission (PR) twice consecutively at intervals greater than or equal to 4 weeks (as determined by the investigator according to RECIST v 1.1). Once all patients have been enrolled and a minimum follow-up of about 6 months has been achieved in these patients, a primary efficacy analysis is performed, and these patients remain on follow-up for ORR assessment. In the primary analysis, patients with a missing ORR rating were considered to have failed to achieve a response. Single sample z-test for ratios was used to compare ORR of the combined arms of tiryleiguzumab and atuzumab to historical reference values. The ORR estimate for each treatment arm was calculated and its 95% CI (Clopper-Pearson; clopper and Pearson 1934). It is expected that the 95% of ORR in the combination arm ci lower limit (table 61) and ORR observed in the monotherapy arm (table 62) should exclude the reference point.

TABLE 61 Overall statistical efficacy comparing ORR in combined arms of Tirayleigh Euzumab and Atlizumab to 14.6% reference point

MDO = minimum detectable observation; ORR = total response rate.

^a The source is as follows: chung et al 2019.

^b MDO is defined as the smallest observed ORR that results in statistical significance in the final analysis.

TABLE 62 probability of ORR greater than the reference point for the final analysis of ORR observed in the alemtuzumab monotherapy arm

ORR = total response rate.

The secondary efficacy goals of this study were to evaluate the efficacy of the combination of tirleivuzumab and atuzumab, as well as the efficacy of the aleuzumab monotherapy, based on duration of remission (DOR), disease Control Rate (DCR), best Clinical Response (BCR), progression Free Survival (PFS), and Overall Survival (OS). For patients with objective remission, DOR is defined as the time from the first onset of recorded objective remission (CR or PR) to the day of disease progression or death for any reason (whichever occurs first), as determined by IRC according to RECIST v 1.1. DCR is defined as the proportion of patients with CR, PR or SD as determined by IRC according to RECIST v 1.1. BCR is defined as the proportion of patients with CR, PR or SD as determined by the investigator. PFS is defined as the time from randomization to the first onset of disease progression or death for any reason (whichever occurs first), as determined by IRC according to RECIST v 1.1. OS is defined as the time from randomization to death from any cause.

Other exploratory efficacy endpoints may further include disease control (defined as SD or CR or PR > 6 weeks) as determined by researchers according to RECIST v 1.1.

To assess the safety and tolerability of the combination of tirylereumab and atuzumab compared to atuzumab monotherapy, the incidence, nature and severity of Adverse Events (AEs), e.g., graded according to the american national cancer institute adverse event general term standard version 5.0 (NCI CTCAE v 5.0), were measured (adverse events not specifically listed in NCI CTCAE were measured according to table 63). The severity of Cytokine Release Syndrome (CRS) was also determined according to the american society for transplantation and cell therapy CRS consensus rating scale. In addition, clinically significant changes in vital signs, physical examination results, and clinical laboratory results during and after administration of the combination of tenecteuzumab and atuzumab compared to atuzumab monotherapy were also measured.

TABLE 63 adverse event severity rating Scale for events not explicitly listed in NCI CTCAE

^a The instrumental daily life activities refer to preparing meals, purchasing groceries or clothes, using a telephone, managing money, and the like.

^b Self-care activities in daily life include bathing, dressing and undressing, self-eating, getting to the toilet and taking medicine, all of which are performed by non-bedridden patients.

Time horizon of result measurement

The time frame for the primary outcome measure, objective Remission Rate (ORR), will be the day of first onset of documented objective remission to disease progression or death for any reason, whichever comes first (up to 36 months). The time ranges for the secondary outcome measurements can be found in table 64.

TABLE 64 time Range of Secondary result measurements

D. Biomarkers

Patient samples, including archived tumor tissue as well as serum, plasma, whole blood and stool, were collected for exploratory biomarker assessment of all patients in the randomized study. In addition to assessing PD-L1 status, biomarkers associated with drug resistance, disease progression and clinical benefit of ibritumumab tiuxetan and/or atuzumab were also analyzed. For example, potential predictive and prognostic biomarkers associated with the clinical benefit and safety of ibritumumab and/or atelizumab were analyzed.

Tumor tissue and blood samples collected at baseline (tumor tissue collected at the time of disease progression if the investigator deems it clinically viable) enable Whole Exome Sequencing (WES) and/or Next Generation Sequencing (NGS) to identify somatic mutations that can be predictive of response to a study treatment, associated with progression to a more severe disease state, associated with acquired resistance to a study treatment, associated with susceptibility to developing an adverse event, or can increase knowledge and understanding of disease biology.

Biomarkers include, but are not limited to, PD-L1 and/or TIGIT expression on tumor tissue; germline and somatic mutations (including but not limited to mutation burden, MSI and MMR deficiency) from tumor tissue and/or from circulating tumor DNA in blood, by WGS and/or NGS, a gene pair (e.g., CD 274) or gene signature (e.g., T274) associated with tumor immunobiology _effector Gene) analysis for identification; PD-L1; TIGIT; an HPV alteration; a subpopulation of lymphocytes; a bank of T cell receptors; cytokines involved in T cell and NK cell activation and plasma-derived cytokines.

To assess the effects of the PD-L1/PD-1 pathway on ORR, PFS, DOR, and/or OS in the main patient population, the effects of the relationship between protein, RNA, DNA, tumor mutational burden and other exploratory biomarkers in tumor tissue and/or blood on efficacy, safety, PK, immunogenicity, and Patient Reported Outcome (PRO) can be assessed. Furthermore, to assess the effect of the TIGIT pathway on ORR, PFS, DOR, and/or OS tracking in the major population ORR, DOR, PFS, and OS can be assessed in a population of patients whose tumors have TIGIT expression, as defined by protein and/or RNA expression.

Exploratory biomarker analyses can be performed in an effort to understand the association of these markers (e.g., TIGIT IHC status) with the efficacy of study treatment. The therapeutic outcome may be explored in a population of patients whose tumors have high TIGIT expression, as determined by IHC and/or RNA analysis. Exploratory analysis of WGS data can be performed in the context of this study and explored with data from other studies to increase the researcher's understanding of disease pathobiology and guide the development of new therapeutic approaches.

E. Immunogenicity assays

To assess the immune response to tirayleigh immuzumab and atelizumab, the incidence of anti-drug antibodies (ADA) appearing in the treatment and their potential impact on safety, efficacy and Pharmacokinetics (PK) were assessed.

By 12 months 2019, in the phase Ia part of study GO30103, no anti-drug antibodies (ADA) were detected that appeared in treatment against teleyretamab. In the study of stage Ib portion of GO30103, 3 of 154 evaluable patients (1.9%) were positive for ADA appearing in treatment with tenecteuzumab. By 10 months in 2019, 1 of 66 patients evaluated in study GO40290 (1.5%) were positive for ADA appearing in treatment with teleyuzumab. By 10 months in 2019, 1 of 66 patients evaluated in study GO40290 (1.5%) were positive for ADA appearing in treatment with tiryleigumab and the patient was positive at only one time point.

F. Pharmacokinetic analysis

To characterize the pharmacokinetics when tiplexeumab is administered in combination with atuzumab, the serum concentration of tiplexeumab was determined from the subject at various time points. Furthermore, to characterize the pharmacokinetics of the combined administration of atuzumab with tirayleigh umab or when administered as monotherapy, plasma concentrations of atuzumab were obtained from the subject at different time points during the study.

Example 14A phase Ib, open label, multiple cohort study relating to the safety, efficacy and pharmacokinetics of the combination of Tirayleigh mab with atuzumab and chemotherapy in patients with triple negative breast cancer

This example describes a phase Ib, open label, multi-cohort study aimed at assessing the safety, efficacy and pharmacokinetics of tirayleigh mab in combination with atuzumab and chemotherapy in patients with early triple negative breast cancer (eTNBC). The study consisted of the following cohorts:

cohort B included patients with clinically assessed T2-4d TNBC who met the surgical conditions (PD-L1 cohort of all participants). Patients were treated with 1: the ratio of 1 was randomized to one of the following two treatment arms:

-an arm: the combination of Tirayleumab with atuzumab, nab-paclitaxel and carboplatin, followed by the combination of Tirayleumab with atuzumab, doxorubicin and cyclophosphamide (abbreviated as Tirayleumab and atuzumab + nab-pac-carbo-AC)

-a B-arm: the combination of the Terayleumab with the alemtuzumab and nab-paclitaxel, and then the combination of Terayleumab with the alemtuzumab, doxorubicin and cyclophosphamide (short for Terayleumab and alemtuzumab + nab-pac-AC)

In addition, AC and G-CSF (e.g., filgrastim or pegylated filgrastim) or GM-CSF are administered as background therapy to patients in cohort B after nab-paclitaxel.

The study was aimed at being able to assess the safety and tolerability, preliminary efficacy and pharmacokinetics of neoadjuvant temeprueumab in combination with atuzumab, nab-paclitaxel and carboplatin, followed by AC or neoadjuvant temeprueumab in combination with atuzumab, nab-paclitaxel, followed by AC in surgically eligible patients with an initial clinical assessment of T2-4d TNBC

A. Design of research

This phase Ib, multiple cohorts, open label, multiple centers, global study aimed at studying the safety and tolerability, primary efficacy and pharmacokinetics of neoadjuvant tenecteuzumab in combination with atelizumab, nab-paclitaxel and carboplatin, followed by doxorubicin and cyclophosphamide (AC) or neoadjuvant tenecteuzumab in combination with atelizumab, nab-paclitaxel, followed by AC in surgically eligible patients with an initial clinical assessment of T2-4d TNBC (PD-L1 cohort of all participants). Fig. 22 illustrates a study design for cohort B.

Consenting and eligible patients were randomized to one of the following two treatment arms at a 1: 1 ratio:

arm a (up to about 20 patients): tirayleigh itumumab (420 mg) and atelizumab (840 mg) were administered by IV infusion Q2W, with nab-paclitaxel (125 mg/m) administered by IV infusion QW ² ) And carboplatin administered by IV infusion Q3W (area under the concentration-time curve [ AUC)]：5mg/mL/min]) Combining for four cycles; followed by tirayleigh immuzumab (420 mg) and atelizumab (840 mg) with doxorubicin (60 mg/m) ² ) And cyclophosphamide (600 mg/m) ² ) Combination ofQ2W administration by IV infusion was supported by granulocyte colony stimulating factor (G-CSF; e.g., filgrastim or pegylated filgrastim) or granulocyte macrophage colony stimulating factor (GM-CSF) for four doses.

B-arm (up to about 20 patients): tirayleigh itumumab (420 mg) and atelizumab (840 mg) were administered by IV infusion Q2W, with nab-paclitaxel (125 mg/m) administered by IV infusion QW ² ) Combined for 12 weeks; followed by tirayleigh immuzumab (420 mg) and atelizumab (840 mg) with doxorubicin (60 mg/m) ² ) And cyclophosphamide (600 mg/m) ² ) Combinations, administered by IV infusion Q2W, supported by G-CSF (e.g., filgrastim or pegylated filgrastim) or GM-CSF for four doses.

Exploratory endpoints (complete remission of pathology (pCR); eradication of invasive tumors from mammary glands and lymph nodes (ypT 0/ypN 0)) were established by local scrutiny after completion of neoadjuvant therapy and surgery. Surgery should be performed no earlier than 14 days but no later than 6 weeks after the last dose of neoadjuvant therapy. Platelet counts should be checked before surgery and should be > 75,000 cells/. Mu.L.

Postoperative patient management may include clinically indicated radiation therapy, and management of patients who do not achieve pCR should follow current standard of care guidelines.

Patients with clinically positive axillary lymph nodes assessed at baseline by physical examination or by any radiographic imaging are advised to undergo fine needle aspiration or core needle biopsy prior to randomization and to undergo Axillary Lymph Node Dissection (ALND) or at least Sentinel Lymph Node Biopsy (SLNB) at the time of definitive surgery. The results of baseline fine needle aspiration or core needle biopsy are used to determine lymph node staging (dissection staging group according to international cancer control alliance/american joint committee for cancer [ UICC/AJCC ], 8 th edition), so patients with positive biopsy results should be staged as lymph node positive (N1-N3 c) while patients with negative biopsy results or equivocal fold negative (N0), regardless of any other clinical measurements.

For patients who demonstrate axillary lymph node negativity at baseline with clinical or fine needle or core needle biopsies, management of axillary surgery after completion of neoadjuvant therapy may include SLNB or ALND. If SLNB is performed, there is a strong recommendation to excise more than one lymph node (a minimum of two to three) and all patients with sentinel lymph node large metastases positive should receive ALND regardless of the number of positive lymph nodes.

During the study, patients underwent clinical and radiological tumor assessments at planned time intervals.

To assess the mechanism of action and possible resistance mechanism of the drug combination in the tumor microenvironment, tumor tissue can be harvested prior to administration on day 1 of cycle 2.

Tumor tissue was collected by biopsy unless clinically not feasible, as assessed and recorded by the investigator, and was collected at the first evidence of disease progression (before the initiation of a new anti-cancer treatment). These samples were used to analyze tumor tissue biomarkers associated with drug resistance or disease progression and the clinical benefit of the combination of tiryleiguzumab and atuzumab.

B. Administration and administration

The treatment protocol is summarized in fig. 22.

On the day of planned infusion of alemtuzumab, tiryleiguzumab, and chemotherapy, chemotherapy is to be administered after infusion of alemtuzumab and tiryleiguzumab.

After an alemtuzumab infusion (840 mg), the patient received 420mg of tenecteuzumab.

The administration of atelizumab, tirletegumab, and chemotherapy is performed in a monitored environment where trained personnel, as well as sufficient equipment and medications, are immediately available to manage potential critical reactions.

For detailed description of the preparation, storage and administration of the drugs, please refer to the pharmacy manual.

Tirayleigh immuzumab and atezumab

Patients in cohort B received atelizumab administered at a fixed dose of 840mg by IV infusion Q2W on days 1 and 15 of each 28 day cycle, followed by tirayleigh immuzumab also administered at a fixed dose of 420mg by IV infusion Q2W on days 1 and 15 of each 28 day cycle (see figure 22). The doses of securityluzumab and atelizumab were fixed and independent of body weight. Infusions of both tirayleigh eculizumab and atlizumab (including the observation period) were administered according to the instructions summarized in table 65.

TABLE 65 administration of the first and subsequent infusion of tireyueuzumab and infusion of atuzumab

Nab-paclitaxel

Nab-paclitaxel was administered to the patient as an IV infusion over 30 minutes.

Nab-paclitaxel should be administered after atuzumab and tiryleyuzumab. The dosage of Nab-paclitaxel is 125mg/m ² The patient was administered QW via IV infusion for 12 weeks. The frequency of Nab-paclitaxel administration should not exceed every 7 days.

As the patient's weight changes, the study center should follow its institutional care standards to determine the dosage adjustments of nab-paclitaxel. The infusion site should be closely monitored for the presence of infiltration during study drug administration.

For more details on the preparation and administration of nab-paclitaxel, please refer to local prescription information.

Carboplatin

Carboplatin was administered after completion of nab-paclitaxel administration by short term IV infusion over 15 to 60 minutes to achieve a target AUC of 5mg/mL/min once every 3 weeks for 4 doses.

There is no excess of known antidotes to carboplatin. If necessary, the patient may require supportive care associated with myelosuppression and impairment of renal, hepatic, and auditory functions. Doses up to 1600mg/m2 are associated with extreme discomfort for the patient, with diarrhea and hair loss. The use of carboplatin at doses higher than the recommended dose is also associated with vision loss. For more details, please refer to local carboplatin prescription information.

Cyclophosphamide

Cyclophosphamide should undergo 3 to 5 minutes IV bolus or IV infusion according to local standard of care. AC should be administered after alemtuzumab and tenectereuzumab. The dose of cyclophosphamide is 600mg/m ² Intravenous administration. Allowing for dose delay and dose reduction due to toxicity. Cyclophosphamide Q2W was administered at four doses (dose dense AC) under support of G-CSF or GM-CSF. Remarking: oral administration of cyclophosphamide is not allowed.

Chemotherapy-induced nausea and vomiting should be prevented and treated according to clinical indications. Because systemic corticosteroids may attenuate the potentially beneficial immune effects of treatment with atelizumab and tenectereuzumab, alternative agents should be considered when clinically feasible.

For details on the preparation and administration of cyclophosphamide, see local prescription information.

Doxorubicin

According to local standard of care, doxorubicin should be administered over a 3 to 5 minute IV bolus or as an IV infusion over 15 to 30 minutes. AC should be administered after alemtuzumab and tenectereumab. The dose of doxorubicin is 60mg/m ² Administered to the patient by IV infusion. Allowing delay and reduction of dosage due to toxicity. Four doses (dose-intensive AC) of doxorubicin Q2W were administered with support of G-CSF or GM-CSF.

For detailed information on the preparation and administration of doxorubicin, please refer to local prescription information

Preventive medication and supportive care

Generally, chemotherapy supportive care should be performed according to the American Society for Clinical Oncology (ASCO), european Organization for Research and Treatment of Cancer (EORTC), or the ESMO guidelines or local standards of care.

Chemotherapy-induced nausea and vomiting should be prevented and treated according to clinical indications. Because systemic corticosteroids may attenuate the potential beneficial immune effects of treatment with atelizumab and tenectereuzumab, alternative agents should be considered when clinically feasible, except for the guidelines provided in the protocol.

Depending on local policy, prophylactic G-CSF or GM-CSF may be used to reduce the risk of hematologic toxicity and is necessary during the AC part of chemotherapy. According to local policy, the use of G-CSF or GM-CSF is allowed for the treatment of neutropenia.

Dose adjustment

In this study, there was no dose adjustment for either astuzumab or ibritumumab. For nab-paclitaxel administration (i.e., dose adjustment and treatment discontinuation rules), see table 25. For guidance on the management of carboplatin, doxorubicin, or cyclophosphamide related toxicities (i.e., dose adjustment and treatment discontinuation rules), please refer to the local prescription information for each drug individually.

C. Concomitant therapy

Concomitant therapy included patients using any medication other than the regimen prescribed treatment (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplements) from 7 days prior to study drug initiation to treatment termination visit.

Allowed therapy

Patients were allowed the following therapies during the study:

oral contraceptives with annual failure rate < 1%

Hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or low molecular weight heparin)

Inactivated influenza vaccine

Administration of megestrol acetate as an appetite stimulant

Mineralocorticoids (e.g., fludrocortisone)

Administration of corticosteroids for chronic obstructive pulmonary disease or asthma

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency

Bisphosphonates for the prevention of skeletal events

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

palliative radiation therapy is permissible as long as it does not interfere with the assessment of the tumor target lesion (e.g., the lesion to be irradiated cannot be the only site of measurable disease). Treatment with tirayleigh itumumab and atelizumab may continue during palliative radiotherapy. Nab-paclitaxel treatment should be discontinued according to institutional standard of care.

G-CSF (e.g., filgrastim or pegylated filgrastim) or GM-CSF treatment allows patients receiving chemotherapy (nab-paclitaxel) and is necessary during the AC portion of chemotherapy

The patient should be under primary prevention according to ASCO, EORTC or ESMO guidelines or local standard practice; that is, in patients ≧ 60 years of age and/or with complications (Smith et al 2006.

In support of limited evidence for the use of long-acting (pegylated) forms of G-CSF in patients receiving nab-paclitaxel weekly, researchers should consider the conventional formulation of G-CSF to be a priority.

At the discretion of the investigator, prophylactic administration of antihistamines, antipyretics and/or analgesics can only be administered for the second and subsequent infusions of atuzumab and tiryleigh itumumab.

Warning therapy

Systemic corticosteroids and TNF- α inhibitors may attenuate the potentially beneficial immune effects of treatment with atelizumab. Therefore, in the case of conventional administration of systemic corticosteroids or TNF- α inhibitors, alternatives, including antihistamines, should be considered. If alternatives are not feasible, the systemic corticosteroid and TNF-. Alpha.inhibitor can be administered at the discretion of the investigator.

At the discretion of the investigator, the use of systemic corticosteroids is recommended to treat specific adverse events associated with the treatment with astuzumab.

Treatment inhibition

The following concomitant therapies were prohibited, as follows:

concomitant therapies aimed at treating cancer (including but not limited to chemotherapy, hormonal therapy, immunotherapy, radiotherapy and herbal therapy), whether approved or experimental by the health authorities, for different periods of time (depending on the agent) before the start of the study treatment and during the study treatment, until disease progression is recorded and the patient has terminated the study treatment except palliative radiotherapy

Investigational therapy within 28 days before initiation of study treatment and during study treatment

Live attenuated vaccines (e.g.,

)

systemic immune stimulants (including but not limited to interferon and IL-2) within 4 weeks or 5 drug elimination half-lives (whichever is longer) before initiation of study treatment and during study treatment, as these drugs may increase the risk of developing autoimmune disease when administered in combination with atelizumab and tiryleyuzumab

Systemic immunosuppressive drugs (including but not limited to azathioprine, methotrexate, and thalidomide) during study treatment, as these drugs may alter the efficacy and safety of alemtuzumab and tenecteuzumab

Other limitations associated with carboplatin chemotherapy

Forbid the concurrent use with yellow fever vaccines and avoid vaccination with other live attenuated vaccines.

Killed or inactivated vaccines can be administered; however, the response to such vaccines may be diminished.

The concomitant use of sodium phenytoin or sodium phenytoin is not recommended because of the risk of exacerbation of spasticity, increased toxicity or loss of efficacy of cytotoxic drugs.

The following agents should be used with caution: cyclosporine, nephrotoxic or ototoxic drugs (e.g., aminoglycosides, vancomycin, capreomycin and diuretics, including loop diuretics [ increase the risk of, aggravate or accumulate toxicity ]).

Concurrent (together or less than 7 days apart) radiation therapy should be avoided.

D. Inclusion criteria

Patients must meet the following general criteria to enter the study:

sign informed consent

Female and male aged 18 years or more when signing informed consent

Ability to comply with the study protocol

ECOG physical Performance status of 0 or 1 (see appendix 5)

Adequate hematology and end organ function, defined as the laboratory results obtained within 14 days before the start of study treatment (day 1 of cycle 1):

ANC ≧ 1.5X 109/L (1500/μ L), no G-CSF support for 2 weeks before day 1 of cycle 1

Lymphocyte count ≥ 0.5X 109/L (≥ 500/μ L)

Platelet count ≧ 100X 109/L (. Gtoreq.100,000/μ L), no transfusion occurred within 2 weeks before day 1 of cycle 1

Hemoglobin ≥ 90g/L (≥ 9 g/dL)

Patients may need transfusion or receive erythropoiesis therapy to meet this criteria.

AST, ALT and ALP ≦ 2.5 × Upper Normal value (ULN)

Serum bilirubin ≦ 1.5 × ULN, except for:

patients with known Gilbert disease with serum bilirubin levels of ≦ 3 × ULN are included.

-INR and aPTT. Ltoreq.1.5 XULN

This applies only to patients who do not receive anticoagulation therapy; patients receiving anticoagulation therapy should maintain a stable dosage.

Creatinine clearance ≥ 30mL/min (calculated using Cockcroft-Gault formula)

Serum albumin ≥ 25g/L (≥ 2.5 g/dL)

HIV test negative at screening

Negative in the hepatitis B surface antigen (HBsAg) test at screening

A positive hepatitis b surface antibody (HBsAb) test at the time of screening, or a negative HBsAb test at the time of screening accompanied by either:

total hepatitis B core antibody (HBcAb) negative

Positive in total HBcAb test, followed by quantitative Hepatitis B Virus (HBV) DNA < 500IU/mL

HBV DNA testing was performed only on patients who were negative for the HBsAg test, negative for the HBsAb test, and positive for the total HBcAb test.

Hepatitis C Virus (HCV) antibody test negative at screening; or positive for HCV antibody test and negative for HCV RNA test when screened

Only patients who tested positive for HCV antibodies were tested for HCV RNA.

For fertile women: consent was either to remain abstinent (avoid sexual intercourse) or to use contraceptive methods, and consent was not to donate ova, defined as follows:

during the treatment period and for at least 5 months after the last administration of atezumab, 90 days after the last administration of tenecteumab, 1 month after the last administration of nab-paclitaxel, 6 months after the last administration of carboplatin or doxorubicin, or 12 months after the last administration of cyclophosphamide, the woman must remain abstinent or use a contraceptive regimen that results in a yearly failure rate of < 1%, whichever is later. At this same time, women must avoid donating eggs.

A woman is considered fertile if it is in menstrual infancy, does not reach postmenopausal status (amenorrhea for more than 12 months without established causes outside the menopause), and has not been subjected to surgical sterilization (removal of ovaries and/or uterus).

Examples of contraceptive methods with annual failure rates of < 1%, if used continuously and correctly, include combined (estrogen and progestin containing) hormonal contraception associated with ovulation inhibition, progestin only hormonal contraception associated with ovulation inhibition, bilateral tubal embolism, male sterilization, intrauterine devices, intrauterine hormone release systems, and sexual abstinence.

The reliability of sexual abstinence should be assessed according to the duration of the clinical study and the patient's preference and usual lifestyle.

Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

Women who want to be pregnant after termination of the study treatment should seek advice on oocyte preservation before the study treatment is initiated, as chemotherapy treatment may lead to irreversible infertility.

For males: consent to maintain abstinence (avoid sexual intercourse) or to use contraceptive measures, and to not donate sperm, is defined as follows:

during the treatment period and 90 days after the last administration of ibritumomab tiuxetan or within 6 months after the last sequential administration of nab-paclitaxel, carboplatin, doxorubicin or cyclophosphamide, the male must remain on abstinence or use a condom plus an additional contraceptive regimen with a annual failure rate of < 1%, whichever is later, with a female partner with fertility or a female partner during pregnancy. During this same period, the male must avoid donation of sperm.

The reliability of sexual desire should be assessed according to the duration of the clinical trial and the patient's preference and usual lifestyle.

Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are unacceptable methods of contraception.

Men who want to live their child after the study treatment is initiated should seek advice on sperm preservation before the study treatment is initiated because chemotherapy treatment may lead to irreversible infertility.

For non-postmenopausal women (non-treatment-induced amenorrhea of > 12 months) or women who have undergone sterilization surgery, negative serum pregnancy test results need to be obtained within 14 days before the study treatment is initiated

Compliance with visit within the program, willingness and competency of treatment programs, laboratory tests and other research procedures patients must meet the following cancer-specific entry eligibility criteria:

histologically recorded TNBC (negative HER2, ER and PR status, as assessed by local test)

Local laboratory assessments defined HER2 negativity as either of the following (Wolff et al, 2018):

ISH non-amplified (HER 2 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 negativity was defined as IHC analysis found < 1% of cells expressing hormone receptors.

Patients with multifocal tumors (more than one discrete tumor localized in the same quadrant as the primary tumor) are eligible provided that at least one lesion is sampled, locally confirmed and recorded as TNBC.

Patients with multicentric tumors (involving multiple tumors in more than one discrete quadrant) are eligible, provided that all discrete lesions are sampled, locally confirmed and recorded as TNBC.

Confirmed tumor PD-L1 assessment as recorded by central testing of representative FFPE tumor tissue samples (preferably) in paraffin blocks or at least 20 unstained slides

Tumor tissue should have good quality based on total and viable tumor content and PD-L1 expression must be assessed prior to enrollment using the Ventana (SP 142) PD-L1 IHC assay, where positive is defined as ≧ 1% of the area of the tumor occupied by any intensity of tumor-infiltrating immune cells that express PD-L1, as determined by the central laboratory. Patients whose tumor tissues were not assessable for PD-L1 expression were ineligible.

If multiple tumor specimens are submitted, the patient may be eligible if at least one specimen is evaluable for PD-L1. Acceptable samples include core needle biopsies for deep tumor tissue (a minimum of three core needles) or for excision, incision, perforation or forceps biopsies of skin, subcutaneous or mucosal lesions.

FFPE tumor specimens in paraffin blocks are preferred.

Fine needle aspiration, brushing, pleural effusion cell precipitation, bone metastases, and lavage samples are unacceptable.

At least one imaging or clinical measurement of the primary breast tumor size > 2cm

Performance staging: cT2-cT4, cN0-cN3 and cM0

Patient consent for appropriate surgical management after completion of neoadjuvant therapy (e.g., including axillary lymph node surgery and partial or total mastectomy)

Baseline Left Ventricular Ejection Fraction (LVEF) > 53%, as measured from Echocardiography (ECHO) or multi-gated acquisition (MUGA) scans

E. Exclusion criteria

Patients who met any of the following criteria were excluded from the study:

pregnancy or lactation, or intended pregnancy at the following times: during study treatment, greater than 90 days after treatment with tenecteromumab, 5 months after treatment with alemtuzumab, 6 months after treatment with nab-paclitaxel, carboplatin, or doxorubicin, or 12 months after treatment with cyclophosphamide

The serum pregnancy test results must be negative in fertile women within 14 days prior to initiation of study treatment.

There is evidence that there is significant uncontrolled complication, possibly affecting compliance with the regimen or interpretation of the outcome, including significant liver disease (such as cirrhosis, uncontrolled severe seizures or superior vena cava syndrome)

Significant cardiovascular diseases, such as New York Heart Association heart disease (grade II or higher), myocardial infarction, unstable arrhythmia or unstable angina that occurred within 3 months prior to initiation of study treatment

Patients with known LVEF < 53% were excluded.

Patients with known coronary artery disease or congestive heart failure who do not meet the above criteria.

Severe infection occurred within 4 weeks before initiation of study treatment, including, but not limited to, hospitalization due to complications of infection, bacteremia, or severe pneumonia

Eligible patients receiving conventional antibiotic prophylaxis (e.g., preventing chronic obstructive pulmonary disease exacerbations or for tooth extractions) were treated with oral or IV antibiotics within 2 weeks prior to initiation of study treatment.

Major surgery was performed within 28 days before initiation of study treatment or was expected to be required during the study except for diagnosis

Placement of a central venous access catheter (e.g., port or similar catheter) is not considered a major procedure and is therefore permissible.

History of severe allergic, allergic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

Known to have allergic or allergic reactions to biopharmaceuticals produced in CHO cells or to any component of a preparation of tenecteuzumab or atelizumab

Activity or history of autoimmune diseases, including, but not limited to, 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-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis

Patients with a history of autoimmune-mediated hypothyroidism and who are receiving stable doses of thyroid replacement hormone meet the criteria of this study.

Patients with type 1 diabetes who are receiving a stable insulin regimen are eligible for this study.

Patients with eczema, psoriasis, chronic lichen simplex, or vitiligo with only dermatological manifestations (e.g., no psoriatic arthritis) are allowed provided that they meet the following conditions:

the rash must cover < 10% of the body surface area

Disease is well controlled at baseline and only low potency topical corticosteroids need be used

Acute exacerbation of the underlying condition requiring psoralen plus ultraviolet a radiation, methotrexate, retinoids, biologicals, oral calcineurin inhibitors or high potency or oral corticosteroids does not occur within the last 12 months

Previous allogeneic stem cell or solid organ transplantation

History of idiopathic pulmonary fibrosis (including pneumonia), drug-induced pneumonia, organized pneumonia (i.e. bronchiolitis obliterans, cryptogenic organized pneumonia), or evidence of active pneumonia at the time of screening at chest Computed Tomography (CT) scan

A history of radiation pneumonitis (fibrosis) in the radiation field was allowed.

EBV Virus Capsid Antigen (VCA) IgM test positive at screening

EBV Polymerase Chain Reaction (PCR) tests should be performed to screen for active infection or suspected chronic active infection based on clinical indications.

Patients positive for the EBV PCR test were excluded.

Active tuberculosis

Inoculation of live attenuated vaccines within 4 weeks prior to initiation of study treatment or the anticipated need for such live attenuated vaccines during the study period

Patients must agree not to receive live attenuated vaccine within 28 days prior to initiation of study treatment, during treatment or within 5 months after the last dose of study treatment (e.g.,

)。

previous treatments with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, 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 treatment or within 5 drug elimination half-lives (whichever is longer) of the drug

Treatment with systemic immunosuppressive drugs (including, but not limited to, prednisone, dexamethasone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [ anti-TNF ] agents) within 2 weeks prior to initiation of study treatment, or the anticipated need for use of systemic immunosuppressive drugs during the study

Patients who had received acute, low dose, systemic immunosuppressive medication (e.g., a single dose of dexamethasone to treat nausea) could be enrolled in the study.

Allows for treatment of chronic obstructive pulmonary disease with inhaled corticosteroids, treatment of orthostatic hypotension patients with mineralocorticoids (such as fludrocortisone), and treatment of adrenal insufficiency with low dose supplemental corticosteroids.

History of invasive breast cancer

Stage IV (metastatic) Breast cancer

Previous systemic therapy for the treatment and prevention of breast cancer

Previous therapy with anthracyclines, platinum or taxanes for any malignancy

Remarking: patients with non-polymorphic LCIS (untreated or treated with surgery) are eligible.

Simultaneous bilateral invasive Breast cancer

Previous incisions and/or excisional biopsies of primary tumors and/or axillary lymph nodes

Axillary lymph node dissection prior to initiation of neoadjuvant therapy

Other malignancies have a history within the first 5 years of screening, except for those with negligible risk of metastasis or death (e.g., 5 years OS > 90%), such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, or stage I uterine cancer

An unexpected history of cerebrovascular events within 12 months before initiation of study treatment

Cardiopulmonary dysfunction, defined as the occurrence of any of the following before the initiation of study treatment:

NCI CTCAE v5.0 ≧ 3 grades of symptomatic congestive heart failure or New York Heart Association grade II or higher cardiac history

Angina pectoris in need of antianginal medication, critical arrhythmias which cannot be controlled by appropriate medication, severe conduction abnormalities or clinically significant valvular diseases

High risk of uncontrolled arrhythmias (i.e. tachycardia, resting heart rate > 100/min, pronounced ventricular arrhythmia [ ventricular tachycardia ] or higher level atrioventricular [ AV ] block [ type 2 [ Mobitz 2] or third level AV block ])

Significant symptoms (grade ≧ 2) associated with left ventricular dysfunction, arrhythmia or cardiac ischemia

Study of myocardial infarction within 12 months before initiation of treatment

Uncontrolled hypertension (systolic pressure > 180mmHg and/or diastolic pressure > 100 mmHg)

Evidence of transmural infarction on ECG

-need for oxygen therapy

Known allergic reactions or allergies to nab-paclitaxel, cyclophosphamide, doxorubicin or components of carboplatin preparations

Known allergic reactions or allergies to G-CSF or GM-CSF formulations

F. Analysis of

Security analysis

Patients were randomized to one of the two arms in cohort B at a 1: 1 ratio to assess the safety of alemtuzumab + nab-pac-carbo + AC relative to tipleyluxuzumab and alemtuzumab + nab-pac + AC. No formal statistical comparisons were made to the primary security endpoints and the security analysis was descriptive. Therefore, no formal efficacy calculations are performed. The sample volume is considered sufficient to provide a descriptive safety analysis to assess the tolerability of alemtuzumab + nab-pac-car-AC relative to tirayleigh itumumab and alemtuzumab + nab-pac. The planned sample volumes allowed observation of adverse events with a true incidence of ≧ 10%, with acceptable probabilities in each treatment arm and the combination of both treatment arms (see table 66).

TABLE 66 opportunity to observe adverse events in view of true incidence

Safety assessments include the incidence, nature and severity of adverse events, protocol-specific vital signs, laboratory abnormalities and other protocol-specific tests deemed critical for safety assessment of the study. Adverse events were graded according to NCI CTCAE v 5.0.

Safety was assessed by aggregating adverse events, changes in laboratory test results, changes in vital signs, study treatment exposure and immunogenicity as measured by ADA and presented by the treatment arm.

The verbatim description of the adverse event maps to the MedDRA term.

Events occurring during treatment (defined as events occurring during or after the first dose of study treatment) are summarized in terms of MedDRA terminology, appropriate MedDRA levels, and NCI CTCAE v5.0 rating, regardless of the relationship to study drug as assessed by the investigator. For each patient, the reported maximum severity was used in the summary if the same adverse event occurred multiple times.

Adverse events occurred in the following treatments were individually summarized: adverse events leading to study drug withdrawal, adverse events leading to dose reduction or discontinuation, grade ≧ 3 adverse events, grade 5 adverse events, critical adverse events, and adverse events of particular concern.

All deaths and causes of death were summarized.

The relevant laboratory values are summarized by point in time and the NCI CTCAE level 3 and level 4 values are determined (as appropriate). Changes in NCI CTCAE grade are listed by treatment group.

Analysis of exposures, adverse events, laboratory data, and vital sign data

Safety was assessed by summarizing study treatment exposure, adverse events, changes in laboratory test results, and changes in vital signs and ECG.

Study treatment exposures (such as treatment duration, total dose received, and number of cycles and dose modifications) were summarized with descriptive statistics.

All verbatim adverse event terms are mapped to MedDRA thesaurus terms and the severity of adverse events is graded according to NCI CTCAE v 5.0. All adverse events, critical adverse events, adverse events leading to death, adverse events of particular concern, and adverse events leading to termination of study treatment (i.e., adverse events occurring during treatment) that occurred during or after administration of the first study treatment were summarized by mapped terminology, appropriate thesaurus levels, and severity level. For events of different severity, the highest ranking was used in the summary. Mortality and mortality were summarized.

Relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry and body temperature) and ECG data are displayed over time and rated where appropriate. In addition, the baseline and maximum post-baseline severity ratings were summarized using a transpose table of selected laboratory tests. Vital signs and changes in ECG are summarized.

Analysis of efficacy

Efficacy analysis an ITT method was used, in which any enrolled patients were included in the analysis, regardless of whether the patients received any assigned study medication, with patients in cohort B grouped in a 1: 1 ratio according to assigned treatment at randomization. Analysis based on subsets of the ITT population may also be performed. Unless otherwise stated, the test is assumed to be a two-sided test.

The exploratory therapeutic efficacy of cohort B was aimed at studying the efficacy of tirayleigh immuzumab and atuzumab + nab-pac-carbo-AC versus tirayleigh immuzumab and atuzumab + nab-pac-AC based on the following endpoints:

pCR, defined as the eradication of tumors from both the breast and lymph nodes (ypT 0/is ypN 0)

This therapeutic endpoint is established after neoadjuvant therapy and surgery is completed. Patients with a deletion pCR assessment were counted as not achieving pCR.

EFS, defined as the time from randomization to recording of disease recurrence, progression or death of any cause

Patients without events at the time of analysis were missed on the day they were last known to survive and without events.

Patients without post-baseline information were missed on the day of randomization.

OS, defined as the time from randomization to the day of death due to any cause

Patients that were not reported as dead at the time of analysis were missed on the last day they were known to survive. Patients without post-baseline information were missed on the day of randomization.

Pharmacokinetic analysis

Samples were collected for PK analysis and exposure in this study was compared to exposure obtained in previous studies. Serum concentrations of tirayleigh mab and atelizumab and plasma concentrations of nab-paclitaxel, carboplatin, doxorubicin, and cyclophosphamide were reported as individual values and summarized in treatment arms and cycles (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation) where appropriate and data allows.

Individual and median serum concentrations of securitylyumumab and atelizumab were plotted on treatment arms and days. The titrayleigh immuzumab and atezumab 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 data is warranted. Potential correlations of relevant PK parameters with dose, safety, efficacy, or biomarker outcome can be explored.

Immunogenicity assays

Immunogenicity analysis included patients undergoing any ADA assessment, grouped according to treatment received. The number and proportion of ADA positive and ADA negative patients appearing in treatment were summarized by treatment arm during both treatment and follow-up.

The relationship between ADA status and safety, efficacy and PK endpoint can be analyzed and reported by descriptive statistics.

Biomarker analysis

Although no formal statistical analysis of exploratory biomarkers was performed, the data can be analyzed in the context of this study and summarized as a population with the data of other studies.

Example 15A phase II, randomized, double-blind study on atelizumab plus gatriemeryluzumab and atelizumab plus placebo as first line therapy in patients with relapsed/metastatic PD-L1 positive squamous cell carcinoma of the head and neck

This example describes a phase II, randomized, double-blind, global study aimed at assessing efficacy and safety of attentizumab plus raleigh mab and attentizumab plus placebo as first-line (1L) treatments in recurrent/metastatic PD-L1 positive squamous cells of head and neck cancer (SCCHN). The study consisted of the following arms:

An arm A: the patient received atelizumab at a fixed dose of 1200mg every 3 weeks (Q3W) by IV infusion on day 1 of each 21 day cycle, followed by tirayleigh mab administered to the patient at a fixed dose of 600mg by IV infusion Q3W on day 1 of each 21 day cycle.

And (B) arm: patients received atelizumab at a fixed dose of 1200mg administered by IV infusion of Q3W on day 1 of each 21 day cycle, followed by placebo administered by IV infusion of Q3W on day 1 of each 21 day cycle.

A. Design of research

This phase II, randomized, double-blind, global study was aimed at assessing the efficacy and safety of attentizumab plus rayleigh immuzumab and attentizumab plus placebo as 1L treatments in recurrent/metastatic PD-L1 positive SCCHN. Eligible patients include male and female patients with an age of 18 or more, an Eastern Cooperative Oncology Group (ECOG) physical performance status of 0 or 1, with recurrent disease and/or metastatic PD-L1 positive SCCHN (tumor-associated immune cells (TIC) > 5%) that are not amenable to local therapy for curative purposes, and who have not received prior systemic therapy for recurrent/metastatic disease.

During screening, tumor specimens from each potentially eligible patient were prospectively tested by the central laboratory using a research VENTANA PD-L1 (SP 263) companion diagnostic (CDx) assay to understand PD-L1 expression. Only patients positive for PD-L1 with a TIC > 5% assessed in a central manner were eligible. PD-L1 expression is defined as PD-L1 low with TIC of 5% -19% and PD-L1 high with TIC ≧ 20%.

Eligible patients were stratified by Human Papillomavirus (HPV) status of oropharyngeal cancer (HPV positive oropharyngeal cancer: yes or no) and PD-L1 status (PD-L1: low and high). The upper limit of population for each PD-L1 subgroup (PD-L1 low [ TIC 5% -19% ] and PD-L1 high [ TIC ≧ 20% ]) is about 55% (i.e., about 66 patients) of the planned total population to be enrolled.

Eligible patients were randomized at a 2: 1 ratio to receive either atuzumab plus rayleigh immuzumab (a arm) or atuzumab plus placebo (B arm):

an arm A: the patient received atelizumab at a fixed dose of 1200mg every 3 weeks (Q3W) by IV infusion on day 1 of each 21 day cycle, followed by tirayleigh mab administered to the patient at a fixed dose of 600mg by IV infusion Q3W on day 1 of each 21 day cycle.

And a B arm: patients received atelizumab at a fixed dose of 1200mg administered by IV infusion of Q3W on day 1 of each 21 day cycle, followed by placebo administered by IV infusion of Q3W on day 1 of each 21 day cycle.

Patients were assessed for tumors at baseline, every 6 weeks (+ -7 days) within the first 30 weeks after 1 day of week 1, and every 9 weeks (+ -7 days) after completion of the 30 week tumor assessment. Tumor assessment, whether or not treatment is delayed, continues as planned until patients who continue study treatment following imaging disease progression according to RECIST v1.1 or imaging disease progression according to RECIST v1.1 lose clinical benefit, withdraw consent, die or sponsor termination of the study, whichever occurs first. At the discretion of the investigator, if disease progression or loss of clinical benefit is suspected, the scan must be performed at any time.

Patients who terminated study treatment in the absence of imaging disease progression according to RECIST v1.1 (for any reason including but not limited to clinical decline or toxicity) continued to conduct planned tumor assessments at the above-described frequency until imaging disease progression according to RECIST v1.1, withdrawal consent, death or sponsor termination of the study, whichever occurred first. In the absence of imaging disease progression according to RECIST v1.1, no tumor assessment should be continued regardless of whether the patient started a new anti-cancer therapy. The investigators determined objective remission at a single time point according to RECIST v 1.1.

Serum samples were collected to monitor atuzumab and tiryleigh immuzumab PK and to detect the presence of antibodies to atuzumab and tiryleigh immuzumab. Patient samples, including archived and fresh tumor tissue, plasma, and blood samples, were collected for exploratory biomarker assessment.

Safety assessments include the incidence, nature and severity of adverse events, as well as other protocol-specific tests, such as laboratory abnormalities, which are considered critical to the safety assessment of the study.

After study treatment was terminated, survival follow-up information was collected approximately every 3 months by telephone, patient medical records and/or clinic visits until death, missed visits or the sponsor ended the study, whichever occurred first. Unless patients require exit from survival follow-up (this requirement must be recorded in the source file and signed by the researcher), all patients should be contacted regularly for survival and new anti-cancer therapy information. If the patient exits the life cycle follow-up, the research staff may use a common information source (e.g., a family record) to obtain information about the survival status.

Treatment can continue as long as the patient is experiencing clinical benefit as assessed by the investigator, with no unacceptable toxicity or worsening of symptoms due to disease progression after a combined assessment of imaging data, biopsy results (if available), and clinical status. Patients who met the criteria for disease progression according to RECIST v1.1 but continued local clinical benefit were allowed to continue treatment if they met all the outlined criteria and provided written consent (alemtuzumab plus rayleigh plus avauzumab or alemtuzumab plus placebo).

B. Administration and administration

The treatment protocol is summarized in figure 23.

Abiralizumab

All patients received 1200mg of atlizumab administered by IV infusion on day 1 of each 21-day cycle. The dose of alemtuzumab is fixed and independent of body weight. The alemtuzumab infusions were administered according to the instructions summarized in table 67.

TABLE 67 administration of the first and subsequent Abuzumab infusions

Tirayleigh immuzumab and placebo

Following the alemtuzumab administration and observation period (see table 67), patients received 600mg of tirayleigh eculizumab/placebo administered by IV infusion on day 1 of each 21-day cycle. The tirayleigh mab/placebo dose was fixed and independent of body weight. The tegralyleitumumab/placebo infusion was administered according to the instructions outlined in table 68.

TABLE 68 administration of the first and subsequent ibritumomab tiuxetan/placebo infusions

Astuzumab and tiryleigh Eusumab/placebo

As long as neither alemtuzumab nor ibritumumab/placebo was permanently terminated, the following rules apply:

normally, the treatment cycle begins with the administration of atuzumab and ibritumumab tiuxetan/placebo on day 1 of each 21-day cycle. If any study drug is delayed due to drug-related toxicity, it is recommended that another study drug is also delayed because the safety of atlizumab and tenecteuzumab are similar; however, if the investigator deems appropriate, a cycle may begin with administration of the other study drug.

In the case where one study drug is administered with a delay due to drug-related toxicity, but the other study drug is administered on a schedule, it is recommended that the delayed study drug be administered at the time of the next intra-schedule infusion (i.e., in the next intra-schedule 21-day period).

Dose adjustment

In this study, atelizumab or tegraleigh immuzumab/placebo had no dose adjustments, including dose reductions.

C. Concomitant therapy

Concomitant therapy includes patients using any medication other than the regimen prescribed treatment (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplements) from 7 days prior to initiation of study treatment to the treatment termination visit.

Allowed therapy

Patients were allowed the following therapies during the study:

oral contraceptives with annual failure rate < 1%

Hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or low molecular weight heparin)

Inactivated influenza vaccine

Administration of megestrol acetate as an appetite stimulant

Mineralocorticoids (e.g., fludrocortisone)

Administration of inhaled or low dose corticosteroids for COPD or asthma

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

in patients who do not have imaging disease progression records according to RECIST v1.1, it is strongly recommended to maximize supportive care for symptomatic management and avoid radiotherapy that interferes with tumor target lesion assessment.

Treatment with atelizumab and tegralyleitumumab/placebo can continue during palliative radiotherapy.

Prophylactic administration of antihistamines, antipyretics and/or analgesics may only be administered for the second and subsequent atuzumab and tegralyleitumumab/placebo infusions as appropriate by the investigator.

Generally, according to local care practices, researchers should manage the care (including previous conditions) of patients using supportive therapies rather than therapies defined as prudent or forbidden therapies based on clinical indications. Patients presenting with infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalents of local standard practice. Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and should be managed with supportive care (e.g., supplemental oxygen and β 2 adrenergic agonists) according to clinical indications.

Warning therapy

Systemic corticosteroids and TNF- α inhibitors may attenuate the potentially beneficial immune effects of treatment with atelizumab and/or tenecteuzumab. Thus, where systemic corticosteroids or TNF- α inhibitors are routinely administered, alternatives are contemplated, including antihistamines. If alternatives are not feasible, the systemic corticosteroid and TNF- α inhibitor can be administered at the discretion of the investigator.

Systemic corticosteroids are recommended, as appropriate by the investigator, to treat specific adverse events associated with atelizumab and/or tenecteuzumab.

Treatment inhibition

The following concomitant therapies were prohibited, as follows:

the use of concomitant therapies aimed at treating cancer (including but not limited to surgery, chemotherapy, hormone therapy, immunotherapy, radiotherapy and herbal therapy), whether approved or experimental by the health authorities, is prohibited for different periods of time (depending on the agent) before the study treatment is started and during the study treatment, until disease progression is recorded and the patient has terminated the study treatment, with the exception of palliative radiotherapy and limited therapy in certain circumstances.

The study therapy was prohibited for 28 days before initiation of study treatment and during study treatment.

Prohibition of live attenuated vaccine use (e.g., within 4 weeks prior to initiation of study treatment, during study treatment, within 5 months after last attrituzumab and within 90 days after last tirayleigh uzumab/placebo administration

)。

The use of systemic immune stimulants (including but not limited to interferon and IL-2) was banned within 4 weeks or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment, as these drugs may increase the risk of developing autoimmune disease when given in combination with study treatment.

The use of systemic immunosuppressive drugs (including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide) is prohibited during study treatment because these drugs may alter the efficacy and safety of study treatment.

D. Inclusion criteria

Patients must meet the following conditions to enter the study:

sign informed consent

The age at which the informed consent was signed was 18 years old or older

Ability to comply with the study protocol

Histologically or cytologically confirmed recurrent/metastatic SCCHN affecting the oropharynx, oral cavity, larynx or hypopharynx, which was not curable using local therapy

Patients with tumors of any histology at the primary site of the nasopharynx or parotid gland are ineligible.

Known results of oropharyngeal cancer HPV status tests, as determined locally by p16 Immunohistochemistry (IHC), in situ hybridization or polymerase chain based assays

Remarking: HPV testing for oral, laryngeal and hypopharyngeal cancers is not required.

Absence of prior systemic therapy for metastatic and/or recurrent SCCHN

Patients who received systemic therapy as part of a multimodal treatment (e.g., concurrent chemoradiotherapy) for locally advanced disease and whose last administration of systemic therapy was > 6 months prior to randomization were allowed.

Measurable disease as determined by RECIST v1.1

Only if the site clearly records disease progression after irradiation can the previously irradiated lesion be considered a measurable disease.

TIC ≧ 5% tumor PD-L1 expression, as determined by the investigational VENTANA PD-L1 (SP 263) CDx assay and documented by central testing of previously obtained archived tumor tissues or representative tumor tissue targets from biopsies at the time of pre-screening/screening. After approximately 66 patients (55% of the total planned cohort) were enrolled in the PD-L1 subgroup (PD-L1 low (TIC 5% -19%) and PD-L1 high (TIC ≧ 20%)), the other patients in this PD-L1 subgroup were not enrolled.

The availability of representative tumor specimens in formalin-fixed paraffin-embedded (FFPE) blocks (preferred) or at least 20 slides containing unstained, freshly cut serial sections and associated pathology reports were confirmed. If only 15 to 19 slides are available, the patient may still be eligible for the study after confirmation by the medical supervisor.

If archival tumor tissue is not available or is determined to be unsuitable for the required testing, the tumor tissue must be obtained from a biopsy taken at the time of pre-screening/screening. A biopsy may also be performed at the time of pre-screening/screening if the patient's archived tissue test results do not meet eligibility criteria.

ECOG physical Performance status of 0 or 1

Expected life ≥ 12 weeks

Sufficient blood and end organ function, defined by the following laboratory test results obtained within 14 days before randomization:

-an ANC ≥ 1.5X 109/L (1500/. Mu.L) with support of granulocyte-free colony stimulating factor

Lymphocyte count ≥ 0.5X 109/L (500/μ L)

In the case of no blood transfusion, the platelet count is > 100X 109/L (100,000/. Mu.L)

Hemoglobin ≥ 90g/L (9 g/dL)

Depending on the local SOC, the patient may need to be transfused or receive erythropoiesis treatment to meet this criterion.

AST, ALT and alkaline phosphatase (ALP). Ltoreq.2.5 Xthe Upper Limit of Normal (ULN), with the following exceptions:

patients with liver metastases were recorded: AST and ALT ≤ 5 × ULN

Patients with liver or bone metastases recorded: ALP ≤ 5 × ULN

-total bilirubin ≦ 1.5 × ULN, with the following exceptions:

patients with known gilbert disease: total bilirubin is less than or equal to 3 × ULN

-creatinine ≤ 1.5 × ULN

Albumin ≥ 25g/L (2.5 g/dL)

-for a patient not receiving therapeutic anticoagulation: INR and aPTT. Ltoreq.1.5 × ULN

For patients receiving therapeutic anticoagulation: stabilized anticoagulant

HIV test negative at screening

Negative in the hepatitis B surface antigen (HBsAg) test at screening

Hepatitis B surface antibody (HBsAb) test positive at screening, or HBsAb test negative at screening with either:

total hepatitis B core antibody (HBcAb) negative

Positive in total HBcAb test, followed by quantitative Hepatitis B Virus (HBV) DNA < 500IU/mL

HBV DNA testing must be performed on patients who are negative for the HBsAg test, negative for the HBsAb test, and positive for the total HBcAb test.

Hepatitis C Virus (HCV) antibody test negative at screening; or positive for HCV antibody test and negative for HCV RNA test when screened

Patients who have to test positive for HCV antibodies have to be tested for HCV RNA.

For fertile women: consent to maintain abstinence (avoidance of sexual intercourse) or use of contraceptive measures, as defined below:

women must maintain a contraceptive regimen with a abstinence or annual failure rate < 1% during the treatment period and within 5 months after the last attuzumab dose and within 90 days after the last tiyleigh ewuzumab/placebo dose.

A woman is considered to have fertility potential if after menarche, the woman does not reach a postmenopausal state (continuous > 12 months of amenorrhea, no established cause other than menopause) and is not permanently infertile by surgery (i.e. removal of ovaries, oviducts and/or uterus) or other causes established by investigators (e.g. mullerian tube hypoplasia). The definition of fertility potential may be adjusted according to local guidelines or regulations.

Examples of contraceptive methods with annual failure rates of < 1% include bilateral tubal ligation, male sterilization, hormonal contraceptives to inhibit ovulation, hormone releasing intrauterine devices and copper intrauterine devices.

The reliability of sexual desire should be assessed according to the duration of the clinical trial and the patient's preference and usual lifestyle. Regular abstinence (e.g. calendar, ovulation, symptomatic body temperature contraception or post-ovulation procedures) and withdrawal are inadequate contraceptive methods. If local guidelines or regulations require it, locally recognized appropriate methods of contraception and information regarding the reliability of abstinence are set forth in local informed consent.

For males: consent to maintain abstinence (avoid sexual intercourse) or use of condoms, and consent to not donate sperm, is defined as follows:

along with female partners with fertility or pregnant female partners, men must remain abstinent or use condoms during treatment with tirayleigh immuzumab/placebo and within 90 days after the last administration of tirayleigh immuzumab/placebo to avoid exposure to embryos. During this same period, the male must avoid donation of sperm.

The reliability of sexual desire should be assessed according to the duration of the clinical trial and the patient's preference and usual lifestyle. Regular abstinence (e.g., calendar, ovulation, symptomatic body temperature contraception or post-ovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If local guidelines or regulations require, information regarding the reliability of abstinence is set forth in local informed consent forms.

E. Exclusion criteria

Patients who met any of the following criteria were excluded from the study:

diseases suitable for topical therapy with curative intent

Progression or recurrent disease within 6 months after the last dose of the cure intent systemic treatment for locally advanced SCCHN

Grade 2 non-resolved toxicity associated with surgery or its previous therapy

Patients with grade 2 or less hair loss or neuropathy are allowed.

Patients who undergo major surgery must have recovered adequately, including from any complications associated with the intervention.

Patients who, after consultation with a medical supervisor, have irreversible toxicity that is manageable and not expected to be exacerbated by study medication.

Symptomatic, untreated, or actively progressing Central Nervous System (CNS) metastasis

Asymptomatic patients with treated CNS lesions are eligible provided that all of the following criteria are met:

measurable disease determined according to RECIST v1.1 must be present outside the CNS.

Patient history of no intracranial bleeding or spinal cord bleeding.

Patients were not treated with stereotactic radiotherapy within 7 days before randomization, with whole brain radiotherapy within 14 days before randomization, or with neurosurgical resection within 28 days before randomization.

Patients do not have a constant need for corticosteroids as a therapy for CNS diseases. Allowing the use of stable doses of anticonvulsant therapy.

History of leptomeningeal disease

Uncontrolled tumor-related pain

Patients requiring analgesics must adopt a stable treatment regimen at the time of study entry.

Symptomatic lesions (e.g., bone metastases or metastases causing nerve touch) suitable after palliative radiation therapy should be treated prior to enrollment.

The patient should have recovered from the effects of radiation therapy. A minimum recovery period is not required.

In further increasing cases asymptomatic metastatic lesions that may lead to functional defects or intractable pain (e.g. epidural metastasis that is currently not associated with spinal cord compression), regional treatment should be considered (if appropriate) prior to enrollment.

Uncontrolled or symptomatic hypercalcemia

Autoimmune diseases or immunodeficiency active phases or history, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, wegener's granulomatosis, sjogren's syndrome, guillain-barre syndrome, or multiple sclerosis, with the following exceptions:

Patients with a history of autoimmune-related hypothyroidism and who are receiving stable doses of thyroid-substituting hormone were eligible for the study.

Patients with type 1 diabetes and undergoing an insulin regimen were eligible for this study.

Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with only dermatological manifestations (e.g., excluding psoriatic arthritis patients) are eligible for

Qualification of the study:

the rash must cover < 10% of the body surface area

Disease is well controlled at baseline and only low-potency topical corticosteroids need to be used

Acute exacerbation of the underlying condition requiring psoralen plus ultraviolet a radiation, methotrexate, retinoids, biologicals, oral calcineurin inhibitors or high potency or oral corticosteroids does not occur within the last 12 months

Evidence of idiopathic pulmonary fibrosis, organized pneumonia (e.g., bronchiolitis obliterans), drug-induced pulmonary inflammation, or idiopathic pulmonary inflammation, or the presence of active pulmonary inflammation found in a chest Computed Tomography (CT) scan

A history of radiation pneumonitis (fibrosis) in the radiation field was allowed.

Active tuberculosis

Significant cardiovascular disease (such as New York Heart Association grade II or higher heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable angina pectoris within 3 months prior to initiation of study treatment

Major surgery other than for diagnosis has been performed within 4 weeks before initiation of study treatment or is planned or predicted to be required during the study

In the first 5 years before randomization, there is an additional history of malignancy beyond SCCHN, except for malignancies with negligible risk of metastasis or death (e.g., 5 year OS rate > 90%), such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer

Severe infection occurred within 4 weeks before initiation of study treatment, including, but not limited to, hospitalization due to complications of infection, bacteremia, or severe pneumonia

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment

Patients receiving prophylactic antibiotics (e.g., for preventing urinary tract infection or exacerbation of chronic obstructive pulmonary disease) are eligible for this study.

Previous allogeneic stem cell or solid organ transplantation

Any other disease, metabolic dysfunction, physical examination findings or clinical laboratory findings that prohibit the use of research drugs, may affect the interpretation of the results or may place the patient at high risk for treatment complications

Treatment with live attenuated vaccine within 4 weeks prior to initiation of study treatment, or such vaccine is expected to be required during study treatment, within 5 months after the last attrituzumab or within 90 days after the last tirayleigh ugaumab/placebo administration.

Current treatment with antiviral therapies against HBV or HCV

Positive Epstein-Barr Virus Capsid Antigen (VCA) IgM test at screening

EBV Polymerase Chain Reaction (PCR) tests should be performed to screen for acute infections or suspected chronic active infections according to clinical indications. Patients positive for the EBV PCR test were excluded.

Treatment with investigational therapy within 28 days before initiation of study treatment

Previous treatments with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-TIGIT, anti-PD-L1 and anti-PD-1 therapeutic antibodies

Treatment with a systemic immunostimulant (including, but not limited to, interferon and interleukin 2, [ IL-2 ]) within 4 weeks or within 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment

Treatment with systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or the need for systemic immunosuppressive drugs during study treatment is anticipated, with the following exceptions:

Patients receiving acute, low dose systemic immunosuppressant administration or one-time pulsed dose systemic immunosuppressant administration (e.g., 48 hours corticosteroid for contrast agent allergy) are eligible for the study after medical supervisor confirmation.

Patients receiving mineralocorticoids (e.g. fludrocortisone), inhaled or low dose corticosteroids for chronic obstructive pulmonary disease or asthma or low dose corticosteroids for the treatment of orthostatic hypotension or adrenal insufficiency are eligible for this study.

History of Severe allergic reactions to chimeric or humanized antibodies or fusion proteins

Known to be allergic to Chinese hamster ovary cell products or to any component of the attrituximab or tenecteuzumab preparation

Pregnancy or lactation, or pregnancy planned during the study, within 5 months of the last dose of atuzumab or within 90 days after the last dose of tirayleigh umab/placebo.

A female with fertility must be negative for serum pregnancy test results within 14 days before study treatment initiation.

F. Evaluation of

Patient safety and tolerability were closely monitored throughout the study. The patients were assessed for toxicity prior to each dose; dosing was only performed when clinical assessments and local laboratory test values were 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 history of alcohol and drug abuse, was recorded at baseline. In addition, all medications (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplements) used by the patient within 7 days prior to the start of study treatment were recorded. At each follow-up physical examination, a history of the intervallic disease was obtained and any changes in medication and allergy were recorded.

Demographic data include age, gender, and self-reported race/ethnicity.

ECOG physical fitness status

The performance status is measured using the ECOG performance status gauge.

Physical examination

A thorough physical examination must be performed at screening and should include assessment of the head, eyes, ears, nose and throat, as well as cardiovascular, skin, musculoskeletal, respiratory, gastrointestinal, urogenital and nervous systems. Any abnormalities identified at baseline should be noted.

A limited, symptom-directed physical examination should be performed at a specific post-baseline visit and clinical indication. Abnormalities in changes from baseline should be recorded in the patient's notes. New or worsening clinically significant abnormalities should be recorded as adverse events.

Physical examination

Vital signs include measures of respiratory rate, pulse rate, systolic and diastolic blood pressure, and body temperature. Abnormalities observed at baseline and new or worsening clinically significant abnormalities in subsequent visits were recorded.

Tumor and response assessment

Screening assessments and subsequent tumor assessments must include CT scans of the chest and abdomen (oral or IV contrast) and head and neck (cranial base to clavicle) or Magnetic Resonance Imaging (MRI) (using contrast agents). CT scans with contrast agents should be performed on the pelvis either according to clinical indications or to local SOC at screening and subsequent response assessment. If there is contraindication for contrast agent CT scans (e.g. patients with impaired renal clearance function), a chest non-contrast agent CT scan should be performed and MRI scans using contrast agents must be performed on the craniocerebral, abdominal and pelvic regions (if applicable). If there is a clinical indication at baseline and subsequent response assessment, further studies, such as bone scans, should be performed.

CT scans with contrast agents or MRI scans with contrast agents (if CT with contrast agents is contraindicated) should be performed on the brain according to clinical indications to assess CNS metastases in screening and subsequent response assessment. If a CT scan using a contrast agent is performed and the presence of brain metastases is not considered clear, an MRI scan of the head is required to confirm or deny the diagnosis of CNS metastases at baseline. Patients with active or untreated CNS metastases did not meet the conditions of the study. Patients with a history of irradiated brain metastases at screening do not need to undergo a brain scan in subsequent response assessments unless clinically indicated.

If a CT scan for tumor assessment is performed in a Positron Emission Tomography (PET)/CT scanner, a CT acquisition must be performed to meet the criteria of a full contrast diagnostic CT scan.

Tumor assessments performed as SOC before informed consent was obtained can be used, rather than repeated tests, provided that the scans were of diagnostic quality and performed within 28 days after randomization.

All subsequent tumor assessments must use the same imaging modality (e.g., CT scan with contrast agent) and procedure (e.g., the same CT scan contrast protocol) used in the screening. All known disease sites, including measurable and/or unmeasurable disease, must be recorded at screening and re-assessed at each subsequent tumor assessment.

Patients were evaluated for tumors at baseline, every 6 weeks (+ -7 days) within the first 30 weeks after day 1 at week 1, and every 9 weeks (+ -7 days) after completion of tumor evaluation at week 30. Tumor assessment, whether or not treatment is delayed, continues as planned until patients who continue study treatment following imaging disease progression according to RECIST v1.1 or imaging disease progression according to RECIST v1.1 lose clinical benefit, withdraw consent, die or sponsor termination of the study, whichever occurs first. At the discretion of the investigator, the scan must also be performed at any time if disease progression or loss of clinical benefit is suspected.

Patients who terminated study treatment in the absence of imaging disease progression according to RECIST v.1.1 (for any reason, including but not limited to clinical regression or toxicity) continued to be assessed for tumor response according to the above schedule, regardless of whether new anti-cancer therapies were initiated. Tumor assessment was continued until either imaging disease progression according to RECIST v1.1, withdrawal of consent, death, or host termination of the study, whichever occurred first. Responses were assessed by investigators using RECIST v1.1 based on the imaging mode described above. The investigator's assessment of overall tumor response at all time points should be based on RECIST v1.1 only. If possible, the evaluation should be performed by the same evaluator to ensure internal consistency of visits.

The investigator's assessment of overall tumor response at all time points was based only on RECIST v1.1. For patients to continue to receive study treatment after progression, tumor assessment must continue after disease progression according to RECIST v1.1. This includes continuous measurement of target lesions, assessment of non-target lesions, and assessment of any newly identified lesions in all subsequent assessments.

Laboratory, biomarker and other biological samples

Samples for the following laboratory tests were sent to the local laboratory at the research site for analysis:

hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes)

Chemical composition (serum or plasma): bicarbonate or total carbon dioxide (if considered to be SOC in the region), sodium, potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST and LDH

Coagulation: INR and aPTT

Thyroid function test: thyroid stimulating hormone, free triiodothyronine (T3) (or total T3 at sites not subject to free T3), and free thyroxine (also known as T4)

EBV serology, including the following

οEBV VCA IgM

Omicron EBV VCA IgG or Epstein-Barr Virus Nuclear antigen (EBNA) IgG

Omicron if clinically indicated: EBV PCR

Serology of HIV

HBV serology, consisting of:

all patients' HBsAg, HBsAb and Total HBcAb

HBV DNA of patients who are negative for HBsAg and HBsAb tests and positive for total HBcAb

Patients positive for quantitative HBV DNA at screening time (must be < 500IU/mL according to eligibility criteria) were subjected to additional HBV DNA tests as outlined in the activity schedule.

HCV serology: HCV antibodies and (if HCV antibodies test positive) HCV RNA

For patients with SCCHN affecting the oropharynx: determination of HPV status of tumor tissue by p16 IHC, in situ hybridization or PCR-based assays

Pregnancy test

All fertile women were tested for serum pregnancy at screening. Urine pregnancy tests were performed on day 1 of each cycle during study treatment. Urine pregnancy tests were also performed at treatment termination visits. If the urine pregnancy test is positive, it must be confirmed by the serum pregnancy test.

A woman is considered to have fertility potential if, after menarche, the woman does not reach a postmenopausal state (continuous > 12 months of amenorrhea, no established cause other than menopause) and is not permanently infertile by surgery (i.e. removal of ovaries, oviducts and/or uterus) or other causes established by investigators (e.g. Mullerian tube hypoplasia).

Urinalysis (including pH, specific gravity, glucose, proteins, ketones, and blood); test strip allows

The following samples were sent to one or several central laboratories or sponsors or designers for analysis:

serum samples for analysis of autoantibodies: antinuclear antibodies, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibodies and perinuclear anti-neutrophil cytoplasmic antibodies

Serum samples for C-reactive proteins

Serum samples for PK analysis of atelizumab and tiryleigh itumumab by using validated assays

Serum samples for evaluation of ADA of atelizumab and tiryleiguzumab by using validated assays

Blood and plasma samples for exploratory studies of biomarkers

Blood samples can be processed to obtain Peripheral Blood Mononuclear Cells (PBMCs) and other derivatives (e.g., RNA, DNA, etc.).

Freshly collected tumor tissue samples, archived or obtained at baseline, for determining PD-L1 expression and for exploratory studies of biomarkers

Prior to study enrollment, representative FFPE tumor specimens in paraffin blocks (preferred) or at least 20 slides containing unstained, newly cut serial sections must be submitted along with the relevant pathology report. If only 15 to 19 slides are available, the patient may still be eligible for the study after approval by the medical supervisor.

Based on the total and viable tumor content, the tumor tissue should be of good quality.

The sample must contain a minimum of 50 viable TCs, regardless of the needle gauge or retrieval method, which cells can retain cellular environment and tissue architecture.

Samples collected by resection, core needle biopsy (preferably at least three cores, embedded in a single paraffin block) or resection, incision, punch or jaw biopsy are acceptable. Fine needle aspiration (defined as a sample that does not retain tissue architecture and produces a cell suspension and/or smear), brushing, cell precipitation from pleural effusion, and lavage of the sample are unacceptable. Tumor tissue from bone metastases that have been decalcified is unacceptable.

If archival tumor tissue is not available or is determined to be unsuitable for the required testing, a pre-treatment tumor biopsy is required. A pre-treatment tumor biopsy may also be performed if the patient's archived tissue test results do not meet the eligibility criteria.

Tumor tissue samples obtained at progression, if deemed clinically feasible, for exploratory studies of biomarkers

Biopsies at progression should be performed within 40 days after progression or before the next anticancer therapy, whichever is earlier.

Preferably a sample collected by resection, core needle biopsy (preferably at least three cores) or resection, incision, punch or jaw biopsy.

NGS may be performed by Foundation Medicine. If done by Foundation Medicine, researchers can obtain NGS reports through the Foundation Medicine's web portal. The researcher may share and discuss the results with the patient, unless the patient chooses otherwise, if permitted by local laws. NGS reports are generated for research purposes and are not provided to guide future treatment decisions. Samples that do not meet the test criteria fail to obtain results.

Exploratory biomarker studies may include, but are not limited to, analysis of tumor gene alterations, HPV states or genetic signatures associated with tumor immunobiology, PD-L1, TIGIT, lymphocyte subpopulations and T cell receptor repertoires. The study may involve extraction of DNA, cell-free DNA or RNA; analyzing mutations and other tumor-specific genomic variations; and performing genomic analysis by using genome-wide NGS. DNA extracted from blood can be compared to DNA extracted from tissue to identify somatic variants 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 at the participating sites.

For sampling procedures, storage conditions and shipping instructions, see the laboratory manual.

Unless the patient expressly agrees to save their remaining samples for optional exploratory studies, the biological samples will be destroyed before the final clinical study report is completed, except for:

collection of serum samples for PK or immunogenicity analysis may be required for additional immunogenicity characterization and for development and validation of PK or immunogenicity assay development; therefore, these samples will be destroyed within 5 years after the final clinical study report is completed.

Blood, plasma and PBMC samples collected for biomarker studies will be destroyed within 5 years after the final clinical study report is completed, except for WGS or WES-passed tissue samples, which will be stored until they are no longer needed or until they are used up. However, the storage period is in accordance with the informed consent and applicable law approved by IRB/EC (e.g., requirements of health authorities).

For patients enrolled, the remaining archived tissue blocks should be returned to the site on demand or no later than 18 months after the final clinical study report, first-come. For patients who are not enrolled, the remaining archived tissue blocks will be returned to the site no later than 6 weeks after eligibility is determined.

When the patient exits the study, the sample collected prior to the date of exit may still be analyzed unless the patient specifically requires the destruction of the sample or local laws require the destruction of the sample. However, if the sample has been tested prior to withdrawal, the results of these tests will still be part of the overall study data.

In view of the complexity and exploratory nature of exploratory biomarker analyses, data from these analyses is not typically provided to researchers or patients unless required by law (except for reports from Foundation Medicin, which only apply to biopsies obtained as the disease progresses). Summary results for any performed studies may be obtained according to effective research data distribution sponsor policies.

Electrocardiogram

ECG was required at screening and when clinical indications were available at other time points during the study. The ECG for each patient should be acquired from the same machine as much as possible. Lead placement should be as consistent as possible. ECG recordings must be made after the patient has rested in the supine position for at least 10 minutes.

For safety monitoring purposes, researchers must review, sign all ECG tracings and date. A copy of the ECG tracing is saved at the site as part of the patient's permanent study file. Any morphological waveform changes or other ECG abnormalities must be recorded on the eCRF.

Assessment of clinical results

The PRO questionnaire has been completed to more fully characterize the clinical characteristics of atuzumab plus rayleigh eculizumab and atuzumab plus placebo. In addition, the PRO questionnaire was able to capture the direct experience of atuzumab plus rayleigh immuzumab and atuzumab plus placebo for each patient.

PRO data were collected by using the following questionnaire:

·

project library v 2.0-physical function-short table 10b

·

Project library v 1.0-fatigue-short table 4a

·

Project library v 1.1-pain interference-short Table 4a

·

Number Scale v 1.0-pain intensity 1a

Patient global impression of severity (PGI-S)

Patient global impression of changes and their importance (PGI-CI)

The Most Important Symptom (MIS)

·PRO-CTCAE

PRO questionnaire (i.e. the

PGI-S/PGI-CI, MIS and PRO-CTCAE) during treatment and at treatment termination visit.

Data collection method for clinical outcome assessment

The PRO questionnaire used to characterize the clinical characteristics of alemtuzumab plus rayleigh eculizumab and alemtuzumab plus placebo was administered by self-administration or by an outpatient investigator (if appropriate) at specific time points during the study. By using

PRO data obtained from the PGI-S/PGI-CI, MIS and PRO-CTCAE questionnaires.

These questionnaires are administered at the clinic, unless otherwise indicated, before the patient receives any information about the disease state, before a non-PRO assessment is performed, and before study treatment is performed.

The paper PRO questionnaire (translated into local language, if appropriate) is scheduled to be conducted during an outpatient visit and must be completed by the patient at the beginning of the clinical visit at the study site prior to other study assessments and prior to study treatment administration to avoid as much as possible any assessment bias. The patient completes a paper version of the questionnaire provided by the field staff. Investigator assessments are allowed to be performed, but only by outpatient staff on patients who cannot perform the measurements themselves.

The investigator should check the integrity of all questionnaires before the patient leaves the study site.

During an outpatient visit, the PRO questionnaire should be administered as follows:

the patient's health should not be discussed prior to administration of the questionnaire.

Sites must administer formal versions of each questionnaire that the host provides. The questionnaire must not be copied from the protocol.

The site should allow enough time for the patient to complete the questionnaire, which is expected to be 15 minutes on day 1 of cycle 1 and 2, with each subsequent cycle being less than 10 minutes.

Sites should be applied in quiet areas, minimizing disruption and interruptions.

The patient should be instructed to answer the question to the best of his or her best ability; there is no correct or incorrect answer.

Site workers should not interpret or explain the questions, but may be asked to read the questions verbatim.

The patient should not obtain suggestions or help from others (e.g., family or friends) when completing the questionnaire.

The site staff should check all completed questionnaires and should ask the patient to correct any responses that are not explicitly marked in place. If the response is missing, the site staff should ask the patient to fill out the project or confirm that the project is deliberately empty.

Description of clinical results assessment questionnaire

Project library v 2.0-body function-short table 10b

Project library v 2.0-physical Performance-short Table 10b consists of 10 questions aimed at measuring self-reported physical performance, including upper limb (dexterity), lower limb (walking or activity), and central region (neck, back) functions, as well as instrumental daily activitiesAnd (6) moving. All questions were scored on a scale of 1 to 5, with 5 representing the highest functional capacity of the patient and 1 representing the lowest functional capacity of the patient. The recall period was 7 days.

Project library v 1.0-fatigue-short table 4a

Project library v 1.0-fatigue-short table 4a consists of four projects aimed at evaluating a series of self-reported fatigue symptoms and the ability of patients to perform daily activities. The items in the questionnaire ask the patient the level of fatigue experienced within the last seven days. These items are scored on a scale of 1 to 5, with 5 points representing the highest level of fatigue experienced by the patient and 1 point representing the lowest level of fatigue experienced by the patient. The recall period was 7 days.

Project library v 1.1-pain interference-short table 4a

The project library v 1.1-pain disturbance-short table-4 a consists of questions on four self-reported scales aimed at assessing the consequences/disturbances of pain on relevant aspects of a patient's life. All questions were scored on a 1 to 5 point scale, with 5 points representing the highest level of pain disturbance and 1 point representing the lowest level of pain disturbance experienced by the patient. The recall period was 7 days.

Number rating scale v 1.0-pain intensity 1a

Numerical rating Scale v 1.0-pain intensity 1a by a self-reported quantityThe questions on the table are composed to assess the average pain level of the patients.

The problem is scored on a scale of 1 to 10, with 10 being equivalent to "the most severe pain imaginable" and 1 being equivalent to "no pain". The recall period was 7 days.

Patient global impression of severity (PGI-S)

Patient global impression of severity (PGI-S) is a self-reported single measure used to assess the patient' S impression of the severity of their overall condition over the past 7 days. PGI-S uses a 5-point response scale, where a score of 5 indicates "very severe" and a score of 1 indicates "none" (adapted from Guy et al 1976).

Patient global impression of changes and their importance (PGI-CI)

The overall impression of change by the patient is a self-reported single measurement used to assess the patient's impression of a change in their condition compared to when the study was initiated. It uses a 7-point response scale where a score of 7 indicates "very poor" and a score of 1 indicates "very much improved" (adapted from Guy et al 1976). In the follow-up questions of the patient's overall impression of changes, the patient is asked to state whether the changes experienced are important to them, if so, the response option is "yes", and if the patient has not experienced any changes, the response option is "no" or "not applicable".

The Most Important Symptoms (MIS)

The purpose of the most important symptom questionnaire is to determine which symptoms are most distressing to the patient over the last 7 days. MIS is based on the importance rating scale of washington university quality of life questionnaire 2.0 and higher, with the addition of some symptoms associated with disease and/or treatment (Rogers et al, 2002). The patient was asked to select the most troublesome 4 symptoms in the past week.

PRO-CTCAE

PRO-CTCAE is a validated library of items that characterize the presence, frequency of occurrence, severity, and/or the burden of interference with daily function of the 78 patient reportable symptomatic treatments toxicity (Basch et al 2014. PRO-CTCAE contains 124 questions that are rated either as dichotomies (determining presence and absence) or 5 points (determining frequency of occurrence, severity, and interference with daily functions). Therapeutic toxicity may occur in observable signs (e.g., emesis) or in unobservable symptoms (e.g., nausea). The standard PRO-CTCAE recall period is "7 days previously".

A subset of the 11 symptoms considered most suitable for current treatment has been selected for this study. The selection of symptoms was based on previous studies on atuzumab plus rayleigh ecumab (Rodriguez-Abreu et al 2020), symptomatic treatment toxicity associated with immunotherapy reported by patients and clinicians (Hansen et al 2020), and symptom recommendations for measuring head and neck cancer (Cella et al 2011 chera et al 2014

Blood samples for whole genome sequencing or whole exome sequencing

At the participating sites, blood samples were collected for DNA extraction to enable WGS or WES to identify specifically occurring variations in individual tumors that could predict response to study drugs, associated with progression to more severe disease states. DNA extracted from blood can be compared to DNA extracted from tissue to identify somatic variants 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 depends on the IRB/EC of each site and, if applicable, the review and approval of exploratory studies by the appropriate regulatory bodies. This part of the scheme is not applicable to a site if the site has not been approved for WGS or WES.

Genomics increasingly informs researchers of the pathobiology of disease. WGS and WES provide a comprehensive characterization of the genome and exome, respectively, and, together with the clinical data collected in this study, may increase the opportunity to develop new therapeutic approaches or new methods to monitor efficacy and safety or predict which patients are more likely to respond to drugs or develop adverse events. The data were analyzed in the context of this study, but could also be explored in combination with data from other studies. The availability of larger data sets helps identify and characterize important biomarkers and pathways to support future drug development.

For sampling procedures, storage conditions and shipping instructions, see the laboratory manual.

Blood samples collected for WGS or WES will be preserved until they are no longer needed or used up. However, the storage period is in accordance with the informed consent and applicable law approved by IRB/EC (e.g., requirements of health authorities).

Samples for studying biological sample libraries

Research biological sample pools (RBRs) are a centrally managed group of facilities for long-term storage of human biological samples, including body fluids, solid tissues and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, storage and analysis of RBR samples facilitates rational design of new agents and development of diagnostic tests that may provide personalized drug therapy to patients in the future.

Samples of RBRs were collected from patients who explicitly agreed to participate in this optional study. Analyzing the RBR sample to achieve one or more of the following goals:

study of the association of biomarkers with efficacy or disease progression

Identification of safety biomarkers associated with susceptibility to adverse events or likely to lead to improved adverse event monitoring or investigation

Increased understanding and understanding of disease biology and drug safety

Investigating drug response, including drug effects and the course of drug absorption and disposal

Development of biomarkers or diagnostic assays and determination of performance characteristics of these assays

Sample collection

The following samples were stored in RBRs and used for research purposes, including, but not limited to, biomarker studies associated with atuzumab, tiryleiguzumab, head and neck cancer, or drug safety:

residual blood, plasma, PBMC and tumor tissue samples (except for residual archived tissue pieces returned to the site) and any derivatives thereof (e.g., DNA, RNA, proteins, peptides), including residual tissue samples from medically indicated procedures (e.g., bronchoscopy, esophagogastroduodenoscopy, colonoscopy) performed at the discretion of the researcher during the course of the study

Optional blood samples collected for DNA extraction at any time during the study

Optional fecal samples taken between dosing on day 1 of cycle 1 and dosing on day 15 of cycle 2 and day 1 of cycle 3. These samples can be collected at home.

The samples can be sent to one or more laboratories for microbial community analysis by whole genome sequencing, microbial culture, germline or somatic variants via WGS, WES or other genomic analysis methods. Genomics is increasingly informing researchers of the understanding of the pathobiology of disease. WGS and WES provide a comprehensive characterization of the genome and exome, respectively, and, together with the clinical data collected in this study, may increase the opportunity to develop new therapeutic approaches or new methods to monitor efficacy and safety or predict which patients are more likely to respond to drugs or develop adverse events.

The data generated from the RBR samples were analyzed in the context of this study, but could also be aggregated with data from other studies and explored. The availability of larger data sets helps identify and characterize important biomarkers and pathways to support future drug development.

The RBR sample will be stored until it is no longer needed or used up. However, the RBR storage period is in accordance with the IRB/EC approved informed consent and applicable law (e.g., requirements of health authorities).

G. Treatment and patient termination

Termination of treatment

Study treatment must be terminated permanently if the patient experiences any of the following conditions:

intolerable toxicity (including the development of immune-mediated adverse events) associated with study treatment, which investigators determined to be unacceptable in view of the potential response of individual patients to therapy and the severity of the event

If the patient continues with the study treatment, any medical condition may jeopardize his or her safety

Determination of termination of treatment by the researcher or sponsor to correspond to the greatest benefit of the subject

Use of another non-protocol anti-cancer therapy

Pregnancy

Imaging disease progression according to RECIST v1.1

Except for the following cases: after RECIST v1.1 disease progression criteria are met, the patient is allowed to continue study treatment if the patient meets all criteria for continuing treatment improvement after imaging progression has occurred.

For patients who continue treatment after the imaging progression according to RECIST v1.1 has occurred: loss of clinical benefit, as determined by the investigator after a comprehensive assessment of the imaging data, biopsy results (if available), and clinical status

The main reason for study treatment termination should be recorded in the appropriate eCRF. Patients who prematurely terminate study treatment will not be replaced.

Patients returned to the clinic for study treatment termination visit no more than 30 days after the last dose of study treatment. The visit at which the response assessment showed disease progression could be used as the treatment termination visit, in which case all assessments related to the treatment termination visit should be made at that time.

If a patient terminates study treatment for an adverse event believed to be associated with study treatment, including an adverse event of particular interest, and that event persists 30 days after the last dose of study treatment, the event must be tracked until the event subsides or the investigator determines that the event has become stable or irreversible.

Follow-up assessment

Assessment of tumors

Patients who terminate study treatment (for any reason, including but not limited to clinical regression or toxicity) in the absence of imaging disease progression according to RECIST v.1.1 must continue to undergo tumor assessment as outlined in the activity program above, regardless of whether the patient initiates new anti-cancer therapy until imaging disease progression according to RECIST v1.1, withdrawal consent, death, or sponsor termination of the study, whichever occurs first. At the discretion of the investigator, if disease progression is suspected, the scan must be performed at any time.

Survival and follow-up therapy

After treatment termination, information about survival follow-up and new anti-cancer therapies is collected approximately every 3 months by telephone, patient medical history, and/or outpatient visits until death (unless the patient withdraws consent for survival follow-up or the host terminates the study).

Information on subsequent anti-cancer therapies includes systemic therapies (e.g., chemotherapy, targeted therapy, immunotherapy), surgery (e.g., removal of local and/or metastatic disease), and radiation procedures (e.g., radiation therapy on tumor lesions).

Patient termination

Patients were given the right to voluntarily withdraw from the study for any reason at any time. In addition, the investigator has the right to leave the patient from the study at any time.

Reasons for patient termination of the study may include, but are not limited to, the following:

patient withdrawal consent

Termination of study or site shutdown

Missed visit

Patient non-compliance, defined as non-compliance with protocol requirements determined by the investigator or sponsor

All effort should be expended to obtain the reason for patient termination of the study. The main reason for terminating the treatment should be recorded in the appropriate eCRF. If the patient requests to withdraw from the study (i.e., requires withdrawal from all life-cycle follow-up visits), the request must be recorded in the source file and signed by the researcher. Patients who exited the study (i.e., on-life follow-up) were not replaced.

If the patient exits the study (i.e., a survival follow-up), the study staff may use a common information source (e.g., a household record) to obtain information about the survival status.

H. Analysis of

Analysis of efficacy

End of primary efficacy

The primary efficacy endpoint was confirmed ORR. Confirmed objective remission was defined as confirmed CR or PR 2 consecutive times at 4 weeks or more apart and was determined by the investigator using RECIST v 1.1. Patients who did not meet these criteria (including patients who did not receive any post-baseline tumor assessment) were considered non-responders. The confirmed ORR is defined as the proportion of patients with confirmed objective remission.

Once all patients have been enrolled and a minimum follow-up of about 5 months has been achieved in these patients, a primary efficacy analysis is performed, and these patients remain on follow-up for ORR assessment.

The primary efficacy analysis population consisted of all randomized patients grouped according to their assigned treatment. The estimate of ORR for each treatment arm and its 95% CI was calculated using the Clopper Pearson method.

Secondary efficacy endpoints

Duration of mitigation

DOR was assessed in patients who had achieved confirmed objective remission, as determined by the investigator according to RECIST v 1.1. DOR is defined as the time interval from the date of first appearance of confirmed objective remission until the date of first recording of disease progression or death from any cause as determined by the investigator according to RECIST v1.1, whichever precedes. Patients who did not develop progression at the time of analysis and did not die were missed at the last tumor assessment date. Median DOR was estimated for each treatment group using the Kaplan-Meier method and a Kaplan-Meier curve was generated. 95% CI of the median DOR in each treatment group was constructed using the Brookmeyer-Crowley method.

Progression free survival including 6 months

PFS is defined as the time between the date of randomization and the date of disease progression or death as assessed by investigators according to RECIST v1.1, whichever comes first. Patients who did not experience disease progression or did not die before the data expiration date were scored at the last tumor assessment. Patients who did not have a post-baseline tumor assessment were missed at randomization.

Median PFS was estimated for each treatment group using the Kaplan-Meier method and a Kaplan-Meier curve was generated. 95% CI of the median PFS for each treatment group was constructed using the Brookmeyer-Crowley method. Estimate PFS rate at 6 months post-randomization for each treatment arm using the Kaplan-Meier method, calculate 95% CI with the standard error given by the Greenwood equation.

Total survival including 6 months and 12 months

OS is defined as the time between the randomized date and death for any reason. Data for patients not reported as dead by the expiration date were deleted on the last day they were known to survive. Data for patients without post-baseline information were censored on the day of randomization. OS and OS rates at 6 months and 12 months were analyzed using the same methods as described for PFS.

Results reported by the patient

Use of

The project library v 2.0-body function TTCD of short table 10b is defined as the time from the date of randomization to the first confirmation of clinically significant deterioration. Confirmation of clinically significant deterioration of body function is defined as a clinically significant decrease from baseline that must be maintained in at least two consecutive assessments, or an initial clinically significant increase from baseline followed by death. T score variation > 4 points is considered to have clinical significance for physical function subscales scores.

TTCD was assessed in the ITT population. Patients who experienced no confirmed clinically significant exacerbations at the clinical expiration date were scored at the last time they completed the assessment. Patients were censored on the day of randomization if baseline or post-baseline assessments were not made. Use of the same method as PFS

TTCD of the scale.

Scales (pain, fatigue and physical function)Exploratory analysis includes aggregating statistical data and average changes in ITT populations relative to baseline, such as by using

Pain, pain,

Fatigue and fatigue

Physical function questionnaire report and base

Score manual calculation report.

Summary statistics including counts and ratios are provided for PGI-CI, PGI-S and most important symptoms and are exploratory.

The analysis of PRO-CTCAE is exploratory in nature and primarily descriptive, with emphasis on describing disease patterns and symptomatic treatment toxicity during the study. The results of these exploratory analyses are presented separately from other security analyses. The PRO-CTCAE data are analyzed at the project level according to current NCI recommendations for data processing. For each treatment arm, the number (percentage) of patients reporting symptoms in the "frequency", "severity", "interference" and "presence" categories was reported at each assessment.

In addition, the frequency of the symptoms and the severity of the symptoms are cross-tabulated to explore the effect of the symptoms when they occur. A summary by treatment arm is also provided reporting the percentage of patients with symptom severity "severe" or "very severe" during the study.

Security analysis

The safety analysis population consisted of all randomized patients receiving at least one dose of atuzumab or tirayleigh itumumab/placebo.

Safety analysis was performed per treatment arm and based on the actual treatment received. Specifically, if the patient received any number of tenecteuizumab, the patient was included in the safety analysis of the atlizumab plus tenecteuizumab arm regardless of the initial treatment allocation at randomization.

Drug exposure, including duration, dose, and dose intensity, was summarized.

The verbatim description of adverse events is mapped to the MedDRA narrative terms and ranked according to NCI CTCAE v5.0, and the severity of CRS is also ranked by researchers according to the ASTCT consensus rating scale. All adverse events were summarized by treatment arm and NCI CTCAE grade. CRS was also summarized by treatment arm and ASTCT consensus grade. In addition, critical adverse events, immune-mediated adverse events, and adverse events leading to termination or discontinuation of study treatment were summarized accordingly. Multiple occurrences of the same event were counted once with maximum severity.

All deaths and causes of death were summarized by treatment arm.

Laboratory data were identified with values outside the normal range. Selected laboratory data, including ADA results, are also summarized.

Pharmacokinetic analysis

PK samples of securitylyumumab and atelizumab were collected in this study. The tiryleigh immuzumab and atuzumab serum concentration data (minimum and maximum serum concentrations) were tabulated and summarized.

Descriptive statistics include mean, median, range, and standard deviation, as appropriate.

Based on the availability of data, additional PK analyses are performed, if appropriate.

Immunogenicity assay

Immunogenicity analysis included patients for any ADA assessment, grouped according to treatment received. The number and proportion of ADA positive and ADA negative patients appearing during treatment were summarized in the treatment arm.

The relationship between ADA status and safety, efficacy and PK endpoints can be analyzed and reported by descriptive statistics.

Biomarker analysis

Biomarker analysis is exploratory. Descriptive statistics were used to summarize biomarker subgroups and their relationship to efficacy endpoints; the data may be analyzed in the context of the present study, or may be analyzed along with data from other studies.

Middle term analysis

When approximately 60 patients have been enrolled and have had an opportunity to complete follow-up for approximately at least 5 months, the IMC program performs an interim efficacy analysis and reviews thereof.

Example 16A phase Ib/II, open label, multicenter, randomized umbelliform study on the assessment of efficacy and safety of various 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 to 8 weeks, providing the patient with neoadjuvant therapy to improve the recurrence rate and window of opportunity for OS. The benefit of neoadjuvant chemotherapy is modest, with a 5% increase in Overall Survival (OS) in patients receiving neoadjuvant chemotherapy compared to cystectomy alone (Vale et al, eur Urol,48, 202-205, 2005). Patients who achieved complete remission of pathology (pCR) benefited the most from receiving cisplatin-based neoadjuvant chemotherapy, with 80-90% of patients surviving at the 5-year follow-up; however, up to 50% of patients may have high risk disease remaining at the time of surgery (pT 2 or higher), with 5-year survival rates below 50% (Rosenblatt et al, eur Urol,61 1229-1238, 2011 bhindi et al, eur Urol, 72. Thus, pCR can serve as a surrogate marker for the increased efficacy and survival of neoadjuvant therapy for MIBC.

WO39613 is a phase Ib/II, open label, multicenter, randomized umbrella study on the evaluation of efficacy and safety of various immunotherapy-based treatments and combinations in patients with MIBC that are not eligible for cisplatin use. The design of the study has flexibility to open new treatment arms when new therapies are available, close existing treatment arms exhibiting minimal clinical activity or unacceptable toxicity, or adjust patient populations (e.g., with respect to previous anti-cancer treatments or biomarker status). Patients were randomly assigned to either a control arm (atezumab (Atezo)) or an experimental arm consisting of atezumab in combination with tenecteuzumab (Atezo + Tira)) (fig. 24 and table 69).

TABLE 69 treatment regimens

Atezo: attrituzumab; MIBC: muscle-invasive bladder cancer; tira: and (3) teneuizumab. ^a The host may decide to delay or pause the grouping of a given treatment arm. Thus, all experimental arms may not be opened into the group at the same time. ^b If clinical activity was observed in the experimental arm during the initial phase, approximately 25 additional patients were included in the arm during the extended phase. ^c The randomization ratio depends on the number of experimental arms that were open randomized (e.g., if one arm was added or one arm was paused for a preliminary period of outcome analysis), with no more than 35% chance of committing to the control arm being specified.

Table 70 summarizes the objective and proposed mechanism of action classifications for atelizumab and tenectereuzumab.

TABLE 70 Objective and proposed mechanism of action Classification of Abiralizumab and Tirayleigh mab

PD-L1= programmed death ligand 1; TIGIT = T cell immunoreceptor with Ig and ITIM domains.

The specific goals of the study and the corresponding endpoints are summarized in table 71 below.

TABLE 71 targets and corresponding endpoints

ADA = anti-drug antibody; CR = complete remission; DOR = duration of remission; EFS = event-free lifetime; irrecist = immune RECIST; MIBC = muscle-invasive bladder cancer; NCI CTCAE v4.0= american national cancer institute adverse event general term standard version 4.0; OS = overall lifetime; PK = pharmacokinetics; RFS = relapse free survival.

Researchers evaluated overall responses at a single time point using RECIST v 1.1. The total response according to irrecist is calculated programmatically by the host based on the individual lesion data assessed by the investigator.

Approximately 150 to 350 patients were enrolled and divided into MIBC cohort 1 (PD-L1 +) and MIBC cohort 2 (PD-L1-). The experimental arm was run in two phases, namely the initial phase and the extension phase. In the initial phase, all treatment arms of MIBC cohort 1 (PD-L1 +) and MIBC cohort 2 (PD-L1-) were identical. After a focused PD-L1 test on transurethral cystectomy (turbo) samples using the VENTANA PD-L1 (SP 142) assay, patients were assigned to MIBC cohort 1 (PD-L1 +) or MIBC cohort 2 (PD-L1-). Patients with a PD-L1 Immune Cell (IC) score of 2 or 3 (IC 2/3, corresponding to any intensity of discernible PD-L1 staining in tumor-infiltrating immune cells covering > 5% of the tumor area occupied by tumor cells, associated intratumoral and continuous peritumoral stroma) were assigned to MIBC cohort 1 (PD-L1 +). Patients with an IC score of 0 or 1 (IC 0/1, corresponding to any intensity of discernible PD-L1 staining in tumor-infiltrating immune cells covering ≦ 5% of the tumor area occupied by tumor cells, associated intratumoral and continuous peritumoral stroma) were assigned to MIBC cohort 2 (PD-L1-).

During the initial period, up to 30 patients were enrolled in the Atezo + Tira arm, and approximately 15 patients were enrolled in all other arms of each MIBC PD-L1 cohort. If clinical activity was observed in the experimental arm during the initial phase, approximately 25 additional patients were included in the arm during the extended phase.

The host may decide to delay or pause the grouping of a given treatment arm. The experimental arm with insufficient clinical activity or unacceptable toxicity did not expand. Additional patients may be included to ensure a balance between treatment arms in terms of demographics and baseline characteristics, including potential predictive biomarkers, for further sub-group analysis.

The randomization ratio depends on the number of experimental arms available (e.g., if one arm is added or one arm is paused for a preliminary period of outcome analysis), where the likelihood of a prescribed transfer to a control arm does not exceed 35%. Randomization takes into account arm-specific exclusion criteria. Patients do not meet the conditions of a particular arm if they meet any of the exclusion criteria outlined for that arm.

Patients in the control and experimental arms of astuzumab were treated until unacceptable toxicity or loss of clinical benefit as determined by the investigator after comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease). Patients received post-operative treatment for up to 1 year, followed by 2 years of 3-month follow-up assessment.

A. Assessment and monitoring

Adverse events were closely monitored throughout the study in all patients and ranked according to the national cancer institute adverse event general terminology standard version 4.0 (NCI CTCAE v 4.0). Patients were assessed for tumors every 9 weeks (starting on day 1 of cycle 1) and every 12 weeks for the first 54 weeks. Responses assessed by researchers using RECIST v1.1 (Eisenhauer et al, eur J Cancer, 45. If clinical activity is demonstrated in the laboratory arm, the host may request that a oncology assessment scan of the arm be submitted for evaluation by a separate reading institution.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy at the time of study entry. If the researcher deems the biopsy to be unfeasible, an archive of the tumor tissue may be submitted. Tumor tissue is also collected from patients who have terminated phase 1 due to unacceptable toxicity or loss of clinical benefit, as determined by the investigator (if the investigator deems clinically feasible). These samples, as well as blood samples collected during the study, were used for biomarker studies.

To characterize the Pharmacokinetic (PK) profile and/or immunogenicity of alemtuzumab and other therapeutic agents, blood samples were obtained at different time points before and during study treatment administration.

B. End of study and duration of study

The end of the study was defined as the day when the last patient in both phases completed the last visit, including a survival follow-up by phone or at the visit site.

The total length of the study (from screening of the first patient to the end of the study) will be about 3 to 5 years.

C. Fundamental principles of research design

Study rationale and benefit-risk assessment

The study was aimed at accelerating the development of Cancer Immunotherapy (CIT) combinations by identifying early signs and establishing proof-of-concept clinical data for patients with MIBC that did not meet cisplatin use conditions.

Platinum neoadjuvant chemotherapy is associated with OS improvement, but is only applicable to a few patients. Given the relatively limited treatment options for MIBC patients who are not eligible for cisplatin use, and the poor prognosis and potential toxicity associated with locally advanced or metastatic UC treatment, these populations require treatment options and are therefore considered suitable for the testing of novel treatment candidates. The current approach to CIT is to circumvent immune escape mechanisms and to stress anti-tumor responses by targeting T cell suppressors such as programmed death ligand 1 (PD-L1)/programmed death 1 (PD-1).

CIT has shown significant clinical efficacy, with significant survival benefits observed in a variety of advanced malignancies, and there is evidence that PD-1/PD-L1 checkpoint blockade can produce pCR and a persistent response in patients with UC (Powles et al, nat Med,25 1706-1714, 2019 necchi et al, int J Clin Oncol,36 3353-3360, 2018. Although these targets have brought significant clinical therapeutic success for various cancer indications, ongoing studies indicate that a series of stepwise events are necessary for the 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 event is also susceptible to several mechanisms of tumor immune escape. Thus, there is a need to identify and circumvent various factors that lead to the lack of or escape of an effective anti-cancer immune response, which is crucial for the spread of cancer immunity and the advancement of the field of CIT. Alemtuzumab in combination with agents directed against different immune escape mechanisms or a novel second generation CPI could further increase the response rate of this population and reduce the rate of disease recurrence.

The potential risk of patients with MIBC is associated with adverse events associated with study treatment. In most countries, patients wait an average of 4 to 8 weeks between definitive diagnosis of urothelial cancer and surgery. Participation in this trial, including preoperative treatment, is not expected to result in the participants' associated operative delays. Furthermore, in the ABACUS study, alemtuzumab did not affect operability or increase risk associated with surgery (Powles et al, nat Med, 25.

Basic principle of perioperative treatment of muscle invasive bladder cancer

The therapeutic sharing of neoadjuvant and post-operative maintenance therapies is not clear. The WO39613 study was aimed at assessing therapeutic efficacy and performing extensive biomarker analysis on sequential patient tissues.

Imvisor 010 is a phase III randomized study that randomized MIBC patients to receive altlizumab, compared to observations as adjuvant therapy after surgical resection and lymph node clearing. Although this study did not reach its primary endpoint, i.e., intended to show disease-free survival benefits of alemtuzumab adjuvant therapy in the treatment population, analysis of a subset of T3 and T4 patients as well as non-clinical data (Liu et al, cancer Discov,6, 1382-1399, 2016 pai et al, immunity, 50.

D. Evidence for immunotherapy in patients with muscle-invasive bladder cancer who is not amenable to cisplatin-based chemotherapy

Approximately 50% of patients with MIBC are ineligible to receive cisplatin-based neoadjuvant chemotherapy, and there is currently no proposed perioperative systemic treatment for these patients; cystectomy with bilateral pelvic lymphadenectomy is standard of care. In addition, due to personal preference or other complications, less than half of patients with MIBC eligible for neoadjuvant chemotherapy will receive neoadjuvant chemotherapy. Therefore, new therapies are needed to improve the prognosis of patients with MIBC.

If the patient's tumor is PD-L1+, PD-1/PD-L1 checkpoint immunotherapy is approved for all patients who progressed during chemotherapy for mUC and patients with 1LMUC who are either not eligible for platinum-based chemotherapy or cisplatin-based chemotherapy. The largest study to study the safety and efficacy of PD-1/PD-L1 checkpoint neoadjuvant immunotherapy in patients with MIBC is the ABACUS and PURE-01 study (Powles et al, nat Med,25, 1706-1714, 2019 necchi et al, int J Clin Oncol,36 333353-3360, 2018.

E. Rationale for complete remission of pathology as the primary endpoint

Pathological complete remission (pCR) and pathological degradation (exploratory endpoint) have been validated as surrogate markers of activity in this case, as it is associated with persistent remission-free survival (Rosenblatt et al, euro Urol,61 1229-1238, 2011, bhindi et al, eur Urol, 72.

Increased baseline CD 8T cell infiltration and PD-L1+ disease have been shown to increase the probability of pCR using immunotherapy in a neoadjuvant setting (Powles et al, nat Med,25 1706-1714, 2019.

F. Rationale for using atelizumab as a comparator

There is no standard of care for providing systemic therapy to patients with MIBC who refuse or do not comply with cisplatin-based neoadjuvant chemotherapy either before or after surgical resection.

The alemtuzumab was chosen as a comparative treatment because the ABACUS and PURE-01 studies have shown that PD-1/PD-L1 checkpoint immunotherapy is active and safe for patients with MIBC with response rates comparable to the historically observed cisplatin-based chemotherapy. Based on the ABACUS and PURE-01 data, MIBC are generally more inflamed than muuc and are therefore more likely to benefit from PD-1/PD-L1 checkpoint immunotherapy, as PD-L1 expression was only observed in 25% and 28.5% of patients treated for mUC in the imvisor 211 and KN-045 studies, respectively.

Randomized studies evaluating immunotherapy combinations will identify safe and effective treatments for patients with MIBC who are not eligible for cisplatin-based chemotherapy, while also significantly increasing the understanding of cancer biology and improving the ability to iterate when designing new trials and treatments for all patients with MIBC. The study may also include future potential arms and cohorts using combinations of immunotherapies that have proven adequate clinical safety.

G. Rationale for separate PD-L1+ and PD-L1-queues

PD-1/PD-L1 blockade has been FDA approved for 2L mUC and for patients with PD-L1+ mUC who are not eligible to receive cisplatin-based chemotherapy, but are not approved for use in patients with MIBC. Although the pCR benefit (37.1%; n = 13/35) was greater in patients with PD-L1+ disease treated with atezumab in the ABACUS study than in patients with PD-L1-disease (24.5%; n = 12/49), some patients with PD-L1-disease may still benefit from the combination of atezumab or immunotherapy. The design of the study allowed the sponsor to separately evaluate the efficacy of the atlizumab and other immunotherapy combinations in these patient subpopulations and to shut down the cohort of multiple arms in each cohort without affecting the other cohort studies, with no evidence of benefit.

H. Rationale for studying the effect of perioperative therapy on ctDNA of the muscle invasive bladder cancer cohort

Changes in circulating tumor DNA (ctDNA) concentration over time are likely to be useful in detecting disease recurrence (Moding et al, nat Cancer, 1. ctDNA shed from cancer cells into peripheral blood can be collected non-invasively and tested for the presence of tumor-specific mutations. Several features of UC make it a strong candidate for predicting disease recurrence using ctDNA detection:

UC carries a high somatic mutation rate; thus, a very small number of genes or targeted regions can provide a wealth of information for predicting disease characteristics: (

Et al, bladder Cancer,4:1929, 2018).

Metastatic relapses in UC have been observed to have clonal origin, with no significant difference from the original tumor in mutation analysis (Thomsen et al, sci Rep,7 11702, 2017.

Analysis of matched tumors in UC identified few subclones, enhancing the prognostic potential of longitudinal ctDNA detection after definitive therapy (Lamy et al, cancer Res,76, 5894, 2016 nodentoft et al, cell Rep, 7.

Samples taken longitudinally from 68 patients with MIBC who received neoadjuvant chemotherapy and cystectomy were analyzed using the Natera signatea ctDNA assay. This analysis found that the overall relapse rate was 76% in patients who were ctDNA positive at any time point after cystectomy, and 0% in patients who remained ctDNA negative after cystectomy (median follow-up 21 months) (Christiensen et al J Clin oncol.37 (18): 1547-1557, 2019).

These data present a biomarker-selected subset of MIBC patients whose need for urgent treatment options is not met. However, there is currently no data on: 1) The effect of neoadjuvant immunotherapy on ctDNA before and after cystectomy in patients with urothelial cancer; 2) Whether maintenance immunotherapy helps to prevent recurrence of urothelial cancer after cystectomy in patients treated with neoadjuvant immunotherapy; 3) Whether maintenance immunotherapy would reduce the risk of disease recurrence if patients treated with neoadjuvant immunotherapy had measurable ctDNA after cystectomy.

As part of this study, retrospective measurements of ctDNA were performed on all patients with PD-L1+ MIBC treated with atuzumab and atuzumab plus rayleigh mab at 4 time points: 1) Before day 1 of cycle 1; 2) Before cystectomy; 3) 4 to 6 weeks after cystectomy; and 4) 6 months after cystectomy. The association between ctDNA results at these time points and event-free lifetime (EFS) and OS was investigated. These results will provide information on design for future studies to study the impact of neoadjuvant and maintain therapeutic value in patients receiving checkpoint immunotherapy. ctDNA was studied in the other arms of the study at these time points to await the results of these studies and the clinical activity observed in the other arms.

This design and use of ctDNA allows evaluation of 1) the effect of neoadjuvant therapy on ctDNA and pathological responses; 2) The effects of surgery on ctDNA remaining after neoadjuvant immunotherapy treatment; 3) Whether maintenance immunotherapy can reduce the risk of postoperative ctDNA and disease recurrence in patients with MIBC.

Example 17 materials and methods of the WO39613 study

A. Inclusion criteria

The patient must meet all of the following criteria:

Age ≥ 18 years.

Ability to comply with the protocol at the discretion of the investigator.

Eastern Cooperative Oncology Group (ECOG) physical Performance Status (PS) is 0 or 1.

Patients who reject cisplatin-based neoadjuvant chemotherapy or who are not eligible for cisplatin-based neoadjuvant therapy. Non-compliance with cisplatin use conditions for this study was defined as creatinine clearance < 60mL/min and/or grade 2 hearing loss and/or grade 2 neuropathy.

Fitting and planning for cystectomy.

Histologically documented MIBC (pT 2-4, N0, M0), also known as TCC or bladder urothelial cell carcinoma.

Residual disease after turbo (surgical opinion, cystoscopy/endoscopy or radiology present).

Patients with mixed histology need to have a dominant transitional cell pattern.

Availability of TURBT, which is suitable for determining PD-L1 and other biomarker status by central testing.

Omicron turbo specimen must be submitted along with the relevant pathology report. Tumor tissue was treated by two different methods (i.e., paraffin fixed tissue and fresh tissue were required for separate biomarker analysis). The tumor tissue of the bladder or upper urinary tract should be of good quality based on total and viable tumor content and must contain the muscle layer invasive component of the tumor (i.e., T2 or greater) as confirmed by local pathological examination.

Patients with additional tissue samples from procedures performed at different times in their MIBC process (e.g., samples from previous turbo) will be requested (but not required) to also submit these samples for centralized testing.

CT or MRI-indicated N0 or M0 disease (within 4 weeks post-enrollment).

Appropriate blood and end organ function, defined by the following laboratory test results obtained within 14 days before the initiation of study treatment:

absolute Neutrophil Count (ANC) of ≥ 1.5x10 without support of G-CSF ⁹ /L(1500/μL)

White Blood Cell (WBC) count ≥ 2.5x10 ⁹ /L(2500/μL)

Lymphocyte count ≥ 0.5x10 ⁹ /L(500/μL)

In the case of no blood transfusion, the platelet count is > 100X10 ⁹ /L(100,000/μL)

Hemoglobin ≥ 90g/L (9.0 g/dL)

The patient may need to be transfused with blood; however, transfusions were not allowed within 2 weeks of screening laboratory tests for eligibility.

Erythropoietin stimulating agents may be used by patients with isolated kidneys or chronic kidney disease with low erythropoietin production.

AST, ALT and alkaline phosphatase (ALP). Ltoreq.2.5 x Upper Limit of Normal (ULN)

Bilirubin ≦ 1.5x ULN, except for:

patients with known gilbert disease: bilirubin level is less than or equal to 3 x ULN

Albumin ≥ 25g/L (2.5 g/dL)

Creatinine clearance ≥ 30mL/min (calculated using Cockcroft-Gault formula)

-for a patient not receiving therapeutic anticoagulation:

partial Thromboplastin Time (PTT) or aPTT ≤ 1.5 × ULN

Prothrombin Time (PT) or International Normalized Ratio (INR) ≦ 1.5 x ULN

HIV test negative at screening.

Unless local regulations do not permit, patients who have no previous HIV test results positive will receive HIV tests at the time of screening.

Total hepatitis B core antibody (HBcAb) test negative at screening or total HBcAb test positive at screening, followed by quantification of Hepatitis B Virus (HBV) DNA < 500IU/mL

Hepatitis C Virus (HCV) antibody test negative at screening; or positive for HCV antibody testing at screening, followed by negative for HCV RNA testing.

For fertile women: consent was maintained to abstain (avoid sexual intercourse) or use of contraceptive measures, and consent was not to donate ova.

For males: consent was maintained to abstinence (avoidance of sexual intercourse) or use of contraceptive measures, and consent was not donated sperm.

B. Exclusion criteria

Patients who met any of the following criteria were excluded. The event ranking in the exclusion criteria was based on NCI CTCAE v4.0.

Prior therapy with systemic immunostimulants (including but not limited to targeting CTLA-4, interferon and interleukin 2) prior to study of initiation of therapy

Condition of control arm only

Previous allogeneic stem cell or solid organ transplantation

Treatment with systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or it is expected that systemic immunosuppressive drugs will be required during study treatment, except:

patients receiving acute, low dose systemic immunosuppressant administration or one-time pulsed dose systemic immunosuppressant administration (e.g., 48 hours corticosteroid for contrast agent allergy) met the criteria of this study.

Patients receiving mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low doses of corticosteroids for treatment of orthostatic hypotension or adrenal insufficiency are eligible for this study.

Treatment with live attenuated vaccines within 4 weeks prior to initiation of study treatment, or such vaccines are expected to be required during treatment with atuzumab or within 5 months after the last dose of atuzumab.

Uncontrolled tumor-associated pain. Patients requiring analgesics must adopt a stable treatment regimen at the time of study entry.

Autoimmune diseases or immunodeficiency active phases or history, 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-barre syndrome or multiple sclerosis, with the following exceptions:

patients with a history of autoimmune-related hypothyroidism and who are receiving stable doses of thyroid replacement hormone are eligible for this study.

Patients with type 1 diabetes and undergoing a stable insulin regimen were eligible for this study.

Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with only dermatological manifestations (e.g. with the exception of psoriatic arthritis patients) qualify for the present study if all of the following conditions are met:

the rash must cover < 10% of the body surface area.

The disease is well controlled at baseline and only low-potency topical corticosteroids need to be used.

No acute exacerbation of the underlying condition requiring psoralen plus ultraviolet a radiation, methotrexate, retinoids, biologies, oral calcineurin inhibitors or high potency or oral corticosteroids has occurred within the last 12 months.

There is a history of idiopathic pulmonary fibrosis, organized pneumonia (e.g., bronchiolitis obliterans), drug-induced lung inflammation, or idiopathic lung inflammation, or evidence of active lung inflammation found in a chest Computed Tomography (CT) scan.

With the exception of malignancies with a history of malignancy other than UC, but with negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) within the first 2 years of screening, such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer. Patients with localized prostate cancer (defined as stage pT2c, gleason score < 7, and Prostate Specific Antigen (PSA) at the time of prostate cancer diagnosis < 20 ng/mL) who were treated for curative purposes and had no recurrence of PSA were eligible. Patients with pre-existing low risk prostate cancer (defined as stage cT1/T2a, gleason score ≦ 6, and PSA ≦ 10 ng/mL) who were treated initially and are undergoing active surveillance are eligible.

Active Tuberculosis (TB) (i.e., with signs and symptoms of TB).

Severe infections occurred within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization due to complications from infection, bacteremia, or severe pneumonia, or any active infection that researchers believe may affect patient safety.

Treatment with therapeutic oral or IV antibiotics within 2 weeks before initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., for preventing urinary tract infection or exacerbation of chronic obstructive pulmonary disease) are eligible for this study.

Significant cardiovascular diseases such as new york heart association heart disease (grade III or higher), myocardial infarction or cerebrovascular accident, unstable arrhythmia or unstable angina within 3 months prior to randomization.

Uncontrolled hypertension (defined as systolic > 140mmHg and/or diastolic > 95 mmHg). Allowing antihypertensive treatment to achieve these parameters.

Grade 3 bleeding or bleeding episodes occurred within 28 days before initiation of study treatment.

Major surgery other than diagnostic was performed within 4 weeks before initiation of study treatment or is expected to be required during the study in addition to cystectomy or nephroureterectomy. Placement of a central venous access catheter (e.g., port or similar catheter) is not considered a major procedure and is therefore permissible.

Any other disease, metabolic dysfunction, physical examination findings or clinical laboratory findings that prohibit the use of study medication, may affect the interpretation of the results, impair the ability of the patient to participate in the study or may place the patient at high risk for treatment complications.

History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins.

Allergic reactions to Chinese hamster ovary cell products or recombinant human antibodies are known.

Known intolerance or allergy to any study drug or its excipients, including histidine, trehalose dihydrate and polysorbate 20.

Known to be intolerant to any drug (acetaminophen, ranitidine, diphenhydramine, and methylprednisolone) required for prophylactic use.

Pregnancy or lactation, or pregnancy intended during the study. A female with fertility must be negative for serum pregnancy test results within 14 days before study treatment initiation.

Additional exclusion criteria for the attrituzumab + tiryleyuzumab arm

Patients who met any of the following criteria were excluded from the alemtuzumab + tenecteumab arm:

active Epstein-Barr Virus (EBV) infection at screening or known or suspected chronic active EBV infection

Patients who were positive for the EBV Virus Capsid Antigen (VCA) IgM test at the time of screening were excluded from this arm. EBV Polymerase Chain Reaction (PCR) tests should be performed to screen for active infection or suspected chronic active infection based on clinical indications. Patients who were positive for the EBV PCR test were excluded from the arm.

C. Allowed therapy

Patients were allowed the following therapies during the study:

oral contraceptives

Hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or a stable dose of low molecular weight heparin)

Administration of prophylactic antibiotics or antiviral treatments according to institutional criteria

Inactivated influenza vaccine

Administration of megestrol acetate as an appetite stimulant

Mineralocorticoids (e.g., fludrocortisone)

Administration of corticosteroids for chronic obstructive pulmonary disease or asthma

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency

Hormone therapy using gonadotropin-releasing hormone agonists or antagonists for prostate cancer

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

after 2 cycles of treatment, palliative radiation therapy is permissible as long as it does not interfere with the assessment of the tumor target lesion (e.g., the lesion to be irradiated cannot be the only site of measurable disease). Treatment with astuzumab may continue during palliative radiation therapy.

Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) as outlined below:

Patients who experience mixed responses requiring topical therapy to control three or fewer lesions remain eligible for continued study treatment after approval by a medical supervisor. Patients receiving local therapy for the target lesion are no longer evaluable for imaging response, but are still evaluable for progression.

Prophylactic administration of antihistamines, antipyretics and/or analgesics may only be administered for the second and subsequent atuzumab infusions, as appropriate by the researcher.

Patients presenting with infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or an H2 receptor antagonist (e.g., famotidine, cimetidine) or equivalent drugs as are standard in the local practice. Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and should be managed with supportive therapy (e.g., supplemental oxygen and beta) based on clinical indications ₂ Adrenergic agonists).

D. Materials and methods for attrituzumab arms

Alemtuzumab was administered at a fixed dose of 1200mg every 3 weeks (Q3W) (1200 mg on day 1 of each 21 day cycle) (table 72), which is an approved dose ((Q3W))

U.S.Package Insert；

SmPC). Antitumor activity was observed in the dose range of 1 to 20mg/kg Q3W. In the study PCD4989g, the maximum tolerated dose of atelizumab was not reached, and no dose-limiting toxicity was observed at any dose. A fixed dose of 1200mg Q3W (equivalent to an average body weight-based dose of 15mg/kg Q3W) was selected based on two non-clinical studies (Deng et al, MAbs,8, 593-603, 2016) and available clinical pharmacokinetic, efficacy, and safety data.

Patients in the altlizumab control arm received treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator after a comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease). Treatment must be initiated no later than 7 days after treatment assignment. The patient underwent surgery after cycle 3; treatment in cycle 4 should be restarted 4 to 6 weeks after surgery.

TABLE 72 treatment regimen for the Atlizumab arm

Length of cycle	Dosage, route and regimen
		21 days	At day 1 of each cycle, atlas mab 1200mg IV

The administration of the atezumab will be performed in a monitored environment where trained personnel and sufficient equipment and medications are immediately available to manage the potentially critical reactions.

The attritumab infusions were administered according to the instructions summarized in table 73.

TABLE 73 administration of the first and subsequent attrituzumab infusions

D. Material and method for attrituzumab and tiryleyuuzumab arm

Astuzumab was administered as described above (see table 73).

Ibritumomab tiuxetan was administered at a fixed dose of 600mg IV Q3W (600 mg on day 1 of each 21-day cycle). The fixed dose of 600mg IV Q3W was selected based on available clinical PK, efficacy and safety data from a combined phase Ia/Ib study GO30103 using either tirayleigh immuzumab alone or a combination of tirayleigh immuzumab and atlizumab. In the phase Ia part of the study using tirayleigh itumumab as single drug, MTD was not reached and DLT was not observed in dose escalation. By the clinical cutoff date, anti-drug antibodies (ADA) against telithromycin were rare at phase Ia or phase Ib fractions at all dose levels. Prolonged disease stabilization was observed in patients in the phase Ia part of the study when the tiryleigh ewuzumab dose was started at 400 mg. In the phase Ib fraction of the study using tirayleigh eculizumab plus atelizumab, MTD was not reached. When tenectereuzumab is combined with 1200mg atelizumab, anti-tumor activity is observed across doses ranging from 30mg up to 600mg, as measured by imaging partial remission.

Patients in the attritumab + tiregumab arm received treatment as outlined in table 74 until unacceptable toxicity or loss of clinical benefit as determined by the investigator after comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease). The patient underwent surgery after cycle 3; treatment in cycle 4 was restarted 4 to 6 weeks after surgery.

TABLE 74 treatment regimens for the alemtuzumab + tireyueuzumab arms

Ibritumomab was administered at a fixed dose of 600mg by IV infusion on day 1 of each 21 day cycle with a post-infusion observation period as described in table 75. Administration of tireylauzumab is performed in a monitored environment where trained personnel and sufficient equipment and medications are immediately available to manage potential critical reactions.

TABLE 75 administration of first and subsequent infusion of ibritumomab tiuxetan

EXAMPLE 18 safety assessment of the WO39613 study

A. Security parameters and definitions

The security assessment consists of: monitoring and recording adverse events, including critical adverse events and adverse events of particular concern, performing protocol-specific safety laboratory assessments, measuring protocol-specific vital signs, and conducting other protocol-specific tests deemed critical to the safety assessment of the study.

B. Adverse events

According to good clinical practice guidelines of the international coordination council (ICH), an adverse event refers to any adverse medical event that occurs when a drug is used in a clinical study subject, regardless of its causal relationship. Thus, an adverse event may be any of:

any adverse and unexpected signs (including abnormal laboratory test results), symptoms or disease associated with the use of a drug, whether or not considered to be associated with the drug.

Any new disease or worsening of an existing disease (worsening in the characteristics, frequency or severity of a known disease).

Recurrence of intermittent medical conditions (e.g., headache) that did not exist at baseline.

Any worsening of laboratory values or other clinical tests (e.g., ECG, X-ray) associated with the symptoms or resulting in study treatment or concomitant changes in treatment or termination of study treatment.

Adverse events associated with the regimen prescribed intervention, including adverse events that occurred prior to dispensing study treatment (e.g., screening for invasive procedures such as biopsies).

Critical adverse event

A critical adverse event is any adverse event that meets any of the following criteria:

is fatal (i.e., an adverse event actually causes or results in death).

Is life-threatening (i.e., adverse events, in the opinion of the investigator, expose the patient to an immediate risk of death). This does not include any adverse events that could lead to death if they occur in a more severe form or were allowed to continue.

Requiring or extending hospital stay.

Resulting in persistent or significant disability/disability (i.e., adverse events result in substantial disruption of a patient's ability to perform normal life functions).

Congenital abnormalities/birth defects in newborns/infants born to mothers exposed to study treatment.

Is a significant medical event at the discretion of the researcher (e.g., the patient may be compromised or medical/surgical intervention may be required to prevent one of the above outcomes).

The terms "severe" and "critical" are not synonymous. Severity refers to the intensity of an adverse event (e.g., graded as mild, moderate, or severe, or according to NCI CTCAE; the event itself may have relatively little medical significance (such as severe headache without any further findings)).

Adverse events of particular interest

Adverse events of particular interest for the attritumab + tiryleyuzumab arm were as follows:

potential drug-induced cases of liver damage, including ALT or AST elevation in combination with bilirubin elevation or clinical jaundice (as defined by heuch's Law).

Transmission of infectious pathogens suspected of being carried out by study therapy, defined as follows:

any organism, virus or infectious particle (e.g., prion protein that transmits transmissible spongiform encephalopathies), whether pathogenic or non-pathogenic, is considered an infectious pathogen. Transmission of the source of the infection may be suspected based on clinical symptoms or laboratory findings that indicate infection in patients exposed to the drug. The term applies only in cases where the study treatment is suspected to be contaminated.

Pneumonia.

Colitis.

Endocrine diseases: diabetes, pancreatitis, adrenal insufficiency, and hypophysitis.

Hepatitis, including AST or ALT > 10X upper limits of normal.

Systemic lupus erythematosus.

Disorders of the nervous system: guillain-Barre syndrome, myasthenia syndrome or myasthenia gravis and meningoencephalitis.

Events suggestive of anaphylaxis, IRR, cytokine release syndrome, influenza-like disease, HLH and MAS.

Nephritis.

Ocular toxicity (e.g., uveitis, retinitis, and optic neuritis).

Myositis.

Myopathies, including rhabdomyolysis.

≧ 2 heart disorders (e.g., atrial fibrillation, myocarditis, pericarditis).

Vasculitis.

Autoimmune hemolytic anemia.

Severe skin reactions (e.g. Stevens-Johnson syndrome, bullous dermatitis or toxic epidermal necrolysis).

Example 19 statistical consideration and analysis planning for the WO39613 study

The WO39613 study analysis was based on patient data collected by study termination. If not otherwise specified, the efficacy analysis is based on a efficacy evaluable population, defined as all patients receiving at least one dose of each drug in their assigned treatment regimen, and the safety analysis is based on a safety evaluable population, defined as all patients receiving any amount of study treatment.

The results of the analysis are summarized in terms of the treatment actually received by the patient. Data are described and summarized in terms of sample amounts. The continuous variables were summarized by using mean, standard deviation, median, and minimum and maximum values. Categorical variables were aggregated by using counts and percentages. If the sample size is small, a list is used instead of a table.

A. Determination of sample amount

The WO39613 study is not intended to make explicit efficacy and class I error considerations for hypothesis testing. Instead, the study was aimed at obtaining preliminary efficacy, safety and PK data for an immunotherapy-based therapeutic combination when administered to patients with MIBC that did not meet cisplatin use conditions. Approximately 150 to 350 patients were randomized to the control arm and experimental arm during the study.

B. Analysis of efficacy

Primary end of efficacy

The primary efficacy endpoint was complete remission of pathology (pCR), defined as the proportion of patients with no residual invasive cancer present in the completely resected specimen. pCR rates and 90% confidence intervals were calculated for each arm. pCR differences between experimental and control arms were also calculated, as well as 90% confidence intervals. The confidence interval is estimated by the exact method or the Wald method, depending on the sample amount. Patients with missing or no response assessments were classified as non-responders.

Secondary efficacy endpoints

Secondary efficacy endpoints are landmark recurrence-free survival (RFS), landmark event-free survival (EFS), and landmark Overall Survival (OS), each at a specific time point (e.g., 12, 18, 24 months). These endpoints are described below. The landmark RFS rate, landmark EFS rate, and landmark OS rate for each study arm were estimated using the Kaplan-Meier method, and 90% CI was calculated by using the Greenwood formula.

Exploratory therapeutic endpoint

Exploratory efficacy endpoints are RFS, EFS, OS and pathological degradation rate.

Recurrence-free survival (RFS) is defined as the time from day 1 of the first cycle after surgery to the first recorded recurrence of the disease or death from any cause. For patients with no documented disease recurrence or death, RFS was deleted on the day of last tumor assessment after surgery.

Event-free lifetime (EFS) is defined as the time from randomization to any of the following events (whichever occurs first): disease progression excluding surgery assessed by investigators; local or distant disease recurrence; or death from any cause. Patients who did not experience such events were deleted at tumor evaluation after the last tumor.

Overall Survival (OS) is defined as the time from randomization to death for any reason. Data for patients who did not die were deleted on the last known survival date.

The pathological degradation rate is defined as the proportion of patients who reach pT1pN0 at cystectomy.

The Kaplan-Meier method was used to estimate the median RFS, EFS and OS of each study arm. The Brookmeyer and Crowley method was used to construct 90% CI of the median RFS, EFS and OS for each study arm.

C. Security analysis

The word-by-word recorded adverse event terms are mapped to the supervised active medical dictionary thesaurus terms and the adverse event severity is ranked according to NCI CTCAE v 4.0.

Safety was assessed by aggregating adverse events, changes in laboratory test results, changes in vital signs and ECG, and exposure to study drugs. The length of the exposure and safety follow-up of the combination treatment was summarized by treatment arm within each stage.

Adverse events that occurred in the treatment after initiation of treatment were summarized. For each patient, the maximum reported severity for each adverse event was used in the summary to rank the severity. All adverse events occurring during treatment, critical adverse events, adverse events leading to withdrawal from study treatment, grade > 3 adverse events, causes of death and death were listed and summarized in mapping terms, appropriate synonym levels and NCICTCAE severity ratings.

Relevant laboratory, vital signs (pulse rate, respiration rate, blood pressure, pulse oximetry and body temperature) and ECG data are displayed over time and rated where appropriate. In addition, a transpose table of selected laboratory test results is used to summarize baseline and maximum post-baseline severity ratings. Changes in vital signs are summarized.

D. Pharmacokinetic analysis

Sparse samples were collected for PK analysis of atezumab (patients receiving at least one dose of atezumab) and drug administered in combination with atezumab (patients receiving at least one dose of the drug). Serum or plasma concentrations of each study drug were reported as individual values and, where appropriate and data allowed, summarized by treatment arm, period and day (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean coefficient of variation). Individual and median serum or plasma concentrations for each study drug were plotted in terms of treatment arm and cycle and day. PK data for the combination drug can be compared to available historical data from internal and published prior studies. Concentration data can be combined with data from other studies to derive PK parameters such as clearance, volume of distribution and area under the curve using established population PK models.

The relationship between PK parameters and safety, efficacy, PK and biomarker endpoints can be analyzed and reported via descriptive statistics.

E. Immunogenicity assays

The immunogenicity of the alemtuzumab and other study treatments was assessed, if appropriate. The immunogenicity assay included all patients evaluated for at least one anti-drug antibody (ADA). Patients were grouped according to treatment received or if no treatment was received before the study break, according to treatment assigned.

For alemtuzumab, the number and proportion of ADA positive and ADA negative patients at baseline (baseline incidence) and after drug administration (post-baseline incidence) were summarized by treatment group. In determining the post-baseline incidence, patients are considered ADA positive if they are ADA negative or missing baseline data, but develop an ADA response after study drug exposure (treatment-induced ADA response), or if they are ADA positive at baseline and the titer of one or more post-baseline samples is at least 0.60 titer units higher than the titer of baseline samples (treatment-enhanced ADA response). A patient is considered ADA negative if they are ADA negative or missing baseline data and all post-baseline samples are negative, or if they are ADA positive at baseline but without any post-baseline sample titers that are at least 0.60 titer units higher than the titer of the baseline sample (treatment unaffected).

For other study treatments that tested ADA against, positivity was determined according to standard methods established in previous studies of the drug.

The relationship between ADA status and safety, efficacy, PK and biomarker endpoints can be analyzed and reported by descriptive statistics.

F. Biomarker analysis

Exploratory biomarker analyses were performed to understand the association of these biomarkers with the response to the study drug, taking into account efficacy, safety, PK, immunogenicity, and other biomarker endpoints.

G. Middle term analysis

Interim analyses were performed during the study, the earliest of which occurred when at least one experimental arm had completed the initial enrollment and the patients had completed their post-operative pCR assessments. Further interim analysis may be performed if deemed appropriate by the sponsor. Posterior probabilities can be used to guide further cohorts based on interim analysis of clinical activity of the experimental arm compared to the control arm. If the interim analysis indicated that the experimental arm had higher activity than the control arm, the experimental arm could be further advanced to 25 additional patients (extension phase) for each MIBC cohort. A final decision to expand and terminate the phase 1b trial is made that takes into account the overall benefit-risk balance and the integrity of the data, including time-to-event endpoints and safety data, as well as new emerging external information.

Example 20A phase Ib/II, open label, multicenter, randomized umbelliform study on assessing the efficacy and safety of a combination of Tirayleigh mab and atzelizumab in patients with metastatic urothelial carcinoma (mUC)

WO39613 is a phase Ib/II, open-label, multicenter, randomized umbelliform study evaluating the efficacy and safety of a combination of tenecteuzumab and atuzumab in patients with locally advanced or metastatic UC who have progressed during or after platinum-containing regimens. The design of the study has flexibility to open new treatment arms when new therapies are available, close existing treatment arms exhibiting minimal clinical activity or unacceptable toxicity, or adjust patient populations (e.g., with respect to previous anti-cancer treatments or biomarker status). A eligible patient is initially assigned to one of several treatment arms (see fig. 25). Patients who experience a loss of clinical benefit or unacceptable toxicity during phase 1 may be eligible for continued treatment with a different treatment regimen during phase 2 (see fig. 25).

A. Stage 1

During phase 1, patients were randomly assigned to either a control arm (atezumab [ Atezo ]) or an experimental arm consisting of atezumab in combination with tenellulose (Atezo + Tira)) (see fig. 25 and table 76).

TABLE 76 phase 1 treatment regimen

Atezo = atezumab; tira = tirayleigh zeuzumab. ^a The host may decide to delay or pause the grouping of a given treatment arm. Thus, all experimental arms may not be opened into the group at the same time.

^b If clinical activity was observed in the experimental arm during the initial phase, approximately 25 additional patients were included in the arm during the extended phase. ^c The randomization ratio depends on the number of experimental arms that were open randomized (e.g., if one arm was added or randomization was paused to one arm to wait for a preliminary period of results analysis) and provides that the probability of being transferred to a control arm set does not exceed 35%.

TABLE 77 Classification of targets and proposed mechanisms of action for study drugs

PD-L1= programmed death ligand 1; TIGIT = T cell immunoreceptor with Ig and ITIM domains.

The experimental arm was carried out in two phases: a preliminary phase and an extension phase. During the initial period, approximately 15 patients were enrolled. If clinical activity is observed in the experimental arm during the initial phase, approximately 25 additional patients may be included in the arm during the extension phase.

The host may decide to delay or pause the grouping of a given treatment arm. The experimental arm with insufficient clinical activity or unacceptable toxicity did not expand. Additional patients may be included to ensure a balance between treatment arms in terms of demographics and baseline characteristics, including potential predictive biomarkers, for further sub-group analysis. By revising the protocol, new experimental arms can be added during the study.

Patients were randomly assigned to treatment arms with the exception of the phase 2 treatment arm. The randomization ratio also depends on the number of experimental arms available (e.g., if one arm is added or one arm is paused for a preliminary period of outcome analysis), where the likelihood of a prescribed transfer to a control arm does not exceed 35%. Randomization takes into account arm-specific exclusion criteria. Patients do not meet the conditions of a particular arm if they meet any of the exclusion criteria outlined for that arm (see below).

Patients in the control and experimental arms of alemtuzumab were treated until unacceptable toxicity or loss of clinical benefit as determined by the investigator after comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease). Since immune cell infiltration may lead to an initial increase in tumor burden in the context of a T cell response (known as pseudoprogression) with Cancer Immunotherapy (CIT), such as atelizumab, imaging progression according to the solid tumor efficacy assessment criteria version 1.1 (RECIST v 1.1) may not indicate true disease progression. In the absence of unacceptable toxicity, patients who meet the criteria for disease progression according to RECIST v1.1 during treatment with a CIT drug are allowed to continue study treatment if all of the following criteria are met:

Evidence of clinical benefit, as determined by the investigator after review of all available data.

Absence of symptoms and signs (including laboratory values such as new or worsening hypercalcemia) indicative of definite disease progression.

Absence of ECOG PS decline attributable to disease progression.

No tumor progression at critical anatomical sites (e.g. leptomeningeal disease) that are not addressed by the medical intervention allowed by the protocol.

B. Stage 2

During phase 1, patients experiencing loss of clinical benefit (as determined by the investigator) or unacceptable toxicity may be eligible to receive a different combination of treatments at phase 2 (see fig. 25) provided they meet eligibility criteria. Phase 2 patients eligible to perform more than one treatment arm are assigned one treatment arm by the investigator.

Phase 2 treatment must begin and continue within 3 months after the patient has experienced loss of clinical benefit or unacceptable toxicity until loss of clinical benefit or unacceptable toxicity as determined by the investigator. The patient is advised to begin phase 2 treatment as soon as possible.

If appropriate, the sponsor may decide to maintain or terminate the grouping of phase 2 treatment arms based on review of safety data, preliminary efficacy data, and supportive information (e.g., biomarker study data).

C. Fundamental principles of research design

Rationale for patient population and attrituzumab control arm

This study included patients with locally advanced or metastatic UC who developed progression during or after the platinum-containing regimen.

Abiralizumab

UC, non-small approved for treatment of patients who progress during or after platinum-containing regimensBased on data from cohort 2 of the ongoing phase II study GO29293 (evigor 210), second line treatment of UC patients progressing after previous platinum-containing regimens was approved, which was then based on results from both IMvigor210 and phase III study GO29294 (evigor 211), with full approval for the same indications in europe. In IMvigor210 cohort 2, by 12 days 7/2017, 310 patients had been enrolled and an ORR of 16% (95% ci 13, 21) was observed with a Complete Remission (CR) rate of 7% and a median duration of remission (DOR) of 24.8 months (95% ci. Safety assessments found that 8% of patients experienced adverse events that led to withdrawal of treatment, and 16% of patients experienced treatment-related grade 3 or 4 adverse events, with the most common events being fatigue, diarrhea, and pruritus. 12% of patients develop immune-mediated events, and 7% of patients develop grade 3 or 4 immune-mediated events ( grade 3 or 4 rash [1% ]) ]ALT elevation (2%]And the increase of blood bilirubin is 2%]And rhabdomyolysis [1%]). In IMvigor211, by 2017, 3 months and 13 days, a median OS of 8.6 months, an ORR of 13.4% (10.5, 16.9), and a median DOR of 21.7 months was observed in the Intent To Treat (ITT) population.

Although single drug checkpoint inhibition has promising application, only a relatively small proportion of patients would benefit, highlighting the necessity for a combination of immunotherapies. The various co-partners in this study are expected to stimulate the immune system by multiple mechanisms, aiming to extend the benefits of atlizumab to a larger population of surgically inoperable locally advanced and metastatic UCs.

Basic principle of stage 2

The advent of immunotherapy provided the first real advance in the case of mUC for 30 years. Despite this progress, more work is still required to extend the benefit to a greater proportion of patients. The key to advancing the ability of immunotherapy is a better understanding of the underlying tumor immune environment and how the treatment sequence will affect the response.

The phase 2 portion of the study allows some patients to continue subsequent CIT combinations after disease progression to advance a scientific understanding of the mechanisms of immune escape of patients who do not respond to a CIT regimen or who have progressed during that regimen. The key to the patient's enrollment in stage 2 is whether they can take a biopsy to assess the immune environment and any changes that may occur during stage 1 treatment. Participation in phase 2 enables patients and providers to obtain treatment regimens with long lasting responses and improved toxicity profiles that are not available through traditional chemotherapy. Stage 2 treatment would exclude treatment with other, possibly more standard, options; thus, patients will be informed during phase 2 consent and will be given up treatment that may have a survival benefit, at phase 2, into the cohort.

Basic principles of phase 2 Atezo + EV arm and Atezo + SG arm

After loss of clinical benefit, patients may have an opportunity to receive phase 2 treatment with Atezo + EV or Atezo + SG.

The combination of Atezo + EV was chosen for phase 2 because a strong therapeutic response was recorded in patients receiving the single drug vildagliptin-enfratuzumab who had received prior CPI treatment. Specifically, in phase I trials of vilin-Enfratuzumab, 8 of 17 patients with metastatic bladder cancer cysts treated with the recommended phase II vilin-Enfratuzumab dose (47%; 95% CI 23, 72.2) obtained PR (Petrylak et al, J Clin Oncol,35 (15 Suppl): 106, 2017). These findings suggest that vildagliptin-enfratuzumab may provide benefits in the field of post-CPI. The addition of atuzumab to viltin-enritumumab may improve the duration of remission. In addition, microtubule disrupting therapies have the potential to induce immunogenic cell death and initiate anti-tumor immune responses.

The combination of Atezo + SG was chosen for phase 2 because a strong therapeutic response was observed in patients with mmuc who received the single drug govericin-shaxituzumab that had progressed during platinum-based therapy and checkpoint inhibitor therapy. Specifically, in the phase II TROPHY-U-01 study, the ORR of gavittacon-saritumumab in 35 patients was 29% and that included in patients with liver metastases was 25.0% (agawa et al, J Clin Oncol,37 (7 Suppl): 3199-3212, 2019). These findings suggest that gavitikang-saxituzumab may provide benefits in the field of post CPI. The combination of alemtuzumab with gaulthienzin-shacettuzumab can provide a synergistic effect in patients who develop progress after chemotherapy and immunotherapy, enabling alemtuzumab to enhance the anti-tumor immune response from inflammation mediated by the anti-tumor activity of gaulthienzin-shacettuzumab.

Rationale for immunotherapy-based treatment after initial imaging progression

In the study of immunotherapeutics, CR, partial Remission (PR) and disease stabilization all appear to occur following imaging evidence of a significant increase in tumor burden. This initial increase in tumor burden caused by immune cell infiltration in the context of T cell responses is called pseudo-progression (Hales et al, ann Oncol, 21.

In studying PCD4989g, evidence of response after tumor growth was observed in several tumor types. Furthermore, in some responsive patients with evidence of imaging progression, biopsies of new lesions or newly grown regions in existing lesions show immune cells but no viable cancer cells. Since responses may occur following spurious progression, the study allows patients randomized to the immunotherapy-based treatment group to continue combination therapy following significant imaging progression according to RECIST v1.1, provided that the benefit-risk ratio is judged to be favored by researchers. Patients should be discontinued due to unacceptable toxicity or loss of clinical benefit as determined by researchers after comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status.

The specific goals of the study and the corresponding endpoints are summarized in tables 78 and 79 below.

TABLE 78 stage 1 goals and corresponding endpoints

ADA = anti-drug antibody; CR = complete remission; DOR = duration of remission; irrecist = immune RECIST; ncitcae v4.0= standard 4.0 for universal term for adverse events at the national cancer institute of america; OS = overall lifetime; PFS = progression-free survival; PK = pharmacokinetics; PR = partial mitigation; RECIST v1.1= solid tumor efficacy assessment criteria version 1.1.

TABLE 79 stage 2 goals and corresponding endpoints

ADA = anti-drug antibody; CR = complete remission; DOR = duration of remission; iRECIST = immune RECIST; ncitcae v4.0= standard 4.0 for universal term for adverse events at the national cancer institute of america; OS = overall lifetime; PFS = progression-free survival; PK = pharmacokinetics; PR = partial mitigation; RECIST v1.1= solid tumor efficacy assessment criteria version 1.1.

D. Assessment and monitoring

Adverse events were closely monitored throughout the study in all patients and ranked according to the national cancer institute adverse event general terminology standard version 4.0 (NCI CTCAE v 4.0). Patients were assessed for tumors every 9 weeks (starting on day 1 of cycle 1) and every 12 weeks for the first 54 weeks. Responses assessed by researchers using RECIST v1.1 (Eisenhauer et al, eur J Cancer, 45. If clinical activity is demonstrated in the laboratory arm, the host may request that a oncology assessment scan of the arm be submitted for evaluation by a separate reading institution.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy at the time of study entry. If the researcher deems the biopsy to be unfeasible, an archive of the tumor tissue may be submitted. Tumor tissue is also collected from patients who have terminated phase 1 due to unacceptable toxicity or loss of clinical benefit, as determined by the investigator (if the investigator deems clinically feasible). These samples, as well as blood samples collected during the study, were used for biomarker studies.

To characterize the Pharmacokinetic (PK) profile and/or immunogenicity of alemtuzumab and other therapeutic agents, blood samples were obtained at different time points before and during study treatment administration.

E. End of study and duration of study

The end of the study was defined as the day when the last patient in both phases completed the last visit, including a follow-up visit for survival by phone or at the visit site.

The total length of the study (from screening of the first patient to the end of the study) will be about 3 to 5 years.

Example 21 materials and methods of the WO39613 mUC study

A. Stage 1 inclusion criteria

The patient must meet all criteria outlined below to qualify for stage 1 entry.

The age at which the informed consent was signed was 18 years or more.

Life expectancy > 3 months, as determined by the investigator.

Histologically recorded locally advanced (T4 b, any N; or any T, N2-N3) or metastatic UC (stage M1, IV) (also known as TCC or urothelial carcinoma; including renal pelvis, ureter, bladder and urethra). Patients with mixed histology need to have a dominant transitional cell pattern. Locally advanced bladder cancer must be inoperable based on pelvic sidewall or adjacent visceral involvement (clinical stage T4 b) or massive lymph node metastasis (N2-N3).

Availability of a representative tumor specimen suitable for determining PD-L1 and/or other biomarker status by a central test. Baseline tumor tissue samples are collected from all patients, preferably by biopsy at the time of entry into the study.

Representative formalin paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at least 16 slides containing unstained, freshly cut serial sections must 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. Based on the total and viable tumor content, the tumor tissue should be of good quality.

Fine needle aspiration, brushing, pleural effusion cell precipitation, bone metastases, and lavage samples are not acceptable. For core needle biopsy specimens, at least three cores should be submitted for evaluation. Patients with less than three available cores may still be eligible. TURBT specimens must contain the muscle layer invasive components of bladder tumors (i.e., T2 or greater), as evidenced by local pathological examination. If the TURBT specimen does not contain a muscle layer invasive component, specimens obtained at cystectomy/nephroureterectomy or metastatic spread (i.e., samples from metastatic lesions) are required prior to randomization.

Disease progression during or after treatment with no more than one platinum-containing regimen (e.g., GC, MVAC, carboGem) in the absence of surgery, locally advanced or metastatic UC, or disease recurrence. A regimen is defined as a patient receiving at least two cycles of a platinum-containing regimen. Patients who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months after treatment with platinum-containing adjuvant/neoadjuvant regimens were considered second-line patients. Patients may have received more than two prior treatment regimens for their advanced or metastatic UC (including the required platinum-based regimen). Patients must demonstrate disease progression during or after all previous treatment regimens. Patients with disease progression after chemoradiotherapy must demonstrate progression outside of the prior radiation therapy portal.

B. Inclusion criteria for stages 1 and 2

The patient must meet all criteria outlined below to qualify for stage 1 and stage 2 entry.

Ability to comply with the study protocol at the discretion of the investigator.

ECOG PS is 0 or 1.

Measurable disease (at least one target lesion) according to RECIST v 1.1. Only if the site clearly records disease progression after irradiation can the previously irradiated lesion be considered a measurable disease.

Adequate hematology and end organ function, defined as the following laboratory test results, obtained within 14 days before initiation of study treatment:

ANC ≥ 1.5X 10 under the support of granulocyte-free colony stimulating factor (G-CSF) ⁹ /L(1500/μL)。

-WBC count ≥ 2.5X 10 ⁹ /L(2500/μL)。

Lymphocyte count ≥ 0.5X 10 ⁹ /L(500/μL)。

In the case of no blood transfusion, the platelet count is ≥ 100X 10 ⁹ /L(100,000/μL)。

Hemoglobin. Gtoreq.90 g/L (9.0 g/dL).

The patient may need to be transfused with blood; however, transfusions were not allowed within 2 weeks of screening laboratory tests for eligibility.

Erythropoietin stimulating agents may be used by patients with isolated kidneys or chronic kidney disease with low erythropoietin production.

AST, ALT and alkaline phosphatase (ALP). Ltoreq.2.5 Xthe Upper Limit of Normal (ULN), with the following exceptions:

Patients with liver metastases were recorded: AST and/or ALT ≦ 5 × ULN

Patients with liver or bone metastases were recorded: ALP is less than or equal to 5 × ULN.

Bilirubin ≦ 1.5 × ULN, with the following exceptions:

patients with known gilbert disease: the bilirubin level is less than or equal to 3 × ULN.

Albumin ≥ 25g/L (2.5 g/dL).

Creatinine clearance ≧ 30mL/min (calculated using the Cockcroft-Gault equation).

-for a patient not receiving therapeutic anticoagulation:

PTT or aPTT is less than or equal to 1.5 multiplied by ULN

PT or INR is less than or equal to 1.5 × ULN.

For patients receiving therapeutic anticoagulation therapy: a stable anticoagulant regimen was used within 14 days prior to initiation of study treatment.

HIV test negative at screening. Patients who have not previously been positive for HIV test results will be tested for HIV at the time of screening unless permitted by local regulations.

Total hepatitis B core antibody (HBcAb) test negative at screening or total HBcAb test positive at screening, followed by quantification of Hepatitis B Virus (HBV) DNA < 500IU/mL. HBV DNA testing was performed only on patients who tested positive for total hbcabs.

Hepatitis C Virus (HCV) antibody test negative at screening; or positive for HCV antibody testing and then negative for HCV RNA testing when screened. Only patients who tested positive for HCV antibodies were tested for HCV RNA.

For women with fertility: consent was maintained to abstinence (avoidance of sexual intercourse) or use of contraceptive measures and consent was not donated to ova.

For males: consent was maintained (avoidance of sexual intercourse) or use of contraceptive measures, and consent was not donated sperm.

C. Stage 2 inclusion criteria

The patient must meet all of the following criteria to qualify for stage 2 entry:

patients in the attlizumab control arm: the ability to initiate stage 2 treatment within 3 months after the investigator determined the loss of clinical benefit when receiving control treatment.

Patients in the experimental arm during phase 1: the ability to begin stage 2 therapy within 3 months after receiving stage 1 therapy experiencing unacceptable toxicity or loss of clinical benefit not associated with atlizumab as determined by the investigator.

Availability of tumor specimens from biopsies performed at the end of stage 1.

D. Exclusion criteria

Patients who met any of the following criteria were excluded from the cohort during stage 1 and stage 2. The event ranking in the exclusion criteria was based on NCI CTCAE v4.0.

Exclusion criteria for stage 1

Patients who meet any of the following criteria are excluded from stage 1:

Previous treatments with T cell co-stimulation therapy or CPI, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.

Previous treatments using any protocol-specified study treatment, including treatment with poly (adenosine diphosphate [ ADP ] -ribose) polymerase (PARP) inhibitors, nectin-4 targeting agents, signal-regulatory protein alpha targeting agents, TIGIT targeting agents, trop-2 targeting agents, FAP-directed therapy, 4-1BB (CD 137) directed therapy, or topoisomerase 1 inhibitors.

Treatment with the investigational therapy within 28 days prior to initiation of study treatment.

Any approved anti-cancer therapy, including chemotherapy or hormone therapy, performed within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:

palliative radiotherapy on bone metastases or soft tissue lesions should be done > 14 days treatment before baseline imaging.

Hormone replacement therapy or oral contraceptives

Condition of control arm only

Stage 1 and stage 2 exclusion criteria

Patients who met any of the following criteria were excluded in stage 1 and stage 2:

previous allogeneic stem cell or solid organ transplantation.

Treatment with systemic immunostimulants (including but not limited to interferon and interleukin 2) within 4 weeks or 5 drug half-lives (whichever is longer) before initiation of study treatment.

Treatment with systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-alpha agents) within 2 weeks prior to initiation of study treatment, or the need for systemic immunosuppressive drugs during study treatment is expected, with the following exceptions:

patients receiving acute, low dose systemic immunosuppressant administration or one-time pulsed dose systemic immunosuppressant administration (e.g., 48 hours corticosteroid for contrast agent allergy) met the criteria of this study.

Patients receiving mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low doses of corticosteroids for treatment of orthostatic hypotension or adrenal insufficiency are eligible for this study.

Treatment with live attenuated vaccines within 4 weeks prior to initiation of study treatment, or such vaccines are expected to be required during treatment with atuzumab or within 5 months after the last dose of atuzumab.

Uncontrolled pleural effusion or ascites that requires repeated drainage procedures (once a month or more frequently). Allowing use of indwelling catheters (e.g. for

)。

Uncontrolled tumor-associated pain. Patients requiring analgesics must adopt a stable treatment regimen at the time of study entry. Symptomatic lesions (e.g., bone metastases or metastases that cause nerve contact) suitable for post-palliative radiation therapy should be treated prior to enrollment. The patient should have recovered from the effects of the radiation therapy. A minimum recovery period is not required. In the case of further increasing asymptomatic metastatic lesions (e.g. epidural metastases that are currently not associated with spinal cord compression), which may lead to functional defects or intractable pain, it should be considered (if appropriate) to carry out regional therapy prior to group entry.

Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5mmol/L, calcium > 12mg/dL, or corrected calcium > ULN).

Symptomatic, untreated, or actively progressing CNS metastasis. Asymptomatic patients with treated CNS lesions meet the criteria provided that all of the following criteria are met:

measurable disease determined according to RECIST v1.1 must be present outside the CNS.

Patient history of no intracranial bleeding or spinal cord bleeding.

Patients did not undergo stereotactic radiotherapy within 7 days before study treatment initiation, whole brain radiotherapy within 14 days before study treatment initiation, or neurosurgical resection within 28 days before study treatment initiation.

Patients do not have a constant need for corticosteroids as a therapy for CNS diseases. Allowing the use of stable doses of anticonvulsant therapy.

History of leptomeningeal disease.

Autoimmune diseases or immunodeficiency active phases or history, 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-barre syndrome or multiple sclerosis, with the following exceptions:

patients with a history of autoimmune-related hypothyroidism and who are receiving stable doses of thyroid replacement hormone are eligible for this study. Patients with type 1 diabetes and undergoing a stable insulin regimen were eligible for this study. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with only dermatological manifestations (e.g. with the exception of psoriatic arthritis patients) qualify for the present study if all of the following conditions are met:

the rash must cover < 10% of the body surface area.

The disease is well controlled at baseline and only low potency topical corticosteroids need to be used.

No acute exacerbation of the underlying condition requiring psoralen plus ultraviolet a radiation, methotrexate, retinoids, biologicals, oral calcineurin inhibitors or high potency or oral corticosteroids occurred within the past 12 months.

There is a history of idiopathic pulmonary fibrosis, organized pneumonia (e.g., bronchiolitis obliterans), drug-induced lung inflammation, or idiopathic lung inflammation, or evidence of active lung inflammation found in chest Computed Tomography (CT) scans. A history of radiation pneumonitis (fibrosis) in the radiation field was allowed.

In addition to malignancies with a history of malignancy other than UC during the first 2 years of screening, but with negligible risk of metastasis or death (e.g., 5-year overall survival > 90% [ OS ] rate), such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer. Patients with localized prostate cancer (defined as stage pT2c, gleason score < 7, and Prostate Specific Antigen (PSA) at the time of prostate cancer diagnosis < 20 ng/mL) who were treated for curative purposes and had no recurrence of PSA were eligible. Patients with pre-existing low risk prostate cancer (defined as stage cT1/T2a, gleason score ≦ 6, and PSA ≦ 10 ng/mL) who were treated initially and are undergoing active surveillance are eligible.

Active Tuberculosis (TB) (i.e., with signs and symptoms of TB).

Severe infections occurred within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization due to infection, bacteremia, or complications of severe pneumonia, or any active infection that researchers believe may affect patient safety.

Treatment with therapeutic oral or IV antibiotics within 2 weeks before initiation of study treatment.

Patients receiving prophylactic antibiotics (e.g., for preventing urinary tract infection or exacerbation of chronic obstructive pulmonary disease) are eligible for this study.

Significant cardiovascular diseases such as new york heart association heart disease (grade III or higher), myocardial infarction or cerebrovascular accident, unstable arrhythmia or unstable angina within 3 months prior to randomization.

Uncontrolled hypertension (defined as systolic > 140mmHg and/or diastolic > 95 mmHg). Allowing antihypertensive treatment to achieve these parameters.

Grade 3 bleeding or bleeding episodes occurred within 28 days before initiation of study treatment.

Major surgery was performed within 4 weeks prior to initiation of study treatment except for diagnosis or was expected to be required during the study. Placement of a central venous access catheter (e.g., port or similar catheter) is not considered a major procedure and is therefore permissible.

Adverse events from previous anti-cancer therapies have not improved to ≦ 1 or better, except in the case of alopecia of any grade or peripheral neuropathy of ≦ 2.

Any other disease, metabolic dysfunction, physical examination findings, or clinical laboratory findings that prohibit the use of study medication, may affect the interpretation of the results, impair the ability of the patient to participate in the study, or may place the patient at high risk for treatment complications.

History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins.

Allergic reactions to Chinese hamster ovary cell products or recombinant human antibodies are known.

Known intolerance or allergy to any study drug or its excipients, including histidine, trehalose dihydrate and polysorbate 20.

Known intolerance to any drug (acetaminophen, ranitidine, diphenhydramine and methylprednisolone) required for prophylactic use.

Patients entering stage 2: alemtuzumab could not be tolerated during phase 1.

Pregnancy or lactation, or pregnancy intended during the study. A female with fertility must be negative for serum pregnancy test results within 14 days before study treatment initiation.

Patients entering stage 2: immunotherapy-related adverse events have not resolved to grade 1 or better or baseline upon consent, with the following exceptions: patients with persistent endocrine events that are adequately managed using supplemental therapy are eligible.

Additional exclusion criteria for Atezo + Tira arms during phase 1

During phase 1, patients who met any of the following criteria were excluded from the Atezo + Tira arm:

active EBV infection at screening and known or suspected chronic active EBV infection. Patients who tested positive for EBV virus capsid antigen IgM at the time of screening were excluded from this arm. EBV Polymerase Chain Reaction (PCR) tests are performed to screen for active infection or suspected chronic active infection based on clinical indications. Patients who were positive for the EBV PCR test were excluded from the arm.

E. Allowed therapy

Patients were allowed the following therapies during the study:

oral contraceptives

Hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or a stable dose of low molecular weight heparin)

Administration of prophylactic antibiotics or antiviral treatments according to institutional criteria

Inactivated influenza vaccine

Administration of megestrol acetate as an appetite stimulant

Mineralocorticoids (e.g., fludrocortisone)

Administration of corticosteroids for chronic obstructive pulmonary disease or asthma

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency

Hormone therapy using gonadotropin-releasing hormone agonists or antagonists for prostate cancer

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

after 2 cycles of treatment, palliative radiation therapy is permissible as long as it does not interfere with the assessment of the tumor target lesion (e.g., the lesion to be irradiated cannot be the only site of measurable disease). Treatment with astuzumab may continue during palliative radiation therapy.

Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) as outlined below:

patients who experience mixed responses requiring topical therapy to control three or fewer lesions remain eligible for continued study treatment after approval by a medical supervisor. Patients receiving local therapy for the target lesion are no longer evaluable for imaging response, but are still evaluable for progression.

Prophylactic administration of antihistamines, antipyretics and/or analgesics may only be administered for the second and subsequent atuzumab infusions, as appropriate by the researcher.

Patients presenting with infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalents of local standard practice. Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and should be managed with supportive care (e.g., supplemental oxygen and beta) according to clinical indications ₂ Adrenergic agonists).

D. Materials and methods for attrituzumab arms

Attrituzumab was administered at a fixed dose of 1200mg every 3 weeks (Q3W) (1200 mg on day 1 of each 21 day cycle) (table 80), which is an approved dose: (b)

U.S.Package Insert；

SmPC). Antitumor activity was observed in a dose range of 1 to 20mg/kg Q3W. In the study PCD4989g, the maximum tolerated dose of atelizumab was not reached, and no dose-limiting toxicity was observed at any dose. A fixed dose of 1200mg Q3W (equivalent to a mean body weight-based dose of 15mg/kg Q3W) was selected based on two non-clinical studies (Deng et al, MAbs,8, 593-603, 2016) and available clinical pharmacokinetic, efficacy, and safety data.

Patients in the altlizumab control arm received treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator after a comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease). Treatment must be initiated no later than 7 days after treatment allocation. The patient underwent surgery after cycle 3; treatment in cycle 4 should be restarted 4 to 6 weeks after surgery.

TABLE 80 treatment regimens for the Atlizumab arm

Length of cycle	Dosage, route and regimen
		21 days	At day 1 of each cycle, atlas mab 1200mg IV

The administration of atezumab will be carried out in a monitored environment where trained personnel are immediately accessible as well as sufficient equipment and medications to manage potential critical reactions.

The alemtuzumab infusions were administered according to the instructions outlined in table 81.

TABLE 81 administration of the first and subsequent Abuzumab infusions

F. Material and method for attrituzumab and tiryleyuuzumab arm

Astuzumab was administered as described above (see table 81).

Ibritumomab tiuxetan was administered at a fixed dose of 600mg IV Q3W (600 mg on day 1 of each 21-day cycle). A fixed dose of 600mg IV Q3W was selected based on available clinical PK, efficacy and safety data from a combined phase Ia/Ib study GO30103 using either tegaseritumomab alone or in combination with atuzumab. In phase Ia part of the study using tirayleigh umab as single drug, MTD was not reached and no DLT was observed in dose escalation. By the clinical cutoff date, anti-drug antibodies (ADA) against telithromycin were rare at phase Ia or phase Ib fractions at all dose levels. Prolonged disease stabilization was observed in patients in phase Ia part of the study when the tirleituzumab dose was started at 400mg in phase Ib part of the study with tirleituzumab plus atuzumab, without reaching MTD. When tiregumab is combined with 1200mg of atelizumab, anti-tumor activity is observed across doses ranging from 30mg starting up to as much as 600mg, as measured by partial remission by imaging.

Patients in the alemtuzumab + tenestrizumab arm received treatment as outlined in table 82 until unacceptable toxicity or loss of clinical benefit as determined by the investigator after comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease). The patient underwent surgery after cycle 3; treatment in cycle 4 was restarted 4 to 6 weeks after surgery.

TABLE 82 treatment regimens for Atlizumab + Telleiuzumab arms

Tenecteuzumab was administered at a fixed dose of 600mg by IV infusion on day 1 of each 21-day cycle with a post-infusion observation period, as described in table 83. Administration of the tipleiuzumab is carried out in a monitored environment where trained personnel and sufficient equipment and medications are immediately available to manage potential critical reactions.

TABLE 83 administration of first and subsequent infusions of ibritumumab tiuxetan

The safety assessment of the WO39613mUC study was performed as described in example 18.

Example 22 statistical consideration and analysis plan for the WO39613mUC study

The WO39613 study analysis was based on patient data collected by study termination. If not otherwise specified, efficacy analysis is based on an efficacy evaluable population, defined as all patients receiving at least one dose of each drug in their assigned treatment regimen, and safety analysis is based on a safety evaluable population, defined as all patients receiving any amount of study treatment.

The results of the analysis are summarized by the treatment actually received by the patient and by the phase (phase 1 or phase 2, if applicable). Data are described and summarized in terms of sample amounts. The continuous variables were summarized by using mean, standard deviation, median, and minimum and maximum values. Categorical variables are summarized by using counts and percentages. If the sample size is small, a list is used instead of the table.

A. Determination of sample amount

The WO39613 study is not intended to make explicit efficacy and class I error considerations for hypothesis testing. Instead, the study was aimed at obtaining preliminary efficacy, safety and PK data for immunotherapy-based therapeutic combinations when these therapeutic combinations were advanced to patients with locally advanced or metastatic UC during or after platinum-containing regimens. During the study, approximately 160 to 385 patients were randomly transferred to the control and experimental arms.

B. Analysis of efficacy

End of primary efficacy

The primary efficacy endpoint was the Objective Remission Rate (ORR) during stage 1, as determined by the investigator according to RECIST v 1.1 and defined above (see table 78). Patients with missing or no response assessments were classified as non-responders.

Calculate the ORR (defined as the proportion of patients with CR or PR) for each arm, and 90% CI (Clopper-Pearson exact method). The ORR difference between the experimental and control arms was also calculated, as well as 90% CI. CI is estimated by the exact method or Wald method, depending on the sample volume.

Secondary efficacy endpoints

Secondary efficacy endpoints were Progression Free Survival (PFS), OS at a specific time point (e.g., 12 months), DOR, and disease control during stage 1, as defined above (see table 78). PFS, DOR and disease control were determined by researchers according to RECIST v 1.1.

DOR is derived from patients with appreciable efficacy in CR or PR.

For patients who had not recorded disease progression or death at the study stage, PFS and DOR were deleted on the day of last tumor assessment. Patients who remained alive at the time of OS analysis were missed on the last date they were known to survive.

The Kaplan-Meier method was used to estimate the median of PFS, OS and DOR, and 90% CI was constructed by using Brookmeyer and Crowley methods. The OS rate at a particular point in time is also estimated by using the Kaplan-Meier method, and the 90-percentile CI is calculated based on the Greenwood estimate for the variance.

The disease control rate (defined as the proportion of patients with disease stability ≧ 18 weeks, PR or CR) was calculated for each treatment arm, and 90% CI was estimated by using the Clopper-Pearson exact method.

Exploratory therapeutic endpoint

Exploratory efficacy endpoints were ORR, PFS, DOR, and disease control during stage 1 as determined by the investigator according to iRECIST; and objective remission, PFS, DOR, and disease control during stage 2 as determined by researchers according to RECIST v1.1 and irrecist. ORR, PFS, DOR, and disease control were analyzed using the same methods as described above. DOR is derived from patients with appreciable efficacy in CR or PR.

C. Middle term analysis

Interim analyses were performed during the study, the earliest of which occurred when at least one arm in phase 1 had completed the run-in of the prime and the patient had followed for at least 9 weeks. If deemed appropriate, further interim analysis may be performed. The posterior probability can be used to guide further cohorts based on interim analysis of clinical activity of the experimental arm compared to the control arm. If the interim analysis indicates that the activity of the experimental arm is higher than the control arm, the experimental arm can be further advanced to 25 additional patients in the group (extension phase). A final decision regarding extending and ending this phase 1b trial will be made that takes into account the overall benefit-risk balance and the integrity of the data, including time-to-event endpoints and safety data, as well as emerging external information.

An interim analysis was also performed after approximately 15 patients were enrolled in the phase 2 treatment arm and followed for a minimum of 9 weeks. If no clinical activity was observed in the phase 2 treatment arm, further enrollment of that arm was stopped.

D. Other analysis

Safety assays, pharmacokinetic assays, immunogenicity assays and biomarker assays were performed as described in example 19.

Example 23. A phase Ib/II, open label, multicenter, randomized, umbrella study on the assessment of efficacy and safety of immunotherapy-based therapeutic combinations in patients with locally advanced or metastatic esophageal cancer.

A. Overview of the study design

YO39609 is a phase Ib/II, open label, multicenter, randomized, umbrella study that assesses efficacy, safety, and pharmacokinetics of immunotherapy-based therapeutic combinations in patients with esophageal cancer. The study was aimed at obtaining preliminary efficacy, safety and PK data for immunotherapy-based therapeutic combinations when administered to patients with esophageal cancer. The design of the study also has the flexibility to open new treatment arms when new therapies are available, close existing treatment arms exhibiting minimal clinical activity or unacceptable toxicity, or adjust patient populations (e.g., with respect to previous anti-cancer treatments or biomarker status).

This study included patients with esophageal cancer who had not received prior systemic treatment for their disease. Eligible patients were randomly assigned to one of the three treatment arms. Patients in the control arm that experienced disease progression or unacceptable toxicity during stage 1 may be eligible for continued treatment with a different treatment regimen at stage 2.

Stage 1 treatment

During stage 1, patients with esophageal cancer were randomly assigned to either the chemotherapy cohort arm (cisplatin + 5-FU) or one of the two experimental arms: atuzumab in combination with tirayleigh mab and chemotherapy (Atezo + tirayleigh mab + cisplatin + 5-FU) or atuzumab in combination with chemotherapy (Atezo + cisplatin + 5-FU). Table 84 provides details of the phase 1 treatment regimen.

TABLE 84 phase 1 treatment regimen

1L = one line; 5-FU = 5-fluorouracil; atezo = alemtuzumab; tira = tireylauezumab. ^a The randomization ratio depends on the number of experimental arms that were opened into the cohort (e.g., if one arm was added or one arm was paused for waiting for a preliminary period of outcome analysis), where no more than 35% of patients were prescribed to be randomized to the control arm at a given time. The randomization ratio can be varied to increase the number of enrolled groups that have proven promising for clinical activity. ^b The host may decide to delay or pause the grouping of a given treatment arm. The experimental arm with minimal clinical activity or unacceptable toxicity was not expanded. ^c If clinical activity is observed in the experimental arm during the initial phase,

approximately 25 additional patients were included in the arm during the expansion phase.

Specific goals and corresponding endpoints for study phase 1 are summarized in table 85 below.

TABLE 85 phase 1 targets and corresponding endpoints

ADA = anti-drug antibody; DOR = duration of remission; IC = immune cells; IHC = immunohistochemistry; irrecist = improved RECIST v1.1 for use in an immune-based therapeutic; PFS = progression-free survival; PK = pharmacokinetics; RECIST v1.1= solid tumor efficacy assessment criteria version 1.1; TC = tumor cells; TIGIT = T cell immunoreceptor with Ig and ITIM domains.

Remarking: researchers evaluated the overall response at a single time point using RECIST v 1.1.

The two experimental arms were run in two phases: the initial phase is followed by an extension phase.

Approximately 100 to 165 patients were enrolled during phase 1. During the preliminary period, up to about 40 patients were enrolled in both experimental arms to ensure that there were a sufficient number of patients with high TIGIT and PD-L1 expression to facilitate assessment of benefit and risk in this subpopulation. If clinical activity is observed in the experimental arm during the preliminary phase, approximately 25 additional patients may be included in the arm during the extension phase. The host may decide to delay or pause the grouping of a given treatment arm.

The experimental arm with minimal clinical activity or unacceptable toxicity was not expanded. By revising the protocol, new experimental arms can be added during the study.

Patients were randomly assigned to treatment arms at stage 1 and the randomization rate was dependent on the number of available experimental arms (e.g., if one arm was added or one arm was paused to await a preliminary period of outcome analysis), with a probability of no more than 35% being prescribed for a transfer to a control arm. The randomization ratio can be varied to increase the population in the experimental group that has proven promising for clinical activity. Randomization takes into account arm-specific exclusion criteria. Patients do not meet the conditions for joining a particular arm if they meet any of the exclusion criteria outlined for that arm.

Patients in the control arm were treated until unacceptable toxicity occurred or disease progression according to recistv1.1 occurred. Patients in the experimental arm were treated until unacceptable toxicity or loss of clinical benefit as determined by the investigator after a comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease). Since immune cell infiltration may lead to an initial increase in tumor burden in the context of T cell responses (known as pseudoprogression) with Cancer Immunotherapy (CIT), such as atuzumab, the imaging progression according to RECIST v1.1 may not be indicative of true disease progression. In the absence of unacceptable toxicity, patients who meet the criteria for disease progression according to RECIST v1.1 during treatment with a CIT drug are allowed to continue study treatment if all of the following criteria are met:

evidence of clinical benefit, as determined by the investigator after review of all available data.

Absence of symptoms and signs (including laboratory values such as new or worsening hypercalcemia) indicative of definite disease progression.

Absence of a decline in ECOG physical performance state attributable to disease progression.

No tumor progression at critical anatomical sites (e.g. leptomeningeal disease) that the protocol allows for medical interventions to fail to address.

Written consent of the patients to admit deferral of other treatment options to support continuation of study treatment at the time of initial disease progression.

Stage 2 treatment

Patients in the control arm who experienced disease progression according to RECIST v1.1 may choose to receive different combinations of treatments during stage 2, provided they meet eligibility criteria and the stage 2 arm opens into the group. Stage 2 treatment regimen atuzumab plus rayleigh eculizumab.

Patients who experienced unacceptable toxicity in the control arm may be eligible for phase 2 treatment after approval by a medical supervisor. Phase 2 treatment must begin and continue within 3 months after the patient has experienced disease progression according to RECIST v1.1 or unacceptable toxicity at phase 1 until unacceptable toxicity or clinical benefit is lost as determined by the investigator.

The specific goals and corresponding endpoints for study stage 2 are summarized in table 86 below.

TABLE 86 stage 2 goals and corresponding endpoints

ADA = anti-drug antibody; DOR = duration of remission; iRECIST = modified RECIST v1.1 for use in an immune-based therapeutic; OS = overall lifetime; PFS = progression-free survival; PK = pharmacokinetics; RECIST v1.1= solid tumor efficacy assessment criteria version 1.1.

Remarking: researchers evaluated overall responses at a single time point using RECIST v 1.1.

Phase 2 treatment must begin and continue within 3 months after the patient has experienced disease progression according to RECIST v1.1 or unacceptable toxicity at phase 1 until unacceptable toxicity or clinical benefit is lost as determined by the investigator. However, patients are advised to begin phase 2 treatment as soon as possible.

The sponsor may also decide to terminate the grouping of phase 2 treatment arms based on review of safety data, preliminary efficacy data, and supportive information (e.g., biomarker study data), if appropriate.

B. End of study and duration of study

The end of the study was defined as the day when the last patient completed the last visit, including a follow-up visit for life by phone or at the visit site.

The total length of the study (from screening of the first patient to the end of the study) will be about 3 to 6 years.

C. Rationale for study design and patient population

The study is aimed at accelerating the development of Cancer Immunotherapy (CIT) combinations by identifying early signals and building proof-of-concept clinical data for patients with esophageal cancer.

CIT has enjoyed exceptional success with significant survival benefits observed in a variety of advanced malignancies. Currently, the prevalent CIT approach is to circumvent immune escape mechanisms and to re-mount the anti-tumor response by identifying and targeting T cell co-inhibitory surface receptors such as CTLA-4 and PD-L1/PD-1. Although these targets have brought significant clinical therapeutic success for various cancer indications, ongoing studies indicate a series of stepwise events necessary to generate a sustained anti-tumor immune response (Chen and Mellman, immunity, 39. Each event is critical for an effective response, and each event is also susceptible to several mechanisms of tumor immune escape. Therefore, the need to identify and circumvent various factors involved in tumor immune escape is crucial for the propagation of anti-tumor immune responses and the advancement of the CIT field, most likely by combinatorial approaches.

Esophageal cancer is a disease with highly unmet medical needs, with 5-year survival rate for metastatic esophageal cancer being 5%, and 24% for locally advanced disease. Patients with advanced or metastatic esophageal cancer have limited treatment options, poor prognosis, and minimal overall survival benefit. Thus, there is a continuing need for more effective and more tolerable treatments for this patient population.

Example 24 materials and methods of the YO39609 study

During the YO39609 study, approximately 100 to 165 patients with esophageal cancer who had not received systemic therapy in this setting were randomly assigned to the control and experimental arms.

K. Stage 1 inclusion criteria

Patients must meet all of the following criteria outlined below to qualify for stage 1 entry.

The age at which informed consent was signed was 18 years old or older.

ECOG physical performance status is 0 or 1.

Histologically or cytologically confirmed diagnosis of esophageal squamous cell carcinoma or adenocarcinoma in locally advanced or metastatic disease.

A definitive diagnosis of metastatic esophageal cancer is made by evaluating histopathological data in the context of clinical and imaging data.

No previous systemic treatment for esophageal cancer, except:

-for patients receiving chemotherapy in locally advanced stages: metastasis occurred after 6 months from the last dose of chemotherapy.

For patients with adenocarcinoma: at the time of initial diagnosis of disease, HER2 expression was absent in previously collected and assessed tumor tissues, as indicated by ISH negativity.

HER2 negative status was determined as IHC 0 or IHC 1+ based on ISH non-amplification (ratio of HER2 to CEP17 < 2.0 or single probe mean HER2 gene copy number < 4 signals/cell) (if more than one test result is available and not all results meet the inclusion criteria definition, all results should be discussed with a medical supervisor to determine patient eligibility).

Life expectancy > 3 months, as determined by the investigator.

Creatinine clearance (CrCl) ≧ 50mL/min (calculated using the Cockcroft-Gault equation).

Availability of representative tumor specimens suitable for determining PD-L1 and TIGIT levels by IHC and/or other biomarker status by retrospective central testing.

-collecting baseline tumor tissue samples from all patients, preferably by biopsy at the time of entry into the study. If the investigator deems the biopsy to be infeasible, an archived tumor tissue may be submitted after approval by a medical supervisor, provided that the tissue was obtained from a biopsy taken within 6 months prior to enrollment and that the patient did not receive any anti-cancer therapy since the time of biopsy.

FFPE tumor specimens in paraffin blocks (preferred) or at least 16 slides containing unstained, newly cut serial sections must 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 approval by the medical supervisor.

L. inclusion criteria for stages 1 and 2

The patient must meet all of the following criteria outlined below to qualify for stage 1 and stage 2 entry.

Sign informed consent.

Ability to comply with the study protocol at the discretion of the investigator.

Measurable disease as determined according to RECIST v 1.1. Only when disease progression is clearly documented at this site after irradiation can previously irradiated lesions be considered measurable disease.

Appropriate blood and end organ function, defined by the following laboratory test results obtained within 14 days before the initiation of study treatment:

-an ANC of 1.5X 10 or more, supported by granulocyte-free colony stimulating factor ⁹ /L(1500/μL)。

Lymphocyte count ≥ 0.5X 10 ⁹ /L(500/μL)。

In the case of no blood transfusion, the platelet count is ≥ 100X 10 ⁹ /L(100,000/μL)。

Hemoglobin. Gtoreq.90 g/L (9 g/dL). Blood transfusions may be given to patients to meet this criteria.

AST, ALT and alkaline phosphatase (ALP). Ltoreq.2.5 Xthe Upper Limit of Normal (ULN), with the following exceptions:

Patients with liver metastases were recorded: AST and ALT are less than or equal to 5 multiplied by ULN.

Patients with liver or bone metastases were recorded: ALP is less than or equal to 5 × ULN.

Bilirubin ≦ 1.5 × ULN, with the following exceptions:

patients with known gilbert disease: the bilirubin level is less than or equal to 3 × ULN.

Albumin ≥ 25g/L (2.5 g/dL).

-for a patient not receiving therapeutic anticoagulation: INR or aPTT is less than or equal to 1.5 multiplied by ULN.

-for a patient receiving therapeutic anticoagulation: stabilized anticoagulant regimen.

HIV tests were negative at screening, except: patients who tested positive for HIV meet the criteria for screening, provided they are stable during antiretroviral therapy, have a CD4 count of 200/μ L or greater, and no detectable viral load.

The hepatitis B surface antigen (HBsAg) test was negative at the time of screening.

Total hepatitis B core antibody (HBcAb) test negative at screening or total HBcAb test positive at screening, followed by quantification of Hepatitis B Virus (HBV) DNA < 500IU/mL. HBV DNA testing was performed only on patients who tested positive for total hbcabs.

Hepatitis C Virus (HCV) antibody test negative at screening; or positive for HCV antibody testing and then negative for HCV RNA testing when screened. Only patients who tested positive for HCV antibodies were tested for HCV RNA.

For fertile women: consent was maintained to abstinence (avoidance of sexual intercourse) or use of contraceptive measures and consent was not donated to ova.

For males: consent was maintained to abstinence (avoidance of sexual intercourse) or use of contraceptive measures, and consent was not donated sperm.

M. inclusion criteria for stage 2

The patient must meet all of the following criteria outlined below to qualify for stage 2 entry.

ECOG physical performance status is 0, 1 or 2.

Patients randomized to control arm during phase 1: the ability to initiate stage 2 treatment within 3 months after disease progression according to RECIST v1.1 or experiencing unacceptable toxicity upon receiving control treatment (provided medical supervisor approval to enter stage 2 is obtained).

Creatinine ≦ 1.5 × ULN or CrCl ≧ 30mL/min (calculated using the Cockcroft-Gault equation).

A biopsy performed at the end of stage 1 due to unacceptable toxicity or disease progression according to RECIST v1.1 can obtain a tumor specimen (if deemed clinically viable).

N. exclusion criteria

Patients who met any of the following criteria were excluded from cohort during stage 1 and stage 2.

Stage 1 exclusion criteria

Patients who met any of the following criteria were excluded from stage 1:

Prior treatment with study treatment indicated by any protocol.

Patients known to be hearing impaired.

Grade 2 peripheral neuropathy as defined according to the NCI CTCAE v4.0 standard.

Known dihydropyrimidine dehydrogenase deficiencies or thymidylate synthase gene polymorphisms predispose patients to 5-FU toxicity.

Stage 1 and stage 2 exclusion criteria

Patients who meet any of the following criteria are excluded from stage 1 and stage 2:

high risk of esophageal fistulae, such as a previous history or associated symptoms of esophageal fistulae or T4 classification found by sonoendoscopy, found by clinical assessment or imaging.

Symptomatic, untreated, or actively progressing Central Nervous System (CNS) metastasis. Asymptomatic patients with treated CNS lesions are eligible provided that all of the following criteria are met:

measurable disease determined according to RECIST v1.1 must be present outside the CNS.

Patient history of no intracranial bleeding or spinal cord bleeding.

Patients did not undergo stereotactic radiotherapy within 7 days before study treatment initiation, did not undergo whole brain radiotherapy within 14 days before study treatment initiation, or did not undergo neurosurgical resection within 28 days before study treatment initiation.

Patients do not have a constant need for corticosteroids as a therapy for CNS diseases. Allowing the use of stable doses of anticonvulsant therapy.

Metastasis is limited to the cerebellum or supratentorial region (i.e., 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 detected CNS metastases at the time of screening are eligible for the study after receiving radiation therapy or surgery without repeated screening brain scans.

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 when EBV IgM and/or EBV PCR is negative.

History of leptomeningeal disease.

Uncontrolled tumor-associated pain. Patients requiring analgesics must adopt a stable treatment regimen at the time of study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve touch) suitable after palliative radiation therapy should be treated prior to enrollment. The patient should have recovered from the effects of the radiation therapy. A minimum recovery period is not required. In further increasing cases asymptomatic metastatic lesions that may lead to functional defects or intractable pain (e.g. epidural metastasis that is currently not associated with spinal cord compression), regional treatment should be considered (if appropriate) prior to enrollment.

Uncontrolled pleural effusion or ascites requiring repeated drainage procedures (once a month or more). An indwelling catheter (e.g.,

) Is allowed.

Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5mmol/L, calcium > 12mg/dL, or corrected calcium > ULN).

Autoimmune diseases or immunodeficiency active phases or history, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, wegener's granulomatosis, sjogren's syndrome, guillain-barre syndrome, or multiple sclerosis, with the following exceptions:

patients with a history of autoimmune-related hypothyroidism and who are receiving stable doses of thyroid replacement hormone are eligible for this study.

Patients with type 1 diabetes and undergoing an insulin regimen were eligible for this study.

Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with only dermatological manifestations (e.g. with the exception of psoriatic arthritis patients) qualify for the present study if all of the following conditions are met:

the rash must cover < 10% of the body surface area.

The disease is well controlled at baseline and only low potency topical corticosteroids need to be used.

No acute exacerbation of the underlying condition requiring psoralen plus ultraviolet a radiation, methotrexate, retinoids, biologicals, oral calcineurin inhibitors or high potency or oral corticosteroids occurred within the past 12 months.

There is a history of idiopathic pulmonary fibrosis, organized pneumonia (e.g., bronchiolitis obliterans), drug-induced lung inflammation, or idiopathic lung inflammation, or evidence of active lung inflammation found in chest Computed Tomography (CT) scans. A history of radiation pneumonitis (fibrosis) in the radiation field was allowed.

Active tuberculosis.

Significant cardiovascular disease (such as new york heart association grade II or higher heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmia, or unstable angina was experienced within 3 months prior to initiation of study treatment.

Major surgery was performed within 4 weeks prior to initiation of study treatment except for diagnosis or was expected to be required during the study.

With the exception of malignancies with a history of malignancy other than esophageal cancer within 2 years prior to screening, but with negligible risk of metastasis or death (e.g., 5 year OS rate > 90%), such as well-treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer.

Severe infections occurred within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization due to complications from infection, bacteremia, or severe pneumonia.

Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.

Patients receiving prophylactic antibiotics (e.g., for preventing urinary tract infection or chronic obstructive pulmonary disease exacerbations) are eligible for the study.

Previous allogeneic stem cell or solid organ transplantation.

Any other disease, metabolic dysfunction, physical examination findings or clinical laboratory findings that prohibit the use of research drugs, may affect the interpretation of the results or may place the patient at high risk for treatment complications.

Treatment with live attenuated vaccine within 4 weeks prior to initiation of study treatment, or such vaccine is expected to be required during treatment with alemtuzumab or within 5 months after the last dose of alemtuzumab.

Current treatment with antiviral therapies against HBV.

Known allergic reactions or allergies to any study drug or its excipients.

Treatment with the investigational therapy within 28 days prior to initiation of study treatment.

Prior treatments with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-TIGIT therapeutic antibodies.

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 a 5 drug elimination half-life (whichever is longer).

Treatment with systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or the need for systemic immunosuppressive drugs during study treatment is expected, with the following exceptions:

patients receiving acute, low dose systemic immunosuppressant medication or one-time pulsed dose systemic immunosuppressant medication (e.g. 48 hours corticosteroid for contrast agent allergy) are eligible for the study after approval by the medical supervisor.

Patients receiving mineralocorticoids (e.g. fludrocortisone), corticosteroids for Chronic Obstructive Pulmonary Disease (COPD) or asthma or low doses of corticosteroids for the treatment of orthostatic hypotension or adrenal insufficiency meet the criteria of this study.

History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins.

Known to be allergic to chinese hamster ovary cell products or to any component of the attritumab and tenecteuzumab formulations.

Pregnancy or lactation, or plan to be pregnant during the study or within 5 months of the last dose of atelizumab or within 5 months after the last dose of tenecteuzumab. A female with fertility must be negative for serum pregnancy test results within 14 days before study treatment initiation.

O. approved therapy

Patients were allowed the following therapies during the study:

oral contraceptives

Hormone replacement therapy

Prophylactic or therapeutic anticoagulant therapy (such as a stable dose of warfarin or low molecular weight heparin)

Inactivated influenza vaccine

Administration of megestrol acetate as an appetite stimulant

Mineralocorticoids (e.g. fludrocortisone)

Administration of corticosteroids for chronic obstructive pulmonary disease or asthma

Administration of low doses of corticosteroids for orthostatic hypotension or adrenocortical insufficiency

Palliative radiotherapy (e.g., treatment of known bone metastases or relief of pain symptoms) is summarized as follows:

palliative radiotherapy is permissible as long as it does not interfere with the assessment of the tumor target lesion (e.g., the lesion to be irradiated cannot be the only site of measurable disease). Treatment with atelizumab may continue during palliative radiotherapy.

Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) as outlined below:

patients who experience mixed responses requiring topical therapy to control three or fewer lesions remain eligible for continued study treatment after approval by a medical supervisor. Patients receiving local therapy for the target lesion respond to imaging but can still assess progression.

Prophylactic administration of antihistamines, antipyretics and/or analgesics may only be administered for the second and subsequent atuzumab infusions, as appropriate by the researcher.

Patients presenting with infusion-related symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalents of local standard practice. Severe infusion-related events manifest as dyspnea, hypotension, wheezing, bronchospasm, tachycardia, decreased blood oxygen saturation, or respiratory distress, and should be managed with supportive therapy (e.g., supplemental oxygen and beta) based on clinical indications ₂ Adrenergic agonists).

Administration and administration of

Patients in the following treatment arms received treatment as outlined until unacceptable toxicity or loss of clinical benefit as determined by the investigator after comprehensive assessment of imaging and biochemical data, local biopsy results (if any), and clinical status (e.g., worsening of symptoms, such as pain secondary to the disease).

Attrituzumab, terayleigh eryusizumab, cisplatin and 5-fluorouracil arm

Patients in the alemtuzumab + terayleigh immuzumab + cisplatin +5-FU arm received treatment as outlined in table 87.

TABLE 87 therapeutic regimens for alemtuzumab + terayleigh immuzumab + cisplatin +5-FU arm

5-FU = 5-fluorouracil; ^a cisplatin treatment capped after 6 doses. ^b The infusion time of cisplatin and 5-FU can be adjusted according to local standard practice.

Atuzumab + cisplatin + 5-fluorouracil arm

Patients in the alemtuzumab + cisplatin +5-FU arm received treatment as outlined in table 88.

TABLE 88 therapeutic regimens of Atlizumab + cisplatin +5-FU arms

5-FU = 5-fluorouracil; ^a cisplatin treatment capped after 6 doses. ^b The infusion time of cisplatin and 5-FU can be adjusted according to local standard practice.

Contrast arm (cisplatin + 5-FU)

Cisplatin was administered at 80mg/m on day 1 of the first six 21-day cycles ² Is administered by IV infusion over 120 minutes. Starting on day 1 of each 21-day cycle, 5-FU is at 800mg/m ² The dose/24 hours was administered by continuous IV infusion over days 1 to 5 (120 hours). Cisplatin treatment lasted a total of 6 cycles unless unacceptable toxicity occurred or the patient was withdrawn from study treatment for any reason. Patients with cisplatin +5-FU control arm received treatment until unacceptable toxicity or disease according to RECIST v1.1 occurs The disease progresses.

Stage 2 treatment of control arm (Attuzumab + Eityleyumab)

Patients in the alemtuzumab + tenestrizumab arm received treatment as outlined in table 89.

TABLE 89 treatment regimens for alemtuzumab + tenecteuzumab arms

Patients undergoing disease progression according to RECIST v1.1 may choose to receive different combinations of treatments during stage 2 of the study, provided they meet eligibility criteria and stage 2 arms are opened into the group.

Patients experiencing unacceptable toxicity may also be eligible to receive treatment during stage 2, provided they meet eligibility criteria and after they have been approved by a medical supervisor. Stage 2 treatment must begin within 3 months after the patient has experienced disease progression or unacceptable toxicity. An assessment of tumors made during stage 1 prior to or at the time of disease progression or unacceptable toxicity can be taken as a baseline assessment for stage 2, provided that the tumor assessment is made within 28 days prior to initiation of stage 2 therapy (i.e., day 1 of cycle 1). Phase 2 treatment was continued until the investigator determined unacceptable toxicity or loss of clinical benefit.

The attritumab infusions were administered according to the instructions summarized in table 90.

TABLE 90 administration of the first and subsequent Abuzumab infusions

Infusion of telithromumab was administered according to the instructions outlined in table 91.

TABLE 91 administration of first and subsequent infusions of ibritumumab

Period of safety assessment

Given the potential overlapping toxicity in the arms of atuzumab + terayleigh umab + cisplatin +5-FU, enrollment was suspended for safety assessment after approximately 6 patients had been enrolled. Safety assessments are based on safety data from a minimum of 6 patients who have received at least one dose of treatment (i.e., one dose of each agent of a given combination) and completed a safety follow-up for at least one complete treatment cycle. If the combination is determined to be sufficiently safe, the arm's grouping is resumed.

R. assessment and monitoring

Adverse events were closely monitored throughout the study in all patients and ranked according to the national cancer institute adverse event general terminology standard version 4.0 (NCI CTCAE v 4.0). Patients were assessed for tumors every 6 weeks (starting on day 1 of cycle 1) during the first 12 months, and then every 6 or 12 weeks. Responses were assessed by researchers using RECIST v1.1 (Eisenhauer et al, eur J Cancer, 45-228-247, 2009). Responses according to RECIST v1.1 (irrecist) modified for immunotherapy were determined programmatically by the host based on individual lesion data assessed by the investigator (Seymour et al, lancet Oncol,18 e143-152, 2017. If clinical activity is demonstrated in the laboratory arm, the host may request that a oncology assessment scan of the arm be submitted for evaluation by a separate reading institution.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy at the time of study entry. If the researcher deems the biopsy to be unfeasible, an archive of the tumor tissue may be submitted. Tumor tissue was also collected from patients who terminated stage 1 due to unacceptable toxicity, disease progression according to RECIST v1.1 (control arm), or clinical benefit loss as determined by the investigator (experimental arm), if the investigator deemed clinically viable. For patients in the extension phase enrolled arm, treatment session tumor tissue samples were collected 4 weeks (if clinically feasible) after initiation of stage 1 treatment, unless treatment session tissue samples had been collected from a minimum of 15 patients treated with the same CIT combination and were determined to be evaluable. These samples, as well as blood samples collected during the study, were used for biomarker studies.

To characterize the Pharmacokinetic (PK) profile and/or immunogenicity of alemtuzumab and other therapeutic agents, blood samples were obtained at different time points before and during study treatment administration.

Tumor and response assessment

Patients were assessed for tumors at baseline, every 6 weeks (+ -1 week) within the first 12 months after initiation of treatment, and every 12 weeks (+ -2 weeks) thereafter, regardless of dose delay, until progression of imaging disease according to RECIST v1.1, except patients who continued treatment after progression of imaging disease; such patients are evaluated for tumors every 8 weeks (+ -1 week) until the investigator determines a loss of clinical benefit.

Thus, for patients who stop treatment for reasons other than disease progression or loss of clinical benefit, tumor assessment should continue as planned even if they begin a new non-regimen prescribed anti-cancer treatment. Tumor assessment is repeated over time if disease progression is suspected, as appropriate by the investigator.

The baseline tumor assessment for phase 2 must be performed within 28 days before the initiation of phase 2 treatment (i.e., day 1 of cycle 1). For patients eligible for stage 2, the tumor assessment performed during stage 1 before or at the time of unacceptable toxicity or disease progression (control arm) or loss of clinical benefit (experimental arm) according to RECIST v1.1 can be taken as a baseline assessment for stage 2, provided that the tumor assessment is performed within 28 days before initiation of stage 2 treatment.

All measurable and evaluable lesions should be assessed and recorded at screening (both stage 1 and stage 2). Brain metastases treated with radiotherapy or surgery are not considered measurable or evaluable, but are recorded as sites of metastatic disease. Assessment of tumors as a standard of care, performed 28 days before informed consent was obtained and before study treatment was initiated, need not be repeated at screening.

Screening assessments must include CT scans (using oral and/or IV contrast agents) or Magnetic Resonance Imaging (MRI) scans of the chest, abdomen and pelvis. A helical CT scan of the breast can be obtained but is not required. If there is contraindication for contrast agent CT scans (i.e. patients with contrast agent allergies or impaired renal clearance), a chest non-contrast agent CT scan and MRI scans of the abdomen and pelvis (if feasible with IV contrast agents) should be performed. If clinically indicated, bone and CT scans of the neck should also be performed. Other methods of assessing measurable disease according to RECIST v1.1 may be used as appropriate by the investigator.

If a CT scan for tumor assessment is performed in a positron emission tomography/CT scanner, a CT acquisition must be performed to meet the criteria of a full contrast diagnostic CT scan.

All measurable and/or evaluable lesions identified at baseline should be re-assessed in subsequent tumor assessments. Brain metastases identified at baseline that have been treated with radiation therapy or surgery are not considered measurable or evaluable unless there is suspected disease progression in the brain (i.e., the patient presents symptoms). Thus, no subsequent CT scan of the head is required unless clinically indicated. Subsequent tumor assessment should use the same radiological procedure (e.g., the same contrast agent protocol as CT scan) used to assess the disease site at the time of screening. To facilitate evaluation of the response according to iRECIST, for patients who continue to receive treatment after progression, tumor assessment must be continued after disease progression according to RECIST v 1.1. This includes continuous measurement of the target lesion, assessment of non-target lesions (including monitoring the further deterioration of any non-target lesions that have shown clear progression), and assessment of any newly identified lesions (including measurements if the lesion is measurable) in all subsequent assessments. Investigators evaluated overall response at a single time point using RECIST v1.1

Biomarker assessment

Exploratory biomarker studies may include, but are not limited to, analysis of genes or gene signatures related to tumor molecular subtypes and tumor immunobiology, PD-L1, lymphocyte subpopulations, T cell receptor repertoires, cytokines related to T cell activation or density, IC and subsets thereof localization and activation status, and may involve DNA or RNA extraction, somatic mutation analysis, and use of Next Generation Sequencing (NGS), including Whole Exome Sequencing (WES).

Blood samples were collected at baseline and during the study for biomarker assessment. Changes in biomarkers in the blood can provide evidence of the biological activity of a particular therapeutic combination. Correlations between surrogate biomarkers in blood (such as tumor burden markers, cytokines, chemokines, IC subpopulations, gene expression, and circulating tumor DNA) and drug dose, efficacy, and safety endpoints may help in developing blood-based biomarkers to help define future treatments that can predict which patients are more likely to benefit from a particular combination of treatments.

Baseline tumor tissue samples are collected from all patients, preferably by biopsy at the time of study entry. Tumor tissue samples collected at baseline were used for determination of PD-L1 and TIGIT expression and exploratory studies of biomarkers. If the investigator deemed clinically viable, tumor tissue was collected from patients who terminated treatment during phase 1 due to unacceptable toxicity as determined by the investigator, disease progression according to RECIST v1.1, or loss of clinical benefit to enable analysis of tumor tissue biomarkers related to resistance to study treatment, disease progression, and clinical benefit.

If the investigator deemed clinically feasible, patients in the extension phase arm were biopsied during treatment at 4 weeks (+ -7 days) after initiation of phase 1 treatment, unless treatment-period tissue samples had been collected from a minimum of 15 patients treated with the same CIT combination and determined to be evaluable. To better understand the potential biological changes (including immune escape) that occur during treatment with the CIT combination, tissue samples were collected during treatment, to provide evidence of pharmacodynamic effects, or to confirm a postulated mechanism of action.

The tumor samples were evaluated for biomarkers such as tumor infiltration IC, PD-L1, TIGIT, and CD8. Assessing changes in the tumor microenvironment in each arm in response to treatment, including the number and functional status of tumor-infiltrating ICs, can provide verification of putative mechanisms of action and confirmation that the appropriate dose and exposure has been achieved for a particular combination of treatments.

Somatic mutations can be identified by analyzing tumor tissue and blood samples using NGS, including WES, and such mutations can be predictive of response to study drugs, correlate with progression of disease to a more severe state, correlate with acquired resistance to study drugs, correlate with sensitivity to developing adverse events, or can increase knowledge and understanding of disease biology.

Example 25 statistical consideration and analysis planning for the YO39609 study

The final study analysis was based on patient data collected by study termination. If not otherwise specified, the efficacy analysis is based on a efficacy evaluable population, defined as all patients receiving at least one dose of each drug in their assigned treatment regimen, and the safety analysis is based on a safety evaluable population, defined as all patients receiving any amount of study treatment.

The results of the analysis are summarized in terms of the treatment actually received by the patient. Results were also summarized by stage (stage 1 or stage 2) as long as stage 2 treatment was available. Data are described and summarized in terms of sample amounts. Continuous variables were summarized by mean, standard deviation, median and range. Categorical variables are summarized by using counts and percentages. If the sample size is small, a list is used instead of the table.

A new baseline value was established for stage 2 efficacy and safety analysis. To assess tumor response, a new baseline tumor assessment was established. For other endpoints (e.g., changes in vital signs or laboratory test results from baseline), the last non-missing value prior to the first dose to the patient during phase 2 was used as a new baseline.

Determination of sample amount

This study is not intended to make explicit efficacy and class I error considerations for hypothesis testing. In contrast, the present study was aimed at obtaining preliminary efficacy, safety and PK data for an immunotherapy-based therapeutic combination when administered to patients with esophageal cancer.

The study included patients with esophageal cancer who had not received systemic therapy in this situation. Approximately 100 to 165 patients were randomly assigned to the control and experimental arms during the study.

G. Analysis of efficacy

The population for which efficacy can be assessed is defined as all patients receiving at least one dose of each drug in a prescribed treatment regimen. The therapeutic endpoints are summarized according to the actual therapeutic arm.

End of primary efficacy

The primary efficacy endpoint was the Objective Remission Rate (ORR) during stage 1 based on RECIST v1.1, defined as the proportion of patients with objective remission. Objective remission is defined as complete or partial remission achieved twice consecutively at intervals of > 4 weeks, as determined by researchers using RECIST v 1.1. Patients who did not meet this criterion (including patients who did not receive a post-baseline tumor assessment) were considered non-responders. ORR and its 95% CI (Clopper-Pearson method) are summarized. The analysis population for ORR was the one with evaluable efficacy.

Secondary efficacy endpoints

Secondary efficacy endpoints were PFS, OS at specific time points (e.g., 6 months and 12 months), duration of remission (DOR), disease control during stage 1, objective remission in patients with TIGIT positive tumors, and objective remission in patients with PD-L1 positive tumors, as defined in table 77. PFS, DOR and disease control were determined by researchers according to RECIST v 1.1.

DOR was obtained for patients with appreciable efficacy with confirmed complete or partial remission. For patients who had not recorded disease progression or death at the study stage, PFS and DOR were deleted on the day of last tumor assessment. Patients who remained alive at the time of OS analysis were missed on the last date they were known to survive.

The Kaplan-Meier method was used to estimate the median of PFS, OS and DOR, and 90% Confidence Intervals (CI) were constructed by using the Brookmeyer and Crowley methods. The OS rate at a particular time point was also estimated using the Kaplan-Meier method, and the 90-percentile ci was calculated based on the Greenwood estimate for variance.

The disease control rate (defined as the proportion of patients with stable disease ≧ 16 weeks, partial remission or complete remission) was calculated for each treatment arm, and 90-percentile CI was estimated by using the Clopper-Pearson exact method.

Exploratory therapeutic endpoint

Exploratory efficacy endpoints were objective remission, PFS, DOR, and disease control during stage 1 as determined by the investigator according to iRECIST, and objective remission, PFS, DOR, and disease control during stage 2 as determined by the investigator according to RECIST v1.1 and iRECIST.

H. Security analysis

The safety analysis included all patients receiving at least one dose of any component of the study treatment. The study treatment exposure was summarized in its entirety by the actual treatment group at each stage.

The word-by-word recorded adverse event terms are mapped to the supervised active medical dictionary thesaurus terms and the adverse event severity is ranked according to NCI CTCAE v 4.0.

Safety was assessed by aggregating adverse events, changes in laboratory test results, changes in vital signs and ECG, and exposure to study drugs. The length of the exposure and safety follow-up of the combination treatment was summarized by treatment arm within each stage.

Adverse events that occurred in the treatment after initiation of treatment were summarized. For each patient, the maximum reported severity for each adverse event was used in the summary by severity scale. All adverse events occurring during treatment, critical adverse events, adverse events leading to study withdrawal, grade 3 adverse events, mortality, and cause of death were listed and summarized in mapping terms, appropriate synonym levels, and NCICTCAE severity ratings.

Relevant laboratory, vital signs (pulse rate, respiration rate, pulse oximetry, blood pressure and body temperature) and ECG data are displayed over time and rated where appropriate. In addition, the baseline and maximum post-baseline severity ratings were summarized using a transpose table of selected laboratory tests. Vital signs and changes in ECG were summarized.

I. Pharmacokinetic analysis

Sparse samples were collected for PK analysis of atlizumab (patient receiving at least one dose of atlizumab) and the particular drug administered in combination with atlizumab (patient receiving at least one dose of the drug). Serum or plasma concentrations of each study drug were reported as individual values and summarized by treatment arm, period and day (mean, standard deviation, coefficient of variation, median, range, geometric mean and geometric mean coefficient of variation) as appropriate and data allowed. Individual and median serum or plasma concentrations for each study drug were plotted on treatment arms, periods, and days. PK data for the combination drug can be compared to available historical data from internal and published prior studies. The attritumab concentration data can be merged with data from other studies using established population PK models to derive PK parameters such as clearance, volume of distribution and area under the concentration-time curve.

J. Immunogenicity assays

The immunogenicity of the alemtuzumab and other study treatments was assessed, if appropriate. The immunogenicity assay of atuzumab includes all patients evaluated for at least one anti-drug antibody (ADA). Patients were grouped according to treatment received or if no treatment was received before the study break, according to treatment assigned. For alemtuzumab, the number and proportion of ADA positive and ADA negative patients at baseline (baseline incidence) and after baseline (post-baseline incidence) were summarized in the treatment arm. For other study treatments that tested ADA against, ADA positivity was 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 analyses were performed to understand the association of these biomarkers with the response to the study drug, taking into account both efficacy and safety endpoints.

Middle term analysis

The interim analysis was performed throughout the study course, with the earliest (stage 1) interim analysis occurring when at least one experimental arm has completed the enrollment of the preliminary phase and the patient has been followed for at least 6 weeks. Posterior probabilities can be used to guide further cohorts of treatment arms based on interim analysis of clinical activity of experimental arms compared to control arms. If the interim analysis indicates that the experimental arm is more active than the control arm, the experimental arm can be re-entered into 25 patients. Interim analysis was also performed after approximately 15 patients were enrolled in the phase 2 treatment arm and followed for a minimum of 6 weeks. If no clinical activity was observed in the phase 2 treatment arm, further enrollment of this arm was stopped.

Example 26 PD-L1 as predictive biomarker for Tirayleigh Euzumab + Atlizumab treatment

In phase Ib studies (GO 30103; NCT 02794571), tirayleigh itumumab was well tolerated as monotherapy and in combination with atuzumab for multiple solid tumor types. In a randomized phase II CITYSCAPE study against 1LNSCLC (NCT 0356716), clinically significant improvement in ORR and PFS was observed in tiprayleigh itumumab + atuzumab compared to placebo + atuzumab in the treatment Intent (ITT) population. A greater improvement was seen in the subset with PD-L1 Tumor Proportion Score (TPS) > 50% (assessed using PharmDx 22C3 IHC assay; data expiration date 12 months in 2019; median follow-up time 10.9 months).

The value of PD-L1 as a predictive biomarker for the treatment of tirayleigh immuzumab + atuzumab was found to be consistent in different PD-L1 assays. IHC was performed using the pharmDx 22C3 assay (ITT population) and Confortite Europ ene (European compliance) in vitro diagnostics (CE-IVD 0 VENTANA SP263 IHC assay (biomarker evaluable population)) to assess PD-L1 protein expression in all available patient samples; PD-L1 expression levels were scored using established algorithms for each assay. The baseline characteristics of the BEP and ITT populations were similar (table 92).

TABLE 92 administration of first and subsequent infusions of ibritumumab

* Not all patients have tissue samples available for testing in the SP263 IHC assay.

The prevalence of the PD-L1 subgroup was comparable between the two IHC assays (fig. 26). For the PD-L1 22C3 assay, high TPS is classified as TPS ≧ 50%; low TPS is classified as TPS1-49%. For the SP263 IHC assay, high TC is classified as TC ≧ 50%; low TC is classified as TC 1-49%. Comparable improvement in ORR and PFS of the Tirayleigh Euzumab + atuzumab and the atuzumab monotherapy was observed between the PD-L1 positive (TC ≧ 1%) subgroup defined by SP263 (PFS HR 0.56, 95% CI. Comparable improvement in ORR and PFS for the Tirayleigh Uzumab + atlizumab and atlizumab monotherapy was observed between the PD-L1 high (TC ≧ 50%) subgroup defined by SP263 (PFS HR 0.23, 95% CI.

High PD-L1 expression as assessed by 22C3 or SP263 IHC is likely to be an important predictive biomarker for combined treatment with tirayleigh ecumab + atuzumab.

Other examples

Some embodiments of the techniques described herein may be defined in accordance with any of the following numbered embodiment groups a, B, and C.

Example set a:

1. a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: a dose of about 500mg to about 700mg of an anti-TIGIT antagonist antibody every three weeks, a dose of about 900mg to about 1500mg of a PD-1 axis binding antagonist every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

2. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks.

3. A method of treating a subject having cancer, the method 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 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks.

4. The method of embodiment 2 or 3, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

5. The method of any one of embodiments 1 to 4, wherein the anti-TIGIT antagonist antibody is an IgG class antibody, particularly an IgG1 subclass antibody.

6. The method of any one of embodiments 1 to 5, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

(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 KTYYRRFKWYSDYYAVSVKG (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 of any one of embodiments 1 to 6, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region Framework Regions (FRs):

(a) FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLAVSLERRATINC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (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 X1 VQLQQSGPGLVKPPSQTLSLTCASGDSVS (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 of any one of embodiments 1-7, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The method of any one of embodiments 1-8, wherein the anti-TIGIT antagonist antibody is securititumumab.

10. The method of 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 of any one of embodiments 1 to 10, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The method of any one of embodiments 1 to 11, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The method of embodiment 12, wherein the anti-PD-L1 antagonist antibody is Attributumab, MDX-1105, devolumab, avermemab, SHR-1316, CS1001, envollizumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cochlolizumab, lodalizumab, 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 of any one of embodiments 1 to 13, wherein the PD-1 axis binding antagonist is atelizumab.

15. The method of any one of embodiments 1 to 11, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The method of example 15, wherein the anti-PD-1 antagonist antibody is nivolumab, palivizumab, MEDI-0680, sibatuzumab, cimeprimab, BGB-108, palonolizumab, carpriclizumab, sillimumab, tirizumab, tereprimab, dolaprimab, riluzumab, saralalizumab, deaprizumab, CS1003, HLX10, SCT-I10A, serpalizumab, batilizumab, gemumab, BI 754091, celimimab, YBL-006, BAT1306, HX008, brix, AMG 404, CX-188, JTX-4014, 609A, sym021, sym 009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-103, or hAb21.

17. The method of any one of embodiments 2 to 16, wherein the method comprises administering to the subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. The method of embodiment 1 or 17, wherein the non-platinum chemotherapeutic agent is a topoisomerase II inhibitor.

19. The method according to embodiment 18, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid or HU-331, in particular etoposide.

20. The method of embodiment 18 or 19, wherein the topoisomerase II inhibitor is administered at a dose of 100mg/m 2.

21. The method of any one of embodiments 17 to 20, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin, particularly carboplatin.

22. The method of any one of embodiments 17 to 21, wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC =5mg/ml/min on the day of administration.

23. The method according to any one of embodiments 1 to 22, wherein the method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. The method of embodiment 23, wherein the induction period comprises four initial dosing cycles, and wherein 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.

25. The method of embodiment 23 or 24, wherein the maintenance period does not include administration of a platinum-based chemotherapeutic agent and/or a non-platinum-based chemotherapeutic agent.

26. The method of any one of embodiments 1 to 25, wherein the treatment extends Progression Free Survival (PFS) of the subject compared to treatment without the anti-TIGIT antagonist antibody.

27. The method of any one of embodiments 1 to 26, wherein the treatment extends overall survival of the subject compared to treatment without the anti-TIGIT antagonist antibody.

28. The method of any one of embodiments 1-27, wherein the cancer is lung cancer.

29. The method of embodiment 28, wherein the lung cancer is Small Cell Lung Cancer (SCLC), particularly extensive SCLC (ES-SCLC).

30. The method of embodiment 28, wherein the lung cancer is non-small cell lung cancer (NSCLC), particularly locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. The method of embodiment 28, wherein the lung cancer is locally advanced unresectable NSCLC or metastatic non-squamous NSCLC.

32. The method of embodiment 28, wherein the lung cancer is resectable lung cancer.

33. The method of any one of embodiments 1 to 27, wherein the cancer is cervical cancer.

34. The method of any one of embodiments 1 to 27, wherein the cancer is early triple negative breast cancer (eTNBC).

35. The method of any one of embodiments 1 to 27, wherein the cancer is a head and neck cancer.

36. The method according to any one of embodiments 1 to 27, wherein the cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. The method of any one of embodiments 1-27, wherein the cancer is bladder cancer.

38. The method of embodiment 37, wherein the cancer is Urothelial Cancer (UC), particularly metastatic urothelial cancer (mUC).

39. The method according to any one of embodiments 1 to 27, wherein the cancer is pancreatic cancer, in particular Pancreatic Ductal Adenocarcinoma (PDAC).

40. The method according to any one of embodiments 1 to 27, 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 in accordance with the method of any one of examples 1-40 to treat a subject having cancer.

42. The kit of embodiment 41, wherein the kit further comprises 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, wherein the method is according to any one of examples 1-40.

44. Use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for treating a subject having cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the method of any one of examples 1-40.

45. The use of embodiment 44 wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

46. The use of embodiment 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

47. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 80mg to about 2000mg every four weeks.

48. A method of treating a subject having cancer, the method 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 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 20mg to about 1600mg every two weeks.

49. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 10mg to about 1000mg every two weeks and a PD-1 axis binding antagonist at a dose of about 20mg to about 1600mg every two weeks.

50. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 10mg to about 1000mg every two weeks and a PD-1 axis binding antagonist at a dose of about 80mg to about 2000mg every four weeks.

51. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of about 100mg to about 1000mg every six weeks.

52. The method according to any one of embodiments 47 to 51, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

53. The method of embodiment 52, wherein the method comprises administering to the subject a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

54. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

55. The method as in embodiment 53 or 54, wherein the method comprises an induction phase and a maintenance phase.

56. The method of embodiment 55, wherein the induction phase and the maintenance phase each comprise one or more cycles of administration.

57. The method of embodiment 55 or 56, wherein the maintenance period does not include administration of a platinum-based chemotherapeutic agent.

58. The method of any one of embodiments 55-57, wherein the maintenance period does not include administration of the non-platinum chemotherapeutic agent.

59. The method of embodiment 58, wherein the maintenance period comprises one or more of the following for the dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 80mg to 2000mg every four weeks.

60. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks and an anti-PD-1 antagonist antibody at a dose of about 80mg to about 1600mg every three weeks, wherein the anti-PD-1 antagonist antibody is palbociclumab.

61. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tirayleigh immuzumab and palbociclumab, wherein palbociclumab is administered at a dose of between about 100mg to about 1000mg every six weeks.

62. A method for treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, and an antimetabolite administered twice daily at a dose between about 10mg/m2 to about 10000mg/m2, the antimetabolite administered 2 weeks per three weeks/withheld 1 week.

63. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, gemcitabine, and nab-paclitaxel.

64. The method of embodiment 52, wherein the one or more chemotherapeutic agents is gemcitabine and nab-paclitaxel.

65. A method for treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, and a VEGF antagonist at a dose between about 1mg/kg to about 35mg/kg every three weeks.

66. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction phase includes one or more of the following cycles of administration: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is

(b) The maintenance phase includes one or more additional cycles of administration of the following: every three weeks of anti-TIGIT antagonist antibody, every three weeks of PD-1 axis binding antagonist, and every three weeks of a non-platinum chemotherapeutic agent, and wherein the maintenance phase does not include administration of a platinum chemotherapeutic agent.

67. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction phase includes one or more of the following cycles of administration: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is

(b) The maintenance phase includes one or more additional cycles of administration of the following: an anti-TIGIT antagonist antibody at a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 80mg to about 2000mg every four weeks, wherein the maintenance phase does not include administration of a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent.

68. The method of any one of embodiments 56-59, 66, and 67, wherein the induction period comprises four to six dosing cycles.

69. The method of any one of embodiments 53-59 and 66-68, wherein:

(a) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum chemotherapeutic agent is carboplatin, and the non-platinum chemotherapeutic agent is paclitaxel; or

(c) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is etoposide.

70. The method of any one of embodiments 47-69, wherein the cancer is a solid tumor.

71. The method of any one of embodiments 47-70, wherein the cancer is locally advanced or metastatic.

72. The method of any one of embodiments 47-71, wherein the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, gastric cancer, colorectal cancer, kidney cancer, renal 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, particularly locally advanced unresectable NSCLC.

75. The method of embodiment 74, wherein the NSCLC is stage IIIB NSCLC.

76. The method of any one of embodiments 73-75, wherein the lung cancer is recurrent or metastatic NSCLC.

77. The method of embodiment 76, wherein the NSCLC is stage IV 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 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 for one or more dosing cycles, wherein the treatment prolongs progression-free survival (PFS) of the subject 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.

81. A method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles 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 population of subjects of about 8.2 months to about 9.2 months.

82. The method of embodiment 80 or 81, wherein the treatment extends 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 without an anti-TIGIT antagonist antibody.

83. The method of any one of embodiments 80 to 82, wherein the treatment extends PFS of the subject or population of subjects by at least about 2.4 months compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without an anti-TIGIT antagonist antibody.

84. The method of embodiment 83, wherein the treatment extends PFS in the 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 without an anti-TIGIT antagonist antibody.

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 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 for one or more dosing cycles, wherein the treatment prolongs OS of the subject 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.

86. A method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles 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 for the population of subjects of about 15.3 months to about 17.6 months.

87. The method of any one of embodiments 82 to 86, wherein the treatment extends OS in the subject or population of subjects by at least about 3.3 months compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without an anti-TIGIT antagonist antibody.

88. The method of any one of embodiments 82 to 86, wherein the treatment extends OS of the subject or population of subjects by at least about 3 months to about 5.3 months compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without an anti-TIGIT antagonist antibody.

89. The method of any one of embodiments 80-88, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered in each of four initial dosing cycles.

90. The method of any one of embodiments 80 to 89, wherein the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist are further administered in one or more additional cycles after the four initial dosing cycles.

91. The method of embodiment 90, wherein the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor are omitted during each of the one or more additional dosing cycles.

92. The method of any one of embodiments 80-91, wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide.

93. The method of any one of embodiments 80-92, wherein lung cancer is Small Cell Lung Cancer (SCLC).

94. The method of example 93, wherein SCLC is extensive-term SCLC (ES-SCLC).

95. The method of embodiment 94, wherein the subject or subjects are treatment naive to ES-SCLC.

96. The method of any one of embodiments 80-95, wherein the subject or subjects are absent or have no history of brain metastases.

97. The method of any one of embodiments 80-96, wherein lung cancer is not selected for PD-L1 expression.

98. The method of any one of embodiments 80 to 96, wherein 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 PD-L1 expression level.

100. The method of any one of embodiments 80-99, 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 101, wherein the lung cancer has not metastasized to the brain.

103. The method of any one of embodiments 100 to 102, wherein the treatment results in Complete Remission (CR) or Partial Remission (PR).

104. The method of any one of embodiments 80 to 103, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30mg to about 1200mg every two, three or four weeks.

105. The method of any one of embodiments 80 to 104, wherein the PD-1 axis binding antagonist is administered at a dose of about 80mg to about 2000mg every two, three or four 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 topoisomerase II inhibitor are administered sequentially.

107. The method of embodiment 106, wherein 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.

108. The method of any one of embodiments 80-107, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered intravenously.

109. The method of any one of embodiments 80-108, wherein one or more of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor are administered subcutaneously.

110. A method for treating a subject having SCLC, the method comprising administering to the subject one or more of a 21-day dosing cycle of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg on day 1 of each dosing cycle, altlizumab at a dose of about 80mg to about 1600mg on day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each dosing cycle, wherein the treatment prolongs PFS and/or OS in the subject as compared to treatment with altlizumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

111. A method for treating a subject having SCLC, the method comprising administering to the subject one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 800mg on day 1 of each dosing cycle, an altlizumab at a dose of about 900mg to about 1500mg on day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each dosing cycle, wherein the treatment prolongs PFS and/or OS in the subject as compared to treatment with altlizumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

112. The method of embodiment 110 or 111, further comprising administering to the subject one or more additional 21-day dosing cycles of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg on day 1 of each additional dosing cycle and atuzumab at a dose of about 80mg to about 1600mg on day 1 of each additional dosing cycle, wherein carboplatin and etoposide are omitted from each additional dosing cycle of the one or more additional dosing cycles.

113. A method for treating a subject or population of subjects suffering from ES-SCLC, the method comprising administering four initial dosing cycles followed by one or more additional dosing cycles to the subject or population of subjects, wherein:

(a) The four initial dosing cycles include: administering on day 1 of each initial dosing cycle ibritumumab tiuxetan at a dose of about 600mg, alemtuzumab at a dose of about 1200mg on day 1 of each initial dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each initial dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each initial dosing cycle; and is provided with

(b) The one or more additional dosing cycles comprise: administering tenecteukumab at a dose of about 600mg on day 1 of each additional dosing cycle, and administering atelizumab at a dose of about 1200mg on day 1 of each additional dosing cycle,

wherein the four initial dosing cycles and the one or more additional dosing cycles are each 21-day dosing cycles, and wherein the treatment extends PFS and/or OS in the subject or population of subjects as compared to treatment with atelizumab, carboplatin, and etoposide without teryleuthumab.

114. 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 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.

115. The method of embodiment 114, wherein lung cancer has not been evaluated for PD-L1 expression.

116. The method of embodiment 114 or 115, wherein the subject or subjects have not been determined to have a PD-L1 positive tumor cell fraction greater than or equal to 50%.

117. The method of embodiment 116, wherein the subject or subjects have been determined to have a PD-L1 positive tumor cell fraction of less than 50%.

118. The method of embodiment 116 or 117, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263 or 22C3.

119. The method of any one of embodiments 114 to 118, wherein subject or subjects do not have Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations.

120. The method of any one of embodiments 114-119, wherein the subject or subjects have not received prior systemic therapy for lung cancer.

121. The method of any one of embodiments 114-120, wherein the lung cancer is locally advanced lung cancer.

122. The method of any one of embodiments 114 to 121, wherein the lung cancer is NSCLC, particularly locally advanced unresectable NSCLC or metastatic non-squamous NSCLC.

123. The method of embodiment 122, wherein the non-squamous NSCLC is stage IV non-squamous NSCLC.

124. The method of any one embodiments 114 to 123, wherein the dosing regimen comprises an induction period comprising four dosing cycles, and wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and non-platinum-based chemotherapeutic agent are administered on day 1 of each dosing cycle of the induction period.

125. The method of embodiment 124, wherein the dosing regimen comprises a maintenance phase following the induction phase, wherein the maintenance phase comprises one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, and non-platinum chemotherapeutic agent are administered on day 1 of each dosing cycle of the maintenance phase.

126. The method of embodiment 125, wherein the one or more dosing cycles of the maintenance phase do not include administration of a platinum-based chemotherapeutic agent.

127. The method of 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. A method of treating a subject or population of subjects having advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects a dosing regimen comprising four 21-day dosing cycles of tirayleigh mab, atelizumab, carboplatin or cisplatin and pemetrexed, wherein on day 1 of each of the four 21-day dosing cycles, tirayleigh mab is administered at a dose of about 600mg every three weeks, atelizumab is administered at a dose of about 1200mg every three weeks, carboplatin is administered at a dose sufficient to achieve AUC =5mg/ml/min every three weeks or cisplatin is administered at a dose of 75mg/m2 every three weeks, and pemetrexed is administered at a dose of about 500mg/m2 every three weeks.

129. A method of treating a subject or population of subjects having advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects:

(i) The following of the four induction phase dosing cycles: a dose of about 600mg of tenecteuzumab every three weeks, a dose of about 1200mg of alemtuzumab every three weeks, a dose of carboplatin sufficient to achieve AUC =5mg/ml/min every three weeks, and a dose of pemetrexed of about 500mg/m2 every three weeks; and

(ii) One or more of the following maintenance phase dosing cycles: a dose of about 600mg of tenecteuzumab every three weeks, a dose of about 1200mg of alemtuzumab every three weeks, and a dose of about 500mg/m2 of pemetrexed every three weeks, wherein the one or more 21-day periods in the maintenance phase do not comprise administration of carboplatin, wherein the subject or population of subjects has not received prior systemic therapy for advanced non-squamous NSCLC.

130. A method of treating a subject having advanced non-squamous NSCLC, the method comprising administering to the subject:

(i) The following of the four induction phase dosing cycles: a dose of about 600mg of tiregumab every three weeks, a dose of about 1200mg of altlizumab every three weeks, a dose of carboplatin sufficient to achieve an AUC =5mg/ml/min every three weeks, and a dose of pemetrexed of about 500mg/m2 every three weeks; and

(ii) One or more of the following maintenance phase dosing cycles: a dose of about 600mg of tiregumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and a dose of about 500mg/m2 of pemetrexed every three weeks, wherein the one or more 21-day periods in the maintenance phase do not include administration of carboplatin wherein the subject has not received prior systemic therapy for advanced non-squamous NSCLC.

131. A method of treating a subject with advanced non-squamous NSCLC, the method comprising administering to the subject a dosing regimen comprising four 21-day dosing cycles of tirayleigh mab, atezumab, carboplatin or cisplatin, and pemetrexed, wherein on day 1 of each of the four 21-day dosing cycles, tirayleigh mab is administered at a dose of about 600mg every three weeks, atelizumab is administered at a dose of about 1200mg, cisplatin is administered at a dose of 75mg/m2, and pemetrexed is administered at a dose of about 500mg/m 2.

132. The method of any one of embodiments 114 to 131, wherein the treatment extends PFS in the subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. The method of any one of embodiments 114 to 132, wherein the treatment results in a median PFS for the population of subjects of about 12.5 months to about 14.7 months.

134. The method according to any one of embodiments 114 to 133, wherein the treatment extends 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 the treatment results in a median OS for the population of subjects of about 27.5 months to about 32.0 months.

136. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject for one or more dosing cycles: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

137. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

138. A method for treating a subject having lung cancer, the method 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 the dosing cycles comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks as neoadjuvant therapy.

139. A method for treating a subject having lung cancer, the method 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 the dosing cycles comprises administering to the subject: as neoadjuvant therapy, the anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and the PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

140. The method of embodiment 138 or 139, wherein at least one of the dosing cycles comprises administering to the subject a dose of between about 30mg to about 1200mg of the anti-TIGIT antagonist antibody every three weeks and a dose of between about 80mg to about 1600 mg of the PD-1 axis binding antagonist every three weeks as adjunctive therapy.

141. The method of embodiment 140, wherein at least one of the dosing cycles comprises administering to the subject a dose of between about 500mg to about 700mg of the anti-TIGIT antagonist antibody every three weeks and a dose of between about 900mg to about 1500mg of the PD-1 axis binding antagonist every three weeks as adjunctive therapy.

142. The method of any one of embodiments 138-141, wherein lung cancer is resectable lung cancer.

143. The method of any one of embodiments 136-142, wherein the lung cancer is early stage lung cancer.

144. The method of any one of embodiments 136-143, wherein lung cancer is stage II, stage IIIA, or stage IIIB lung cancer.

145. The method of 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 aberrations.

146. The method of any one of embodiments 136-145, wherein the subject is eligible for an R0 resection for healing purposes.

147. The method of any one of embodiments 136-146, wherein the subject has not received prior therapy for lung cancer.

148. The method of embodiment 147, wherein the prior therapy is immunotherapy, chemotherapy, or radiation therapy.

149. The method of any one of embodiments 136-148, wherein the subject is eligible to receive a platinum-based chemotherapy regimen.

150. The method of any one of embodiments 136-149, 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 surgery.

152. The method of embodiment 150 or 151, wherein 4 dosing cycles are completed prior to surgery.

153. The method of any one of embodiments 136-152, wherein at least one dosing cycle is initiated after surgery.

154. The method of embodiment 153, wherein 16 dosing cycles are completed after surgery.

155. The method of any one of embodiments 150-154, wherein the surgery is a segmental resection, a lobectomy, a bilobalectomy, or a pulmonary resection.

156. A method as in any of embodiments 136-155 wherein the method further comprises radiation therapy.

157. The method of embodiment 156 wherein the radiation therapy is post-operative radiation therapy.

158. The method of any one of embodiments 136 to 157, wherein the method further comprises administering one or more chemotherapeutic agents.

159. The method of embodiment 158, wherein the one or more chemotherapeutic agents are administered after surgery.

160. The method of embodiment 159, wherein the one or more chemotherapeutic agents are administered in 4 dosing cycles after surgery.

161. The method of any one of embodiments 158-160, wherein the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

162. The method of embodiment 161 wherein:

(a) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is gemcitabine;

(c) The platinum chemotherapeutic agent is carboplatin, and the non-platinum chemotherapeutic agent is paclitaxel;

(d) The platinum chemotherapeutic agent is cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed; or

(e) The platinum chemotherapeutic agent is cisplatin and the non-platinum chemotherapeutic agent is gemcitabine.

163. The method according to any one of embodiments 136-162, wherein the treatment results in an increase in a Major Pathological Remission (MPR) rate as compared to a reference MPR rate.

164. The method of embodiment 163, wherein the reference MPR rate is the MPR rate of a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

165. The method of any one of embodiments 136 to 164, wherein the treatment results in complete remission of pathology (pCR) and/or an increase in pCR rate as compared to a reference pCR rate.

166. The method of embodiment 165, wherein the reference pCR rate is the pCR rate of a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

167. The method of any one of embodiments 136-166, wherein the treatment results in an increase in event-free survival (EFS) as compared to a reference EFS time.

168. The method of embodiment 167, wherein the reference EFS time is the EFS time of a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

169. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject for one or more dosing cycles: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 600mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

170. A method for treating a subject having lung cancer, the method 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 the dosing cycles comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 600mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks as neoadjuvant therapy.

171. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject for one or more dosing cycles: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent.

172. A method for treating a subject having lung cancer, the method 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 administering to the subject: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent, and a non-platinum chemotherapeutic agent as neoadjuvant therapy.

173. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject for one or more dosing cycles: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, and: (a) (ii) (i) a platinum-based chemotherapeutic agent targeted every three weeks to achieve a dose of AUC of 5mg/mL/min or AUC of 6 mg/mL/min; or (ii) a dose of about 75mg/m2 of a platinum chemotherapeutic agent every three weeks; and (b) (i) an antimetabolite at a dose of about 500mg/m2 every three weeks or at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each administration cycle; or (ii) a taxane at a dose of about 100mg/m2, about 175mg/m2, or about 200mg/m2 every three weeks.

174. A method for treating a subject having lung cancer, the method 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 administering to the subject: (a) An anti-TIGIT antagonist antibody at a dose between about 30mg to about 600mg every three weeks; (b) A PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks; (c) platinum chemotherapeutic agents: (i) A dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) a dose of about 75mg/m2 every three weeks; and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) An antimetabolite at a dose of about 500mg/m2 every three weeks or at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each administration cycle; or (ii) a taxane at a dose of about 100mg/m2, about 175mg/m2, or about 200mg/m2 every three weeks; wherein the treatment is neoadjuvant treatment.

175. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject for one or more dosing cycles: a dose of about 600mg of tirleivuzumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and:

(a)

(i) Carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or

(ii) Cisplatin at a dose of about 75mg/m2 every three weeks; or

(b)

(i) A dose of pemetrexed of about 500mg/m2 every three weeks, or gemcitabine at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each dosing cycle; or

(ii) Paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks.

176. A method for treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of ibritumumab tiuxetan, atuzumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one of the dosing cycles comprises administering to the subject: (a) a dose of 600mg of ibritumomab tiuxetan every three weeks; (b) a dose of 1200mg of atuzumab every three weeks; (c) a platinum chemotherapeutic agent, wherein the platinum chemotherapeutic agent is: (i) Carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) cisplatin at a dose of about 75mg/m2 every three weeks; and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) A dose of pemetrexed of about 500mg/m2 every three weeks or gemcitabine at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each dosing cycle; or (ii) paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; wherein the treatment is neoadjuvant treatment.

177. A method for treating a subject having non-squamous NSCLC, the method comprising administering to the subject one or more dosing cycles of tirayleigh immuzumab and atlizumab, wherein: (a) At least one of the dosing cycles comprises administering to the subject a dose of about 600mg of tiregumab every three weeks and a dose of 1200mg of atuzumab every three weeks as neoadjuvant therapy; and (b) at least one of the dosing cycles comprises administering to the subject a dose of about 600mg of tenecteuzumab per three weeks, and a dose of about 1200mg of atelizumab per three weeks, as adjunctive therapy.

178. A method for treating a subject having non-squamous NSCLC, the method comprising administering to the subject one or more dosing cycles of tirayleigh immuzumab and atlizumab, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of tirayleigh immuzumab every three weeks; (b) About 1200mg dose of alemtuzumab every three weeks as a neoadjuvant therapy; and (c) (i) a dose of carboplatin targeted to achieve an AUC of 5mg/mL/min every three weeks and a dose of pemetrexed of about 500mg/m2 every three weeks; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and pemetrexed at a dose of about 500mg/m2 every three weeks; and (II) at least one such dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks as adjunctive therapy.

179. A method for treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of ibritumumab tiuxetan and atelizumab, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of ibritumomab tiuxetan every three weeks; (b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises administering to the subject: a dose of between about 30mg to about 1200mg every three weeks and a dose of between about 80mg to about 1600mg every three weeks of atuzumab as adjunctive therapy.

180. A method for treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of ibritumumab tiuxetan and atelizumab, wherein:

(I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject:

(a) A dose of about 1200mg of ibritumomab tiuxetan every three weeks;

(b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and

(c)

(i) A dose of carboplatin targeted to achieve an AUC of 5mg/mL/min every three weeks, and a dose of gemcitabine of about 1000mg/m2 on days 1 and 8 of each dosing cycle;

(ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks, and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or

(iii) Cisplatin at a dose of about 75mg/m2 every three weeks, and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and

(II) at least one of the dosing cycles comprises administering to the subject a dose of between about 300mg to about 800mg of tiryleauuzumab and a dose of between about 900mg to about 1500mg of atuzumab every three weeks as adjunctive therapy.

181. A method for treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of tirayleigh immuzumab and atelizumab, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of ibritumomab tiuxetan every three weeks; (b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises administering to the subject: as adjunctive therapy, a dose of about 600mg of tenecteuzumab and a dose of about 1200mg of atelizumab every three weeks were used.

182. A method for treating a subject having resectable squamous NSCLC, the method comprising administering to the subject one or more dosing cycles of ibrinout unumab and atlizumab, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of tirayleigh immuzumab every three weeks; (b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises administering to the subject: tenecteuzumab at a dose of about 600mg every three weeks and attentizumab at a dose of about 1200mg every three weeks was used as adjuvant therapy.

183. The method of any one of embodiments 136 to 182, wherein a detectable protein expression level of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SP 263.

184. The method of embodiment 183, wherein the detectable protein expression level of PD-L1 is greater than or equal to 50% of PD-L1 positive tumor cells.

185. The method of any one of embodiments 73, 114 to 121, and 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, wherein the cancer is cervical cancer.

189. A method for treating a subject or population of subjects having cervical cancer with a detectable PD-L1 expression level, 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 between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

190. A method for treating a subject or population of subjects having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject or population of subjects for one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

191. A method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for said subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist administered at a dose between about 80mg to about 1600mg every three weeks based on PD-L1 expression on tumor cells that has been detected.

192. The method of any one of embodiments 189 to 191, wherein cervical cancer is squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma.

193. The method of any one of embodiments 189 to 191, wherein cervical cancer is stage IVB, metastatic, recurrent or persistent.

194. The method of any one of embodiments 189 to 193, wherein cervical cancer is metastatic and/or relapsed PD-L1-positive cervical cancer.

195. The method of any one of embodiments 189 to 194, wherein the subject or subjects have received at least one prior line of therapy.

196. The method of any one of embodiments 189 to 195, wherein the subject or subjects have received two prior therapy normals.

197. The method of any one of embodiments 189 to 196, wherein the subject or subjects have received more than two prior therapy normals.

198. The method of any one of embodiments 189 to 194, wherein the subject or subjects have not received a previous therapy.

199. The method of any one of embodiments 195-198, wherein the prior therapy is chemotherapy, surgery, and/or radiation therapy.

200. The method of any one of embodiments 189 and 192-199, wherein the treatment results in a clinical response.

201. The method of embodiment 200, wherein the clinical response is an increase in the Objective Remission Rate (ORR) of the population of subjects as compared to a reference ORR.

202. The method of embodiment 201, wherein the reference ORR is the median ORR of a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an 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, wherein the clinical response is an increase in progression-free survival (PFS) of the subject as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject as compared to a reference OS time.

206. The method of embodiment 205, wherein:

(a) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not using an anti-TIGIT antagonist antibody;

(b) The reference DOR time is the median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not using an anti-TIGIT antagonist antibody.

207. A method for treating a subject having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject one or more dosing cycles of: a 600mg dose of anti-TIGIT antagonist antibody every three weeks and a 1200mg dose of alemtuzumab every three weeks.

208. A method of identifying a subject having cervical cancer who is likely to benefit from a therapy comprising one or more cycles of administration of an anti-TIGIT antagonist antibody and atelizumab, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining; and

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1200mg every three weeks based on PD-L1 expression on tumor cells that have been detected.

209. A method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1200mg every three weeks based on PD-L1 expression on tumor cells that have been detected.

210. A method for treating a subject having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject one or more dosing cycles of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

211. A method of treating a subject having cervical cancer, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay 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: (ii) based on the detected PD-L1 expression on the tumor cells, tirayleigh mab administered at a dose of 600mg every three weeks and atuzumab administered at a dose of 1200mg every three weeks; and

(d) Administering a therapy to the identified subject.

212. A method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on tumor cells, tenecteuzumab was administered at a dose of 600mg every three weeks and atelizumab was administered at a dose of 1200mg every three weeks.

213. A method of treating a subject having metastatic and/or recurrent cervical cancer, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay 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: (ii) based on the detected PD-L1 expression on the tumor cells, tirayleigh mab administered at a dose of 600mg every three weeks and atuzumab administered at a dose of 1200mg every three weeks; and

(d) Administering a therapy to the identified subject.

214. A method of selecting a therapy for a subject having metastatic and/or recurrent cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on tumor cells, tenecteuzumab was administered at a dose of 600mg every three weeks and atelizumab was administered at a dose of 1200mg every three weeks.

215. The method of any one of embodiments 189 to 214, wherein the subject is identified as a subject likely to benefit from treatment based on PD-L1 expression on tumor cells that have been detected.

216. The method of any one of embodiments 189 to 215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP 263.

217. The method of any one of embodiments 189 to 216, wherein the detectable PD-L1 expression level is greater than or equal to 5% tumor-associated immune cells (TICs) in the sample from the subject.

218. The method of any one of embodiments 189 to 215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody 22C 3.

219. The method of any one of embodiments 189 to 216, wherein the detectable level of PD-L1 expression is a Composite Positive Score (CPS) greater than or equal to 1 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, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: a dose of about 840mg of tenecteuzumab every four weeks, a dose of about 1680mg of alemtuzumab every four weeks, and nab-paclitaxel dosed at about 100mg/m2 for 3 weeks/withheld for 1 week.

222. The method of embodiment 220 or 221, wherein the breast cancer is Triple Negative Breast Cancer (TNBC).

223. The method of embodiment 222, wherein the TNBC is unresectable locally advanced or metastatic TNBC.

224. The method of any one of embodiments 220-223, wherein the subject or subjects have not received prior systemic therapy for metastatic breast cancer.

225. The method of any one of embodiments 220 to 224, wherein the treatment results in a population of subjects having an ORR of at least about 53% to about 67.5%.

226. The method according to any one of embodiments 222 to 225, wherein the treatment results in a median OS for the population of subjects of about 25.0 months.

227. A method of treating a subject having early triple negative breast cancer (eTNBC), the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 10mg to about 1000mg every two weeks and a PD-1 axis binding antagonist at a dose of about 20mg to about 1600mg every two weeks.

228. The method of embodiment 227, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

229. The method of embodiment 228, wherein the one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The method of embodiment 227, wherein the method further comprises administering (a) one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) one or more cycles of administration of an anti-TIGIT antagonist antibody, a 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).

231. The method of embodiment 229 or 230, wherein the alkylating agent is cyclophosphamide.

232. The method of embodiment 231, wherein cyclophosphamide is administered at a dose of about 600mg/m 2.

233. The method according to any one of embodiments 227 to 229, 231 and 232, wherein the method comprises further administering G-CSF or GM-CSF to the subject.

234. The method of embodiment 230 or 233, wherein G-CSF is pegylated filgrastim or filgrastim.

235. The method of embodiment 234, wherein G-CSF is pegylated filgrastim.

236. The method of embodiment 235, wherein the pegylated filgrastim is administered at a dose of about 6 mg.

237. The method according to any one of embodiments 228, 229 and 231 to 236, wherein the method further comprises administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

238. The method of any one of embodiments 228, 229, and 231-237, wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are each administered once a week, once every two weeks, or once every three weeks.

239. The method of any one of embodiments 229-238, wherein a platinum-based chemotherapeutic agent is administered every three weeks, a taxane is administered every week, a topoisomerase II inhibitor is administered every two weeks, an alkylating agent is administered every two weeks, and G-CSF or GM-CSF is administered every two weeks.

240. The method of any one of embodiments 229-239, wherein the taxane or the taxane and the platinum-based chemotherapeutic agent are administered in the first 12 weeks of the dosing regimen.

241. The method of any one of embodiments 229 to 240, wherein the topoisomerase II inhibitor, alkylating agent, and G-CSF or GM-CSF are administered on weeks 13 to 19 of a dosing regimen.

242. The method of any one of embodiments 227 to 241, wherein the total length of the dosing regimen is 19 weeks.

243. The method of any one of embodiments 227 to 242, wherein the method is neoadjuvant therapy.

244. The method of any one of embodiments 227 to 243, wherein the dosing regimen is followed by surgery.

245. The method of embodiment 244, wherein surgery is performed between two and six weeks after the last dose of the dosing regimen.

246. The method of embodiment 244 or 245, wherein the surgery comprises a mastectomy.

247. The method of any one of embodiments 244-246, wherein surgery comprises axillary lymph node surgery.

248. The method of any one of embodiments 229-247, wherein the topoisomerase II inhibitor is doxorubicin.

249. The method of any one of embodiments 229-247, wherein the taxane is nab-paclitaxel, the platinum-based chemotherapeutic agent is carboplatin, and the topoisomerase II inhibitor is doxorubicin.

250. The method according to embodiment 248 or 249, wherein doxorubicin is administered at a dose of about 60mg/m 2.

251. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane at a dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

252. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, a PD-L1 binding antagonist at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

253. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, an anti-PD-L1 antagonist antibody at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane at a dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

254. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: a dose of about 300mg to about 600mg of tirleivuzumab every two weeks, a dose of about 600mg to about 1200mg of an anti-PD-L1 antagonist antibody every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

255. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, an alemtuzumab at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane at a dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

Wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

256. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: a dose of about 300mg to about 600mg of tirleivuzumab every two weeks, a dose of about 600mg to about 1200mg of atuzumab every two weeks, and:

(a)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly and carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

257. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: a dose of about 420mg tirayleigh-uzumab every two weeks, a dose of about 840mg atelizumab every two weeks, and:

(a)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly and carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

258. The method of any one of embodiments 220 to 257, wherein a detectable protein expression level of PD-L1 in a tumor sample from the subject has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SP 142.

259. The method of embodiment 258, wherein the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating Immune Cells (IC) in the tumor sample is greater than or equal to 1%.

260. The method of any one of embodiments 227 to 259 wherein eTNBC is represented as T2-4d TNBC.

261. The method of any one of embodiments 227 to 260 wherein the eTNBC is represented by 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 complete remission (pCR) of the pathology.

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 a head and neck cancer.

266. The method of embodiment 265, wherein the head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN).

267. A method for treating a subject or population of subjects having a detectable SCCHN having a PD-L1 expression level, 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 between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

268. A method for treating a subject or population of subjects having SCCHN with a detectable PD-L1 expression level, 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 between about 300mg to about 800mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

269. A method of selecting a therapy for a subject or population of subjects having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject or population of subjects having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks and a dose of between about 30mg to about 1200mg of anti-TIGIT antagonist antibody every three weeks.

270. A method for treating a subject or population of subjects having a detectable SCCHN having a PD-L1 expression level, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

271. The method of any one of embodiments 267-270, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

272. The method of any one of embodiments 266 to 271, wherein the SSCHN is Human Papilloma Virus (HPV) positive.

273. The method of any one of embodiments 266 to 272, wherein the SSCHN is HPV negative.

274. The method of embodiment 272 or 273, wherein HPV status is determined by p16IHC, in situ hybridization, or by PCR.

275. The method of any one of embodiments 266-274, wherein the SCCHN is a recurrent and/or metastatic SCCHN.

276. The method of any one of embodiments 265 to 275, wherein the subject or subjects did not receive a previous therapy.

277. The method of embodiment 276, wherein the prior therapy is a prior systemic therapy for recurrent and/or metastatic disease.

278. The method of any one of embodiments 265 to 268 and 270 to 277, wherein the treatment results in CR or PR.

279. The method of any one of embodiments 265 to 268 and 270 to 277, wherein the treatment results in an increase in the Objective Remission Rate (ORR) of the population of subjects as compared to the reference ORR.

280. The method of embodiment 279, wherein the reference ORR is the median ORR of a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

281. The method of embodiment 279 or 280, wherein the reference ORR is at least about 19% to about 36%.

282. The method of any one of embodiments 265 to 268 and 270 to 281, wherein the treatment results in an increase in progression-free survival (PFS) of the subject or population of subjects as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject or population of subjects as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject or population of subjects as compared to a reference OS time.

283. The method of embodiment 282, wherein:

(a) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not using an anti-TIGIT antagonist antibody;

(b) The reference DOR time is the median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

284. The method of embodiment 282, wherein the reference DOR time is at least about 6.7 months to about 23.4 months.

285. The method of embodiment 282, wherein the reference OS time is at least about 11.6 months to about 14.9 months.

286. A method for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks.

287. A method for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a PD-1 axis binding antagonist at a dose of about 1200mg every three weeks and an anti-TIGIT antagonist antibody at a dose of about 600mg every three weeks.

288. A method for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a PD-L1 binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks.

289. A method for treating a subject having a SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more dosing cycles of: a dose of between about 80mg to about 1600mg of atuzumab every three weeks and a dose of between about 30mg to about 1200mg of tiryleiguzumab every three weeks.

290. A method for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

291. A method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay 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: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks; and

(d) Administering the therapy to the identified subject having a detectable PD-L1 expression level.

292. A method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: a PD-1 axis binding antagonist at a dose of about 1200mg every three weeks, an anti-TIGIT antagonist antibody at a dose of about 600mg every three weeks; and

(d) Administering the therapy to a subject identified as having a detectable PD-L1 expression level.

293. A method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay 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: a dose of between about 80mg to about 1600mg of atuzumab every three weeks, a dose of between about 30mg to about 1200mg of ibritumumab tiuxetan every three weeks; and

(d) Administering the therapy to the identified subject having a detectable PD-L1 expression level.

294. A method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: attrituzumab at a dose of about 1200mg every three weeks, ibritumomab tiuxetan at a dose of about 600mg every three weeks; and

(d) Administering the therapy to a subject identified as having a detectable PD-L1 expression level.

295. A method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks and a dose of between about 30mg to about 1200mg of anti-TIGIT antagonist antibody every three weeks.

296. A method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a PD-1 axis binding antagonist at a dose of about 1200mg every three weeks and an anti-TIGIT antagonist antibody at a dose of about 600mg every three weeks.

297. A method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on the PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg alemtuzumab every three weeks and a dose of between about 30mg to about 1200mg teryleuthumab every three weeks.

298. A method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on the PD-L1 expression that has been detected, a dose of about 1200mg of alemtuzumab every three weeks and a dose of about 600mg of telyuzumab every three weeks.

299. The method of any one of embodiments 267-298, wherein the detectable PD-L1 expression level is a detectable protein expression level of PD-L1 determined by an Immunohistochemistry (IHC) assay comprising staining with anti-PD-L1 antibody SP 263.

300. The method of embodiment 299, wherein the detectable protein expression level of PD-L1 is that the tumor-associated immune cells (TICs) in the tumor sample are:

(a) Greater than or equal to 5%;

(b) Greater than or equal to 5% and less than 20%; or

(c) Greater than or equal to 20%.

301. A method of identifying a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 5% TIC identifies the subject as likely to benefit from the therapy.

302. A method of identifying a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 5% and less than 20% of TIC identifies the subject as likely to benefit from the therapy.

303. A method of identifying a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 20% of TIC identifies 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 TIC is determined using the Ventana SP263 IHC assay.

306. The method of any one of embodiments 267-305, wherein a subject or population of subjects is identified as a subject or population of subjects likely to benefit from treatment based on PD-L1 expression on tumor cells that has been detected.

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. A method of treating a subject or population of subjects having hepatocellular carcinoma (HCC), the method comprising administering to the subject or population of subjects one or more cycles of administration an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject or population of subjects did not have received prior systemic treatment for HCC.

310. The method of embodiment 309, wherein the method further comprises administering a VEGF antagonist to the subject or population of subjects.

311. A method of treating a subject or population of subjects suffering from HCC, the 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 embodiments 310 and 311, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 25mg/kg every three 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 30mg to about 1200mg every three weeks.

314. The method of embodiment 313, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30mg to about 800mg every three weeks.

315. The method of any one of embodiments 309-314, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 600mg every three 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 80mg to about 1600mg every three 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 900mg to about 1500mg every three weeks.

318. The method of embodiment 310 or 311, wherein the VEGF antagonist is administered at a dose of about 1mg/kg to about 20mg/kg biweekly.

319. The method of embodiment 318, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 10mg/kg biweekly.

320. The method of embodiment 319, wherein the VEGF antagonist is administered at a dose of about 5mg/kg, about 7.5mg/kg, or about 10mg/kg every two weeks.

321. The method of any one embodiments 309-311 and 318-320, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10mg to about 1000mg biweekly.

322. The method of any one of embodiments 309-311 and 318-321, wherein the PD-1 axis binding antagonist is administered at a dose of about 20mg to about 1600mg every two weeks.

323. The method of embodiments 309-311, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 200mg to about 2000mg every four weeks.

324. The method of any one of embodiments 309-311 and 323, wherein the PD-1 axis binding antagonist is administered at a dose of about 80mg to about 2000mg every four weeks.

325. The method of any one of embodiments 309-311, 323, and 324, wherein the PD-1 axis binding antagonist is administered at a dose of about 1400mg to about 2000mg every four weeks.

326. The method of any one of embodiments 309 to 325, wherein HCC is locally advanced or metastatic HCC.

327. The method of any one of embodiments 309-326, wherein the HCC is a non-resectable HCC.

328. The method of any one of embodiments 309 to 327, wherein the subject or subjects have been determined to have sufficient liver function.

329. The method of embodiment 328, wherein the sufficient liver function is characterized as Child-Pugh grade a.

330. The method of any one of embodiments 309 to 329, wherein the HCC tumor sample obtained from the subject or subjects has been determined to have a detectable level of PD-L1 expression.

331. The method according to any one of embodiments 309 to 330, wherein the method comprises administering to the subject or population of subjects at least four 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. A method of treating a subject or population of subjects suffering from HCC, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg of tirleivuzumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and a dose of about 15mg/kg of bevacizumab every three weeks.

334. The method of any one of embodiments 311 to 333, wherein the subject or subjects did not receive a previous systemic therapy for HCC.

335. The method of any one of embodiments 309 to 334, wherein the treatment results in a median PFS of the population of subjects 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 for treating a subject or population of subjects having MIBC, 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 between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the subject is eligible for treatment with a platinum-based chemotherapeutic agent.

339. A method for treating a subject or population of subjects having MIBC, 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 between about 300mg to about 800mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, wherein the subject is eligible for treatment with a platinum-based chemotherapeutic agent.

340. A method for treating a subject or population of subjects having MIBC, 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 between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

341. A method for treating a subject or population of subjects having MIBC, 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 between about 300mg to about 800mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, wherein the treatment is perioperative treatment.

342. The method of any one of embodiments 338-341, wherein the subject or subjects have a creatinine clearance < 60 mL/min.

343. The method of any one of embodiments 338-342, wherein the subject or subjects have a hearing loss greater than or equal to grade 2.

344. The method of any one of embodiments 338-343, wherein subject or subjects have a grade greater than or equal to 2 neuropathy.

345. The method of any one of embodiments 338-344, wherein the subject or subjects have declined treatment with a platinum-based chemotherapeutic agent.

346. The method of any one of embodiments 338 or 342 to 345, wherein the platinum-based chemotherapeutic agent is cisplatin.

347. The method of any one of embodiments 338-346, wherein the MIBC is operable.

348. The method of embodiment 347, wherein the method further comprises surgery.

349. The method of embodiment 348, wherein at least one dosing cycle is initiated prior to surgery.

350. The method of embodiment 348 or 349, wherein at least 1, 2, or 3 dosing cycles are completed prior to 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 post-surgery.

352. The method of embodiment 351, wherein 1 to 17 dosing cycles are completed after surgery.

353. The method of any one of embodiments 348-352, wherein surgery is cystectomy and/or lymph node dissection.

354. The method of any one of embodiments 338-353, wherein the treatment results in complete pathology remission (pCR).

355. The method of any one of embodiments 338-354, wherein the treatment results in an increase in Relapse Free Survival (RFS) for the subject or subjects as compared to a reference RFS time, an increase in Event Free Survival (EFS) for the subject or subjects as compared to a reference EFS time, or an increase in OS for the subject or subjects as compared to a reference OS time.

356. The method of embodiment 355 wherein:

(a) The reference RFS time is the median RFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not using an anti-TIGIT antagonist antibody;

(b) The reference EFS time is the median EFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

357. The method according to any one of embodiments 338 to 356, wherein the treatment results in pathological degradation.

358. A method for treating a subject or population of subjects having MIBC, 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 between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, wherein the subject is eligible for cisplatin use.

359. A method for treating a subject or population of subjects having MIBC, 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 between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

360. A method for treating a subject or population of subjects having MIBC, 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 between about 30mg to about 1200mg every three weeks, a PD-L1 binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the subject is eligible for cisplatin use.

361. A method for treating a subject or population of subjects having MIBC, 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 between about 30mg to about 1200mg every three weeks, a PD-L1 binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

362. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of between about 30mg to about 1200mg of tirleivuzumab every three weeks, a dose of between about 80mg to about 1600mg of atuzumab every three weeks, wherein the subject is eligible for cisplatin use.

363. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of between about 30mg to about 1200mg of tirleivuzumab every three weeks, a dose of between about 80mg to about 1600mg of atuzumab every three weeks, wherein the treatment is perioperative treatment.

364. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks, wherein the subject or subjects are not eligible for cisplatin.

365. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tirleiuzumab every three weeks, and a dose of about 1200mg of atuzumab every three weeks, wherein the treatment is a perioperative treatment.

366. The method of any one of embodiments 338 to 365, wherein the treatment results in a population of subjects having an ORR of at least about 13.4% to about 15%.

367. The method according to any one of embodiments 338 to 366, wherein the treatment results in a median OS for the population of subjects of at least about 7.9 months to about 8.6 months.

368. The method of any one of embodiments 338 to 367, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SP 142.

369. The method of embodiment 368, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction in which a proportion of a tumor area occupied by tumor infiltrating Immune Cells (ICs) that express PD-L1 is greater than or equal to 5%.

370. The method of embodiment 336, wherein the bladder cancer is Urothelial Cancer (UC).

371. The method of embodiment 370, wherein the UC is metastatic urothelial cancer (mUC).

372. A method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

373. A method for treating a subject or population of subjects having a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

374. A method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the subject has not received prior cancer immunotherapy.

375. A method for treating a subject or population of subjects suffering from uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is second line treatment.

376. The method of any one of embodiments 372, 372 and 375, wherein the subject or subjects have not received prior cancer immunotherapy.

377. The method according to any one of embodiments 372-374, wherein the treatment is second line treatment.

378. The method of any one of embodiments 372-377, wherein the mUC has progression during or after platinum-containing therapy.

379. The method according to any one of embodiments 372-378, wherein the method further comprises administering a second dosing regimen to the subject or subjects after a 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 the ADC is (a) vildagliptin-enfratuzumab or (b) govitegam-shaxituzumab.

382. The method of embodiment 381 wherein (a) vildagliptin-enfratuzumab is administered at a dose of 1.25mg/kg weekly for 2 weeks/withdrawal for 1 week, or (b) govitegam-shaxituzumab is administered at a dose of 10mg/kg weekly for 2 weeks/withdrawal for 1 week.

383. The method of embodiment 381 or 382, wherein (a) the vildagliptin-enritumumab is administered at a dose of 1.25mg/kg on days 1 and 8 of each 21-day cycle, or (b) the govitegam-shaxituzumab is administered at a dose of 10mg/kg on days 1 and 8 of each 21-day cycle.

384. A method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-L1 binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

385. A method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: a dose of between about 30mg to about 1200mg every three weeks and a dose of between about 80mg to about 1600mg every three weeks of atuzumab.

386. A method for treating a subject or population of subjects having a uc, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

387. A method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to 1600mg every three weeks; and is

(b) The second dosing regimen comprises one or more of the following for the dosing cycle: a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks and (i) vildagliptin-enfratuzumab is administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (ii) govittazin-shacetuzumab is administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week, wherein a second dosing regimen is administered to a subject or population of subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity during a first dosing regimen.

388. A method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks and a PD-L1 binding antagonist at a dose of between about 80mg to 1600mg every three weeks; and is

(b) The second dosing regimen comprises one or more of the following for the dosing cycle: a PD-L1 binding antagonist at a dose between about 80mg to about 1600mg every three weeks and (i) vildagliptin-enfratuzumab is administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (ii) goverikang-saxituzumab is administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week, wherein the subject is administered a second dosing regimen after the subject has experienced disease progression or unacceptable toxicity during the first dosing regimen.

389. A method for treating a subject or population of subjects suffering from uc, the method comprising administering a first dosing regimen to the subject or population of subjects followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following cycles of dosing: a dose of about 600mg of tenecteuzumab every three weeks, and a dose of about 1200mg of alemtuzumab every three weeks; and

(b) The second dosing regimen comprises one or more of the following cycles of dosing: about 1200mg dose of alemtuzumab and (i) vildagliptin-enfratuzumab, administered at a dose of 1.25mg/kg weekly for 2 weeks/withdrawal for 1 week every three weeks, or (ii) govittacin-sapientuzumab, administered at a dose of 10mg/kg weekly for 2 weeks/withdrawal for 1 week, wherein a second dosing regimen is administered to the subject after the subject has experienced disease progression or unacceptable toxicity during the first dosing regimen.

390. The method of any one of embodiments 372-389, wherein the treatment results in an ORR of at least about 13.4% to at least about 31% for a population of subjects.

391. The method according to any one of embodiments 372-390, wherein the treatment results in a median OS for the population of subjects of about 7.9 months to about 16.3 months.

392. The method of embodiment 72, wherein the cancer is pancreatic cancer.

393. A method of treating a subject or population of subjects having pancreatic cancer, the 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 about 420mg of tenectereuptab on days 1 and 15 of each 28-day dosing cycle, a dose of about 840mg of atelizumab on days 1 and 15 of each 28-day dosing cycle, a dose of about 1000mg/m2 of gemcitabine on days 1, 8, and 15 of each 28-day dosing cycle, and a dose of nab-paclitaxel on days 1, 8, and 15 of each 28-day dosing cycle.

394. The method of embodiment 392 or 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, wherein the subject or subjects did not receive prior systemic therapy for metastatic PDAC.

397. The method of any one of embodiments 392 to 396, wherein the treatment results in an ORR of at least about 41.7% to about 46.7% in a population of subjects.

398. The method of any one of embodiments 392 to 397, wherein the treatment results in an increase in ORR of at least about 20% as compared to a treatment comprising gemcitabine and nab-paclitaxel without the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

399. The method of any one of embodiments 392 to 398, wherein the treatment results in a median PFS of at least about 5.5 months to about 7 months for the population of subjects.

400. The method of any one of embodiments 392 to 399, wherein the treatment results in a median OS for the population of subjects 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 for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg on day 1 of each dosing cycle.

403. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg on day 1 of each dosing cycle.

404. A method for treating a subject or population of subjects suffering from esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg on day 1 of each dosing cycle, wherein the subject has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

405. A method for treating a subject or population of subjects suffering from esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of between about 300mg to about 800mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 900mg to about 1500mg on day 1 of each dosing cycle, wherein the subject has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

406. The method of embodiment 402 or 403, wherein the subject or subjects have previously been treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. The method according to any one of embodiments 404-406, wherein the subject or subjects have experienced disease progression or unacceptable toxicity during a previous treatment.

408. The method of embodiment 402 or 403, wherein the 21 day dosing cycle further comprises a platinum chemotherapeutic agent and a non-platinum chemotherapeutic agent.

409. The method of embodiment 408 wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six administrations.

410. The method of any one of embodiments 404-409 wherein the platinum-based chemotherapeutic agent is cisplatin.

411. The method of embodiment 410, wherein cisplatin is administered at a dose of about 80mg/m2 on day 1 of each dosing cycle.

412. The method of any one of embodiments 404 to 411 wherein the non-platinum chemotherapeutic agent is an antimetabolite.

413. The method of embodiment 412, wherein the antimetabolite is 5-fluorouracil.

414. The method of embodiment 413, wherein 5-fluorouracil is administered at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle.

415. The method according to any one of embodiments 404-414, wherein the esophageal cancer is advanced or metastatic esophageal cancer.

416. The method of any one of embodiments 402, 403, 408, or 409 wherein the subject or subjects have not previously been treated for metastatic esophageal cancer.

417. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg on day 1 of each dosing cycle, a platinum-based chemotherapeutic agent at a dose of about 80mg/m2 on day 1 of each dosing cycle, and a non-platinum-based chemotherapeutic agent at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses.

418. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 600mg on day 1 of each dosing cycle, a PD-1 axis binding antagonist at a dose of about 1200mg on day 1 of each dosing cycle, cisplatin at a dose of about 80mg/m2 on day 1 of each dosing cycle, and 5-fluorouracil at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses.

419. A method for 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 dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose of about 600mg of tenecteuzumab on day 1 of each dosing cycle, a dose of about 1200mg of atuzumab on day 1 of each dosing cycle, a dose of about 80mg/m2 of cisplatin on day 1 of each dosing cycle, and a dose of 800mg/m2/24 hours of 5-fluorouracil on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses.

420. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more 21-day dosing cycles of a platinum chemotherapeutic agent and a non-platinum chemotherapeutic agent, wherein the platinum chemotherapeutic agent is omitted from the dosing regimen after six doses of the platinum chemotherapeutic agent; and is

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 80mg to 1600mg on day 1 of each dosing cycle.

421. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 80mg/m2 of a platinum-based chemotherapeutic agent on day 1 of each dosing cycle and a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses; and is provided with

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 80mg to 1600mg on day 1 of each dosing cycle.

422. A method for 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 dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a 21 day dosing cycle: cisplatin at a dose of about 80mg/m2 on day 1 of each dosing cycle and 5-fluorouracil at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses; and is

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 600mg of securityluzumab on day 1 of each dosing cycle and a dose of about 1200mg of atezumab on day 1 of each dosing cycle.

423. The method according to any one of embodiments 402 to 422, wherein the treatment results in a population of subjects with an ORR of at least about 14%.

424. The method of any one of embodiments 47 to 423, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

an HVR-H2 sequence comprising the amino acid sequence of KTYYRRFKWYSDYASVSVKG (SEQ ID NO: 2);

an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

425. The method of embodiment 424, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region Framework Regions (FRs):

FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLLGERANC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (SEQ ID NO: 9); and

FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

426. The method of embodiment 424, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs:

FR-H1 comprising the amino acid sequence of X1 VQLQQSGPGLVKPPSQTLSLTCASGDSVS (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 wherein X1 is E.

428. The method of embodiment 426 wherein X1 is Q.

429. The method of any one of embodiments 424-428, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain as in (a) and a VL domain as in (b).

430. The method of any one of embodiments 424-429, wherein the anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO:17 or 18; and

(b) A VL domain comprising SEQ ID NO: 19.

431. The method of any one of embodiments 424-427, 429, and 430, wherein the anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 17; and

(b) A VL domain comprising SEQ ID NO: 19.

432. The method of any one of embodiments 424-427 and 429-431, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 33; and

(b) A light chain comprising SEQ ID NO: 34.

433. The method of any one of embodiments 424-432, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

434. The method of any one of embodiments 424-433, wherein the anti-TIGIT antagonist antibody is a human antibody.

435. The method of any one of embodiments 424-434, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

436. The method of any one of embodiments 424-427 and 429-436, wherein the anti-TIGIT antagonist antibody is securititumumab.

437. The method of any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, 421, and 424-436, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan, bevacizumab, etiglimab, EOS084448, SGN-TGT, or TJ-T6.

438. The method of embodiment 437, wherein the anti-TIGIT antagonist antibody has intact Fc-mediated effector function.

439. The method of embodiment 437 or 438, wherein the anti-TIGIT antagonist antibody has enhanced Fc-mediated effector function.

440. The method of any one of embodiments 437-439, wherein the anti-TIGIT antagonist antibody is SGN-TGT.

441. The method of any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, and 421, wherein the anti-TIGIT antagonist antibody is domavalimab, BMS-986207, ASP8374, or COM902.

442. The method of any one of embodiments 424-431 and 441, wherein the anti-TIGIT antagonist antibody does not have intact Fc-mediated effector function.

443. The method of any one of embodiments 47-442, wherein the 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. The method of embodiment 444, wherein the anti-TIGIT antagonist antibody is tirayleigh immitumab, wiborlizumab, etiglimicab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, domcanalimab, or BMS-986207.

446. The method of any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, and 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 424-434, wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, dual Fab, fab '-SH, fv, single chain variable fragment (scFv), and (Fab') 2 fragments.

449. The method of any one of embodiments 424-448, wherein the anti-TIGIT antagonist antibody is a monospecific antibody.

450. The method of any one of embodiments 424-448, 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 424-451, 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-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 the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1.

456. The method of any one of embodiments 453 to 455, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The method of embodiment 456, wherein the anti-PD-L1 antagonist antibody is Attributumab, MDX-1105, devolumab, avermemab, SHR-1316, CS1001, envollizumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cochlolizumab, lodalizumab, 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, wherein the anti-PD-L1 antagonist antibody is atelizumab.

459. The method of embodiment 456, wherein the anti-PD-L1 antagonist antibody comprises the following HVRs:

An HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);

an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);

HVR-H3 sequence comprising the amino acid sequence of RHWPGFDY (SEQ ID NO: 22);

an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);

an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and

an HVR-L3 sequence comprising the amino acid sequence of QQYLLYHPAT (SEQ ID NO: 25).

460. The method of embodiment 459, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:26 has at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:27 has an amino acid sequence of at least 95% sequence identity; or

(c) A VH domain as in (a) and a VL domain as in (b).

461. The method of embodiment 460, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 26; and

(b) A VL domain comprising SEQ ID NO: 27.

462. The method of embodiment 461, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 28; and

(b) A light chain comprising SEQ ID NO: 29.

463. The method of 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 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 '-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, 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-1 to one or more of its ligand binding partners.

471. The method of embodiment 470, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2.

472. The method of any one of embodiments 469 to 471 wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The method of example 472, wherein the anti-PD-1 antagonist antibody is nivolumab, palboclizumab, MEDI-0680, sibradizumab, cimepril mab, BGB-108, palonolizumab, carpriclizumab, sillimizumab, tirizumab, terilizumab, dolaprimab, refolizumab, saralalizumab, deazaprinumab, CS1003, HLX10, SCT-I10A, serpalizumab, batilizumab, geminlizumab, BI 754091, cetirizumab, YBL-006, BAT1306, HX008, brilizumab, AMG 404, CX-188, JTX-4014, 609A, sym021, smlz 009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-103, or hAb21.

474. The method of any one of embodiments 469 to 471, wherein the PD-1 binding antagonist is an Fc fusion protein.

475. The method of embodiment 474, wherein the Fc fusion protein is AMP-224.

476. The method of any one of embodiments 80-112, 114-127, and 309-312, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks.

477. The method of any one of embodiments 51, 54, 60, 62, 63, 65 to 67, 80 to 112, 114 to 127, 136 to 140, 169 to 174, 189, 191, 267, 269, 286, 288, 291, 295, 301, 302, 303, 313, 315, 338, 340, 358 to 361, 372, 384, 387, 388, 402 to 404, 417, 420, 421, and 476, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody at a dose of about 600mg every three weeks.

478. The method of any one of embodiments 51, 54, 60, 62, 63, 65 to 67, 80 to 112, 114 to 127, 136 to 140, 169 to 174, 189, 191, 267, 269, 286, 288, 291, 295, 301, 302, 303, 309, 313, 315, 338, 340, 358 to 361, 372, 384, 387, 388, 402 to 404, 417, 420, 421, and 476, wherein the method comprises administering to a subject or population of subjects an anti-TIGIT antagonist antibody in a stepped dose based on the weight of the subject, wherein the weight of the subject is:

(a) Less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of about 300mg every three weeks;

(b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of about 400mg every three weeks; or

(c) Greater than 40kg, and the anti-TIGIT antagonist antibody is administered at about 600mg every three weeks.

479. The method of any one of embodiments 47, 48, 77, 78, 82 and 83, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks.

480. The method of any one of embodiments 47, 48, 59, 67, 323, and 479, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody at a dose of about 840mg every four weeks.

481. The method of any one of embodiments 49, 50, and 104, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks.

482. The method of any one of embodiments 49, 50, 227, 251 to 253, 255 and 481, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody at a dose of about 420mg every two weeks.

483. The method of any one of embodiments 47-482, wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose.

484. The method of any one of embodiments 54, 62, 63, 65 to 67, 80 to 109, and 27 to 2698, wherein the method comprises administering the PD-1 axis binding antagonist to a subject or population of subjects at a dose of between about 900mg to about 1500mg every three weeks.

485. The method of any one of embodiments 54, 60, 62, 63, 65 to 67, 80 to 112, 114 to 127, 136 to 140, 169 to 172, 189, 191, 267, 269, 286, 288, 291, 295, 301 to 303, 309, 311, 313, 315, 338, 340, 358 to 361, 372 to 375, 384, 387, 388, 402 to 405, 417, 420, 421, and 484, wherein the method comprises administering to the subject an anti-PD-1 axis binding antagonist at a dose of about 1200mg every three weeks.

486. The method of any one of embodiments 47, 50, 80-109, and 324, wherein the method comprises administering a PD-1 axis binding antagonist to a subject or population of subjects at a dose of about 1400 to 2000mg every four weeks.

487. The method of any one of embodiments 47, 50, 59, 67, 324, and 479, wherein the method comprises administering to the subject a PD-1 axis binding antagonist at a dose of about 1680mg every four weeks.

488. The method of embodiments 48, 49, 80-109 and 481, wherein the method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist at a dose of between about 600mg to about 1200mg every two weeks.

489. The method of any one of embodiments 48, 49, 80 to 109, 227, 251 to 253, and 481, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a dose of about 840mg every two weeks.

490. The method of any one of embodiments 47-489, wherein the dose of PD-1 axis binding antagonist is a fixed dose.

491. The method of embodiment 60 or 61, wherein the method comprises administering to the subject palivizumab at a fixed dose of 200mg every three weeks or about 400mg every six weeks.

492. The method of any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191, wherein each of the one or more dosing cycles is 21 days in length.

493. The method of any one of embodiments 47, 59, 67, 80-109, and 309-311, wherein each of the one or more dosing cycles is 28 days in length.

494. The method of any one of embodiments 49, 80-109, and 309-311, wherein each of the one or more dosing cycles is 14 days in length.

495. The method of any one of embodiments 47-494, wherein the method comprises administering to a subject or population of subjects an anti-TIGIT antagonist antibody on day 1 of each dosing cycle of the one or more dosing cycles.

496. The method according to any one of embodiments 47 to 495, wherein the method comprises administering a PD-1 axis binding antagonist to a subject or population of subjects on day 1 of each dosing cycle of the one or more dosing cycles.

497. The method of embodiment 321 or 493, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody on day 15 of each of the one or more dosing cycles.

498. The method of embodiment 322 or 493, wherein the method comprises administering the PD-1 axis binding antagonist to the subject on day 15 of each of the one or more dosing cycles.

499. The method of any one of embodiments 47 to 498, wherein the method comprises administering a PD-1 axis binding antagonist to the subject or population of subjects prior to the anti-TIGIT antagonist antibody, or the anti-TIGIT antagonist antibody precedes the PD-1 axis binding antagonist.

500. The method of embodiment 499, wherein the method comprises a first observation period after administration of the PD-1 axis binding antagonist or anti-TIGIT antagonist antibody.

501. The method of embodiment 500, wherein the length of the first observation period is between about 30 minutes and about 60 minutes.

502. The method of embodiment 500 or 501, wherein the method comprises a second observation period after administration of the anti-TIGIT antagonist antibody or the PD-1 axis binding antagonist.

503. The method of embodiment 502, wherein the length of the second observation period is between about 30 minutes and about 60 minutes.

504. The method of any one of embodiments 47-503, wherein the method comprises administering a PD-1 axis binding antagonist to the subject or population of subjects concurrently with the administration of the anti-TIGIT antagonist antibody.

505. The method of any one of embodiments 47-504, wherein the method comprises intravenously administering to a subject or population of subjects an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

506. The method of embodiment 505, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

507. The method of embodiment 505 or 506, wherein the method comprises administering to the subject or population of subjects the anti-TIGIT antagonist antibody by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

508. The method of any one of embodiments 47-114 and 116-507, wherein the PD-L1 expression level of a tumor sample obtained from the subject or subjects has been determined.

509. The method of embodiment 508, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

510. The method of embodiment 509, wherein the detectable PD-L1 expression level is a detectable protein expression level of PD-L1.

511. The method of embodiment 510, wherein the detectable protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

512. The method of embodiment 511, wherein the anti-PD-L1 antibody suitable for staining is anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8.

513. The method of embodiment 511 or 512, wherein a detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, pharmDx 22C3 IHC assay, ventana SP142 IHC assay, or pharmDx 28-8 IHC assay.

514. The method of any one of embodiments 47-109, 188, 220-265, and 307-423, wherein the detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP263 has been determined.

515. The method of any one of embodiments 47-220, 265-338, and 370-423, wherein the detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142 has been determined.

516. The method of any one of embodiments 47-113, 136-187, and 220-423, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody 22C 3.

517. The method of any one of embodiments 47-114 and 116-423, wherein a detectable level of protein expression of PD-L1 as determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8 has been determined.

518. The method of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% 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% TIC in the tumor sample.

520. The method of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% TIC in the tumor sample.

521. The method of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 20% TIC 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% 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 method 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% PD-L1 positive tumor cell fraction.

525. The method of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is greater than or equal to 30% PD-L1 positive tumor cell fraction.

526. The method of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is a fraction of PD-L1-positive tumor cells in the tumor sample that is greater than or equal to 1% and less than 50%.

527. The method of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is greater than or equal to 50% of PD-L1 positive tumor cell fraction.

528. The method of embodiment 515, wherein the PD-L1 positive tumor cell fraction is the proportion of the tumor area occupied by PD-L1 expressing tumor infiltrating Immune Cells (IC).

529. The method of embodiment 515, wherein the proportion of tumor area in the tumor sample occupied by PD-L1-expressing tumor infiltrating IC is greater than or equal to 1%.

530. The method of embodiment 515, wherein the proportion of tumor area in the tumor sample occupied by PD-L1-expressing tumor infiltrating IC is greater than or equal to 5%.

531. The method of embodiment 516, wherein the detectable protein expression level of PD-L1 is a Composite Positive Score (CPS) of greater than or equal to 1.

532. The method of embodiment 516, wherein the detectable protein expression level of PD-L1 is CPS greater than or equal to 10.

533. The method of embodiment 516, wherein the detectable protein expression level of PD-L1 is CPS greater than or equal to 20.

534. The method of any one of embodiments 528-530, wherein the IHC assay is a Ventana SP142 IHC assay.

535. The method of embodiment 509, wherein the detectable PD-L1 expression level is a detectable nucleic acid expression level of PD-L1.

536. The method of embodiment 535, wherein the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, massARRAY technology, ISH, or a combination thereof.

537. The method of any one of embodiments 47 to 423, wherein the treatment results in an increase in Overall Survival (OS) of the subject as compared to a reference OS time and/or an increase in progression-free survival (PFS) of the subject as compared to a reference PFS time.

538. The method of embodiment 537 wherein:

(a) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist; and/or

(b) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist.

539. The method 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 wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. The method of embodiments 69, 92, 127, 131, 249, and 540, wherein carboplatin is administered at a dose sufficient to achieve AUC =5mg/ml/min or AUC =6 mg/ml/min.

542. The method of embodiments 69, 127, 162, 164, 166, 168 and 540 wherein cisplatin is administered at a dose of about 75mg/m2 or 80mg/m 2.

543. The method of any one of embodiments 539-542, wherein the one or more non-platinum chemotherapeutic agents is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

544. The method of any one of embodiments 62, 173, 174, and 543, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. The method of any one of embodiments 69, 127, 162, and 544, wherein pemetrexed is administered at a dose of about 500mg/m 2.

546. The method of any one of embodiments 63, 64, 162, 398, and 544, wherein gemcitabine is administered at a dose of about 1000mg/m2 or about 1250mg/m 2.

547. The method of embodiment 544, wherein the antimetabolite is capecitabine.

548. The method of embodiment 544 or 547 wherein capecitabine is administered at a dose of about 1250mg/m 2.

549. The method of any one of claims 173, 174, 229, 230, 239, 240 and 543 to 548, wherein taxane is paclitaxel or nab-paclitaxel.

550. The method of any one of embodiments 69, 162, and 549, wherein paclitaxel is administered at a dose of about 175mg/m2 or about 200mg/m 2.

551. The method of any one of embodiments 63, 64, 249, 398 and 549, wherein nab-paclitaxel is administered at a dose of about 100mg/m 2.

552. The method 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, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331.

553. The method of any one of embodiments 69, 92, and 552, wherein etoposide is administered at a dose of about 100mg/m 2.

554. The method of any one of embodiments 543-553, wherein the one or more chemotherapeutic agents are each administered once a week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.

555. A method according to any one of embodiments 543 to 554, 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 gemcitabine is administered three times every four weeks.

557. The method of any one of embodiments 544 to 556, wherein 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 capecitabine is administered daily for two weeks.

559. The method of any one of embodiments 544 to 558, wherein 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 nab-paclitaxel is administered three times every four weeks.

561. The method of any one of embodiments 549 to 560, wherein nab-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 etoposide is administered every three weeks on days 1 to 3.

563. The method according to any one of embodiments 552 to 562, wherein etoposide is administered on days 1 to 3 of one or more dosing cycles.

564. The method according to any one of embodiments 543 to 563, wherein the one or more chemotherapeutic agents are administered before the PD-1 axis binding antagonist and/or anti-TIGIT antagonist antibody.

565. The method of any one of embodiments 543 to 564, wherein the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist and/or anti-TIGIT antagonist antibody.

566. The method according to any one of embodiments 543 to 565, wherein the one or more chemotherapeutic agents are administered intravenously or orally.

567. The method of any one of embodiments 65, 310, and 311, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 25mg/kg every three weeks.

568. The method of embodiment 312 or 567, wherein the VEGF antagonist is administered at a dose of about 10mg/kg to about 20mg/kg every three weeks.

569. The method of embodiment 318 or 568, wherein the VEGF antagonist is administered at a dose of about 15mg/kg every three weeks.

570. The method of any one of embodiments 65, 310 to 312, 318 to 320, and 567 to 569, wherein the VEGF antagonist is an anti-VEGF antibody.

571. The method of embodiment 570, wherein the anti-VEGF antibody comprises a VH domain and a VL domain of bevacizumab.

572. The method of embodiment 570 or 571, wherein the anti-VEGF antibody is bevacizumab.

573. The method of any one of embodiments 65, 310-312, and 318-320, wherein the anti-TIGIT antagonist antibody is tirayleigh itumumab, the PD-1 axis binding antagonist is atuzumab, and the VEGF antagonist is bevacizumab.

574. The method of any one of embodiments 65, 310 to 312, 318 to 320, and 567 to 573, wherein the method comprises administering a VEGF antagonist to the subject on day 1 of one or more dosing cycles.

575. A method according to any one of embodiments 318 to 320, wherein the method comprises administering a VEGF antagonist to the subject on day 15 of one or more dosing cycles.

576. The method of any one of embodiments 65, 310-312, 318-320, and 567-575, wherein the VEGF antagonist is administered intravenously.

577. The method of embodiment 576, wherein the VEGF antagonist is administered to the subject by intravenous infusion over 90 ± 15 minutes.

578. The method of any one of embodiments 65, 310-312, 318-320, and 567-577, wherein the method comprises administering a PD-1 axis binding antagonist to the subject prior to a VEGF antagonist, and the VEGF antagonist precedes an 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 between about 30 minutes and about 120 minutes in length.

581. The method of any one of claims 113, 128, 129 to 131, 175 to 182, 210 to 214, 221, 256, 257, 270, 289, 290, 293, 294, 297, 298, 333, 362 to 365, 385, 386, 389, 393, 419, and 422, wherein before administration the tirayleigh immuzumab and the atuzumab are combined in an IV infusion bag.

582. The method according to any one of embodiments 47-581, wherein the subject is human.

583. A kit comprising a PD-1 axis binding antagonist and/or an anti-TIGIT antagonist antibody for treating a subject having cancer according to the method of any one of embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582.

584. A kit comprising a PD-1 axis binding antagonist for use in treating a subject having cancer in combination with an anti-TIGIT antagonist antibody according to the methods of any one of embodiments 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582.

585. The kit of embodiment 584, wherein the kit further comprises an anti-TIGIT antagonist antibody.

586. The kit of any one of embodiments 583 to 585, wherein the anti-TIGIT antagonist antibody is teneuiuzumab.

587. The kit of any one of embodiments 583-586, wherein the PD-1 axis binding antagonist is atelizumab.

588. 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 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582.

589. The kit of embodiment 588, wherein the kit further comprises a PD-1 axis binding antagonist.

590. The kit of embodiment 588 or 589, wherein the PD-1 axis binding antagonist is atelizumab.

591. The kit of any one of embodiments 588-590, wherein the anti-TIGIT antagonist antibody is teneuimumab.

592. The kit according to any one of embodiments 583-591, wherein the kit further comprises one or more chemotherapeutic agents.

593. The kit 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 kit of embodiment 593, wherein the one or more platinum-based chemotherapeutic agents is carboplatin or cisplatin.

595. The kit of embodiment 593 or 594, wherein the one or more non-platinum chemotherapeutic agents are antimetabolites, taxanes, or topoisomerase II inhibitors.

596. The kit of embodiment 595, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

597. The kit of embodiment 595 or 596, wherein the taxane is paclitaxel or nab-paclitaxel.

598. The kit according to any one of embodiments 595 to 597, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331.

599. The kit of embodiments 583 to 598, wherein the kit further comprises a VEGF antagonist.

600. The kit of embodiment 599, wherein the VEGF antagonist is an anti-VEGF antibody.

601. The kit of embodiment 600, wherein the anti-VEGF antibody is bevacizumab.

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, wherein the method is carried out according to any one of claims 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582.

603. Use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for treating a subject or population of subjects having cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the method of any one of claims 47-190, 192-208, 210-211, 213, 215-268, 270-294, and 299-582.

604. The use of embodiment 603, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

605. The use of embodiment 603, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

Example 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, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 500mg to about 700mg every three weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 900mg to about 1500mg every three weeks, wherein the treatment further comprises use of a platinum chemotherapeutic agent every three weeks and a non-platinum chemotherapeutic agent every three weeks.

2. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 700mg to about 1000mg every four weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 1400mg to 2000mg every four 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 300mg to about 600mg every two weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 600mg to about 1200mg every two weeks.

4. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to example 2 or 3, wherein the treatment further comprises the use of one or more chemotherapeutic agents.

5. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 1-4, wherein the anti-TIGIT antagonist antibody is an IgG class antibody, particularly an IgG1 subclass antibody.

6. The anti-TIGIT antagonist antibody for use according to any one of embodiments 1-5 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

(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 KTYYRRFKWYSDYYAVSVKG (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) HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

7. The anti-TIGIT antagonist antibody for use according to any one of embodiments 1-6 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable Framework Regions (FRs):

(a) FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLAVSLERRATINC (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 GVPRFSGSGSGTDFTTISSLQAEDDVAVYYC (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 X1 VQLQQSGPVKPPSQTLSLTCASTGDSVS (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 anti-TIGIT antagonist antibody for use according to any one of embodiments 1-7 and a PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 1-8, wherein the anti-TIGIT antagonist antibody is securitumab.

10. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 1-9, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

11. The anti-TIGIT antagonist antibody for use according to any one of embodiments 1-10 and a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The anti-TIGIT antagonist antibody for use according to any one of embodiments 1-11 and the PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to example 12, wherein the anti-PD-L1 antagonist antibody is atelizumab, MDX-1105, devolumab, avermemab, SHR-1316, CS1001, envolumizumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cochlolizumab, lodalizumab, 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 anti-TIGIT antagonist antibody for use according to any one of embodiments 1-13 and the PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is atelizumab.

15. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 1-11, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to example 15, wherein the anti-PD-1 antagonist antibody is nivolumab, palivizumab, MEDI-0680, sibaprimab, BGB-108, palonolizumab, carpriclizumab, sillimirumab, tirlizumab, tirralizumab, tereprimab, dolelizumab, refelizumab, sarlizumab, perinaprimab, CS1003, HLX10, SCT-I10A, serralimab, batilizumab, geminumab, BI 754091, cetilizumab, YBL-006, BAT1306, HX008, briralizumab, AMG 1110, CX-188, JTX-4014 a, sym021, lz, m009, F520, SG001, AM0001, eng 388C 8, um end 4, um end 103-21 b, or STI-21 b.

17. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to any one of embodiments 2-16, wherein the treatment further comprises use of an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to example 1 or 17, wherein the non-platinum chemotherapeutic agent is a topoisomerase II inhibitor.

19. An anti-TIGIT antagonist antibody for use according to example 18 and a PD-1 axis binding antagonist, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331, particularly etoposide.

20. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 18 or 19, wherein the topoisomerase II inhibitor is formulated to be administered at a dose of 100mg/m 2.

21. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 17-20, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin, particularly carboplatin.

22. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 17-21, wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC =5mg/ml/min on the day of administration.

23. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 1-22, wherein the method further comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 23, wherein the induction period comprises four initial dosing cycles, and wherein 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.

25. The anti-TIGIT antagonist antibody for use of embodiment 23 or 24 and the PD-1 axis binding antagonist, wherein the maintenance phase does not comprise administration of a platinum-based chemotherapeutic agent and/or a non-platinum-based chemotherapeutic agent.

26. The anti-TIGIT antagonist antibody for use of any one of embodiments 1-25 and the PD-1 axis binding antagonist, wherein the treatment extends Progression Free Survival (PFS) of the subject compared to treatment without the anti-TIGIT antagonist antibody.

27. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 1-26, wherein the treatment extends overall survival of the subject compared to treatment without the anti-TIGIT antagonist antibody.

28. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 1-27, wherein the cancer is lung cancer.

29. The anti-TIGIT antagonist antibody for use according to example 28 and the PD-1 axis binding antagonist, wherein the lung cancer is Small Cell Lung Cancer (SCLC), particularly extensive SCLC (ES-SCLC).

30. The anti-TIGIT antagonist antibody for use according to example 28 and the PD-1 axis binding antagonist, wherein the lung cancer is non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to example 28, wherein the lung cancer is locally advanced unresectable or metastatic non-squamous NSCLC.

32. The anti-TIGIT antagonist antibody for use of embodiment 28 and the PD-1 axis binding antagonist, wherein the lung cancer is resectable lung cancer.

33. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 1-27, wherein the cancer is cervical cancer.

34. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 1-27, wherein the early stage cancer is triple negative breast cancer (eTNBC).

35. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 1-27, wherein the cancer is a head and neck cancer.

36. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 1-27, wherein the cancer is liver cancer, particularly hepatocellular carcinoma (HCC).

37. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 1-27, wherein the cancer is bladder cancer.

38. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 37, wherein the lung cancer is Urothelial Cancer (UC), particularly metastatic urothelial cancer (mUC).

39. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 1-27, wherein the cancer is pancreatic cancer, particularly Pancreatic Ductal Adenocarcinoma (PDAC).

40. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 1-27, wherein the 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, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist formulated for administration at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

42. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist formulated for administration at a dose of about 1400mg to 2000mg every four weeks.

43. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist formulated for administration at a dose of about 600mg to about 1200mg every two weeks.

44. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, wherein: (a) The method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist formulated for administration at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; (b) The method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist formulated for administration at a dose of about 1400mg to 2000mg every four weeks; or (c) the method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist formulated for administration at a dose of about 600mg to about 1200mg every two weeks.

45. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to embodiment 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

46. The anti-TIGIT antagonist antibody for use according to embodiment 44 and the PD-1 axis binding antagonist, wherein 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 200mg to about 2000mg every four weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 80mg to about 2000mg every four 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 200mg to about 2000mg every four weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 20mg to about 1600mg 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 10mg to about 1000mg every two weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 20mg to about 1600mg 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 10mg to about 1000mg every two weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 80mg to about 2000mg every four 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of about 100mg to about 1000mg every six weeks.

52. An anti-TIGIT antagonist antibody for use according to any one of embodiments 47-51 and a PD-1 axis binding antagonist, wherein the treatment further comprises use of one or more chemotherapeutic agents.

53. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 52, wherein the 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 30mg to about 1200mg every three weeks, the PD-1 axis binding antagonist is formulated to be administered at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

55. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to embodiments 53-54, wherein the method comprises an induction phase and a maintenance phase.

56. The anti-TIGIT antagonist antibody for use according to embodiment 55 and the PD-1 axis binding antagonist, wherein the induction phase and the maintenance phase each comprise one or more dosing cycles.

57. The anti-TIGIT antagonist antibody for use of embodiment 55 or 56 and the PD-1 axis binding antagonist, wherein the maintenance phase does not comprise administration of a platinum-based chemotherapeutic agent.

58. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 55-57, wherein the maintenance phase does not include administration of a non-platinum chemotherapeutic agent.

59. The anti-TIGIT antagonist antibody for use according to embodiment 58 and the PD-1 axis binding antagonist, wherein the maintenance phase comprises the following of one or more cycles of administration: the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 200mg to about 2000mg every four weeks and a dose of about 80mg to 2000mg of PD-1 axis binding antagonist every four weeks.

60. An anti-TIGIT antagonist antibody and an anti-PD-1 antagonist antibody for use in a method of treating a subject having cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 30mg to about 1200mg every three weeks and the anti-PD-1 antagonist antibody is formulated to be administered at a dose of about 80mg to about 1600mg every six weeks, wherein the anti-PD-1 antagonist antibody is palbociclumab.

61. Tirayleigh immuzumab and paribizumab for use in a method of treating a subject with cancer, wherein the treatment comprises use of tirayleigh immuzumab and paribizumab in a dosing regimen comprising one or more dosing cycles of tirayleigh immuzumab and paribizumab, wherein paribizumab is formulated for administration at a dose of between about 100mg to about 1000mg every six weeks.

62. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, and an antimetabolite that is orally administered twice daily at a dose between about 10mg/m2 to about 10000mg/m2, the antimetabolite being administered 2 weeks every three weeks/withdrawal for 1 week.

63. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30mg to about 1200mg every three weeks, a dose of about 80mg to about 1600mg of the PD-1 axis binding antagonist, gemcitabine, and nab-paclitaxel every three weeks.

64. The anti-TIGIT antagonist antibody for use according to embodiment 52 and the PD-1 axis binding antagonist, wherein the one or more chemotherapeutic agents are gemcitabine and nab-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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, and the VEGF antagonist at a dose of between about 1mg/kg to about 35mg/kg every three weeks.

66. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction period includes the following for one or more cycles of administration: an anti-TIGIT antagonist antibody formulated for a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is provided with

(b) The maintenance phase includes one or more of the following additional dosing cycles: every three weeks of anti-TIGIT antagonist antibody, every three weeks of PD-1 axis binding antagonist, and every three weeks of a non-platinum chemotherapeutic agent, and wherein the maintenance phase does not include administration of a platinum 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction period includes the following for one or more cycles of administration: an anti-TIGIT antagonist antibody formulated for a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is provided with

(b) The maintenance phase includes one or more of the following additional dosing cycles: an anti-TIGIT antagonist antibody formulated for a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist formulated for a dose of about 80mg to about 2000mg every four weeks, wherein the maintenance period does not include administration of a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent.

68. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 56-59, 66-67, wherein the induction period comprises four to six dosing cycles.

69. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 53-59 and 66-68, wherein:

(a) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum chemotherapeutic agent is carboplatin, and the non-platinum chemotherapeutic agent is paclitaxel; or

(c) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is etoposide.

70. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47-69, wherein the cancer is a solid tumor.

71. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47-70, wherein the cancer is locally advanced or metastatic.

72. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47-71, wherein the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, gastric cancer, colorectal cancer, kidney cancer, renal cancer, melanoma, or ovarian cancer.

73. The anti-TIGIT antagonist antibody for use according to embodiment 72 and the PD-1 axis binding antagonist, wherein the cancer is lung cancer.

74. The anti-TIGIT antagonist antibody for use according to example 73 and the PD-1 axis binding antagonist, wherein the lung cancer is NSCLC, in particular locally advanced unresectable NSCLC.

75. The anti-TIGIT antagonist antibody for use according to example 74 and the PD-1 axis binding antagonist, wherein the NSCLC is stage IIIB NSCLC.

76. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 73-75, wherein the lung cancer is recurrent or metastatic NSCLC.

77. The anti-TIGIT antagonist antibody for use according to example 76 and the PD-1 axis binding antagonist, wherein the NSCLC is stage IV NSCLC.

78. The anti-TIGIT antagonist antibody for use according to example 77 and the PD-1 axis binding antagonist, wherein the subject has not been previously treated for stage IV NSCLC.

79. The anti-TIGIT antagonist antibody for use according to embodiment 73 and the PD-1 axis binding antagonist, 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a dosing regimen comprising effective amounts of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor for one or more dosing cycles, wherein the treatment prolongs Progression Free Survival (PFS) of the subject 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.

81. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a population of subjects having lung cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a dosing regimen comprising effective amounts of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor for one or more dosing cycles, wherein the treatment results in a median PFS of the population of subjects from about 8.2 months to about 9.2 months.

82. The anti-TIGIT antagonist antibody for use of embodiment 80 or 81 and the PD-1 axis binding antagonist, wherein the treatment extends the Overall Survival (OS) of the subject or population of subjects compared to treatment with the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

83. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 80-82, wherein the treatment extends PFS in the subject or population of subjects by at least about 2.4 months as compared to treatment with the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

84. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 83, wherein the treatment extends PFS in the subject or population of subjects by at least about 3 months to at least about 4 months 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.

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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a dosing regimen comprising effective amounts of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor for one or more dosing cycles, wherein the treatment prolongs OS in the subject 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.

86. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a population of subjects having lung cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in one or more dosing cycles comprising effective amounts of the anti-TIGIT antagonist antibody, the 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 population of subjects from about 15.3 months to about 17.6 months.

87. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 82-86, wherein the treatment extends OS of the subject or population of subjects by at least about 3.3 months as compared to treatment with the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

88. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 82-86, wherein the treatment extends OS in the subject or population of subjects by at least about 3 months to at least about 5.3 months compared to treatment with the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

89. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 80-88, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered in each of four initial dosing cycles.

90. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 80-89, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are further administered in one or more additional cycles after the four initial dosing cycles.

91. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 90, wherein the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor are omitted in each of the one or more additional dosing cycles.

92. The anti-TIGIT antagonist antibody for use of any one of embodiments 80-91 and PD-1 axis binding antagonist, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the topoisomerase II inhibitor is etoposide.

93. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-92, wherein the lung cancer is Small Cell Lung Cancer (SCLC).

94. The anti-TIGIT antagonist antibody for use according to example 93, and the PD-1 axis binding antagonist, wherein SCLC is extensive-stage SCLC (ES-SCLC).

95. The anti-TIGIT antagonist antibody for use of embodiment 94 and the PD-1 axis binding antagonist, wherein the subject or subjects are treatment naive to ES-SCLC.

96. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-95, wherein the subject or subjects are absent or have a history of brain metastases.

97. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-96, wherein lung cancer is not selected for PD-L1.

98. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-96, wherein the lung cancer is selected for PD-L1.

99. The anti-TIGIT antagonist antibody for use of example 98 and the PD-1 axis binding antagonist, wherein the lung cancer is selected for PD-L1 expression by a detectable PD-L1 expression level.

100. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-99, wherein the lung cancer is metastatic.

101. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to example 100, wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal glands.

102. The anti-TIGIT antagonist antibody for use of embodiment 100 or 101 and the PD-1 axis binding antagonist, wherein the lung cancer has not metastasized to the brain.

103. The anti-TIGIT antagonist antibody for use according to any one of embodiments 100-102 and the PD-1 axis binding antagonist, wherein the treatment results in Complete Remission (CR) or Partial Remission (PR).

104. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-103, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30mg to about 1200mg every two, three or four weeks.

105. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 80-104, wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 80mg to about 2000mg every two, three or four weeks.

106. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 80-105, wherein the PD-1 axis binding antagonist, the anti-TIGIT antagonist antibody, the platinum-based chemotherapeutic agent, and the topoisomerase II inhibitor are administered sequentially.

107. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 106, wherein the PD-1 axis binding antagonist is administered prior to the anti-TIGIT antagonist antibody, the anti-TIGIT antagonist antibody is administered prior to the platinum-based chemotherapeutic agent, and the platinum agent is administered prior to the topoisomerase II inhibitor.

108. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-107, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered intravenously.

109. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 80-108, wherein one or more of the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered subcutaneously.

110. An anti-TIGIT antagonist antibody and atuzumab for use in a method of treating a subject having SCLC, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more 21-day dosing cycles comprising: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30mg to about 1200mg on day 1 of each dosing cycle, an attritumab at a dose of about 80mg to about 1600mg on day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each dosing cycle, wherein the treatment prolongs PFS and/or OS in the subject as compared to treatment with the attritumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

111. An anti-TIGIT antagonist antibody and atuzumab for use in a method of treating a subject having SCLC, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more 21-day dosing cycles comprising: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300mg to about 800mg on day 1 of each dosing cycle, an attritumab at a dose of about 900mg to about 1500mg on day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each dosing cycle, wherein the treatment prolongs PFS and/or OS in the subject as compared to treatment with the attritumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

112. The anti-TIGIT antagonist antibody for use and atuzumab according to embodiment 110 or 111, wherein the treatment further comprises one or more of the following for an additional 21-day dosing cycle: an anti-TIGIT antagonist antibody formulated for administration at a dose of about 30mg to about 1200mg on day 1 of each additional dosing cycle and atuzumab at a dose of about 80mg to about 1600mg on day 1 of each additional dosing cycle, wherein carboplatin and etoposide are omitted from each additional dosing cycle of the one or more additional dosing cycles.

113. Tirayleigh mab and atezumab for use in a method of treating a subject or population of subjects with ES-SCLC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in four initial dosing cycles followed by one or more additional dosing cycles, wherein:

(a) The four initial dosing cycles include: on day 1 of each initial dosing cycle, ibritumumab tiuxetan formulated for administration at a dose of about 600mg, atuzumab formulated for administration at a dose of about 1200mg on day 1 of each initial dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each initial dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each initial dosing cycle; and is

(b) The one or more additional dosing cycles comprise: (ii) on day 1 of each additional dosing cycle a securityluzumab formulated for administration at a dose of about 600mg and a certolizumab on day 1 of each additional dosing cycle formulated for administration at a dose of about 1200mg,

wherein the four initial dosing cycles and the one or more additional dosing cycles are each 21-day dosing cycles, and wherein the treatment prolongs PFS and/or OS in the subject or population of subjects as compared to treatment with attrituzumab, carboplatin, and etoposide without tiregumab.

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 using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles of the anti-TIGIT antagonist antibody, the 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.

115. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to example 114, wherein lung cancer has not been evaluated for PD-L1 expression.

116. The anti-TIGIT antagonist antibody for use of embodiment 114 or 115 and PD-1 axis binding antagonist, wherein the subject or subjects have not been determined to have a PD-L1 positive tumor cell fraction of greater than or equal to 50%.

117. The anti-TIGIT antagonist antibody for use of embodiment 116 and the PD-1 axis binding antagonist, wherein the subject or subjects have been determined to have a PD-L1 positive tumor cell fraction of less than 50%.

118. The anti-TIGIT antagonist antibody for use according to embodiment 116 or 117 and a PD-1 axis binding antagonist, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263 or 22C3.

119. The anti-TIGIT antagonist antibody for use of any one of embodiments 114-118 and PD-1 axis binding antagonist, wherein the subject or subjects do not have Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations.

120. The anti-TIGIT antagonist antibody for use of any one of embodiments 114-119 and the PD-1 axis binding antagonist, wherein the subject or subjects did not receive prior systemic therapy for lung cancer.

121. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 114-120, wherein the lung cancer is locally advanced lung cancer.

122. An anti-TIGIT antagonist antibody for use and a PD-1 axis binding antagonist according to any one of embodiments 114-121, wherein the lung cancer is NSCLC, in particular locally advanced unresectable or metastatic non-squamous NSCLC.

123. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 122, wherein the non-squamous NSCLC is stage IV non-squamous NSCLC.

124. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 114-123, wherein the dosing regimen comprises an induction period comprising four dosing cycles, and wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and non-platinum-based chemotherapeutic agent are administered on day 1 of each dosing cycle of the induction period.

125. The anti-TIGIT antagonist antibody for use of embodiment 124 and the PD-1 axis binding antagonist, wherein the dosing regimen comprises a maintenance period following the induction period, wherein the maintenance period comprises 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 administered on day 1 of each dosing cycle of the maintenance period.

126. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to embodiment 125, wherein the one or more dosing cycles of the maintenance phase do not include administration of a platinum-based chemotherapeutic agent.

127. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 114-126, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed.

128. Tirayleigh mab and atelizumab for use in a method of treating a subject or population of subjects having advanced non-squamous NSCLC, wherein the treatment comprises using an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising four 21-day dosing cycles of tirayleigh mab, atelizumab, carboplatin or cisplatin and pemetrexed, wherein on day 1 of each of the four 21-day dosing cycles, tirayleigh mab is formulated to be administered at a dose of about 600mg every three weeks, atelizumab is formulated to be administered at a dose of about 1200mg every three weeks, carboplatin is formulated to be administered at a dose sufficient to achieve AUC =5mg/ml/min every three weeks or is formulated to be administered at a dose of 75mg/m2 every three weeks, and pemetrexed is formulated to be administered at a dose of about 500mg/m2 every three weeks.

129. Tirayleigh immuzumab and atezumab for use in a method of treating a subject or population of subjects having advanced non-squamous NSCLC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in:

(i) The following of the four induction phase dosing cycles: a dose of about 600mg of tiregumab every three weeks, a dose of about 1200mg of altlizumab every three weeks, a dose of carboplatin sufficient to achieve an AUC =5mg/ml/min every three weeks, and a dose of pemetrexed of about 500mg/m2 every three weeks; and

(ii) The following for one or more maintenance phase dosing cycles: a dose of about 600mg of tirleiuzumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and a dose of about 500mg/m2 of pemetrexed every three weeks, wherein the one or more 21-day periods in the maintenance phase do not include administration of carboplatin, wherein the subject or population of subjects has not received prior systemic therapy for advanced non-squamous NSCLC.

130. Tirayleigh immuzumab and atlizumab for use in a method of treating a subject having advanced non-squamous NSCLC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in:

(i) The following of the four induction phase dosing cycles: a dose of about 600mg of tiregumab every three weeks, a dose of about 1200mg of altlizumab every three weeks, a dose of carboplatin sufficient to achieve an AUC =5mg/ml/min every three weeks, and a dose of pemetrexed of about 500mg/m2 every three weeks; and

(ii) One or more of the following maintenance phase dosing cycles: a dose of about 600mg of tiregumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and a dose of about 500mg/m2 of pemetrexed every three weeks, wherein the one or more 21-day periods in the maintenance phase do not include administration of carboplatin wherein the subject has not received prior systemic therapy for advanced non-squamous NSCLC.

131. Tirayleigh mab and atuzumab for use in a method of treating a subject having advanced non-squamous NSCLC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising four 21-day dosing cycles of tirayleigh mab, atuzumab, carboplatin or cisplatin, and pemetrexed, wherein on day 1 of each of the four 21-day dosing cycles, tirayleigh mab is formulated to be administered at a dose of about 600mg every three weeks, atuzumab is formulated to be administered at a dose of about 1200mg every three weeks, cisplatin is formulated to be administered at a dose of 75mg/m2, and pemetrexed is formulated to be administered at a dose of about 500mg/m 2.

132. The anti-TIGIT antagonist antibody for use according to any one of embodiments 114-131, and the PD-1 axis binding antagonist, wherein the treatment extends PFS in the subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 114-132, wherein the treatment results in a median PFS of the population of subjects of about 12.5 months to about 14.7 months.

134. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 114-133, wherein the treatment extends OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months.

135. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 114-134, wherein the treatment results in a median OS for the population of subjects of 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 having resectable lung cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, and the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

137. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having resectable lung cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose between about 300mg to about 800mg every three weeks, and the PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

138. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having lung cancer, wherein the treatment comprises 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 and the PD-1 axis binding antagonist, wherein at least one of the one or more dosing cycles comprises: an anti-TIGIT antagonist antibody formulated for administration at a dose of between about 30mg to about 1200mg every three weeks, and a PD-1 axis binding antagonist formulated for administration at a dose of between about 80mg to about 1600mg every three weeks as neoadjuvant therapy.

139. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having lung cancer, wherein the treatment comprises 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 and the PD-1 axis binding antagonist, wherein at least one of the one or more dosing cycles comprises: an anti-TIGIT antagonist antibody formulated for administration at a dose between about 300mg to about 800mg every three weeks, and a PD-1 axis binding antagonist formulated for administration at a dose between about 900mg to about 1500mg every three weeks as neoadjuvant therapy.

140. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 138 or 139, wherein at least one of the dosing cycles comprises the anti-TIGIT antagonist antibody formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, and the PD-1 axis binding antagonist is formulated to be administered at a dose of between about 80mg to 1600mg every three weeks as an adjunctive therapy.

141. The anti-TIGIT antagonist antibody for use according to embodiment 140 and the PD-1 axis binding antagonist, wherein at least one of the dosing cycles comprises the anti-TIGIT antagonist antibody formulated to be administered at a dose of between about 500mg to about 700mg every three weeks, and the PD-1 axis binding antagonist is formulated to be administered at a dose of between about 900mg to 1500mg every three weeks as an adjunctive therapy.

142. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 138-141, wherein the lung cancer is resectable lung cancer.

143. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-142, wherein the lung cancer is early stage lung cancer.

144. The anti-TIGIT antagonist antibody for use of any one of embodiments 136-143 and the PD-1 axis binding antagonist, wherein the lung cancer is stage II, stage IIIA, or stage IIIB lung cancer.

145. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 136-144, wherein the lung cancer does not have Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations.

146. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-145, wherein the subject is eligible for an R0 resection for healing purposes.

147. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-146, wherein the subject has not received prior therapy for lung cancer.

148. The anti-TIGIT antagonist antibody for use according to embodiment 147 and the PD-1 axis binding antagonist, wherein the prior therapy is immunotherapy, chemotherapy, or radiation therapy.

149. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-148, wherein the subject is eligible to receive a platinum-based chemotherapy regimen.

150. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-149, wherein the first dosing cycle is initiated pre-operatively.

151. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 150, wherein at least 1, 2, 3, or 4 dosing cycles are completed prior to surgery.

152. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiments 150 or 151, wherein 4 dosing cycles are completed prior to surgery.

153. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-152, wherein the first dosing cycle is initiated post-operatively.

154. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 153, wherein 16 dosing cycles are completed post-operatively.

155. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 150-154, wherein the surgery is segmental resection, lobectomy, bilobalectomy, or total lung resection.

156. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-155, wherein the method further comprises radiation therapy.

157. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 156, wherein the radiation therapy is post-operative radiation therapy.

158. The anti-TIGIT antagonist antibody for use according to any one of embodiments 136-157, and PD-1 axis binding antagonist, wherein the treatment further comprises use of one or more chemotherapeutic agents.

159. The anti-TIGIT antagonist antibody for use according to embodiment 158 and the PD-1 axis binding antagonist, wherein the one or more chemotherapeutic agents are administered post-operatively.

160. The anti-TIGIT antagonist antibody for use according to embodiment 159 and the PD-1 axis binding antagonist, wherein the one or more chemotherapeutic agents are administered in 4 dosing cycles post-operatively.

161. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 158-160, wherein the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

162. The anti-TIGIT antagonist antibody for use according to embodiment 161 and a PD-1 axis binding antagonist, wherein:

(a) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is gemcitabine;

(c) The platinum chemotherapeutic agent is carboplatin, and the non-platinum chemotherapeutic agent is paclitaxel;

(d) The platinum chemotherapeutic agent is cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed; or

(e) The platinum-based chemotherapeutic agent is cisplatin, and the non-platinum-based chemotherapeutic agent is gemcitabine.

163. The anti-TIGIT antagonist antibody for use of any one of embodiments 136-162 and the PD-1 axis binding antagonist, wherein the treatment results in an increase in a Major Pathological Remission (MPR) rate as compared to a reference MPR rate.

164. The anti-TIGIT antagonist antibody for use of embodiment 163 and the PD-1 axis binding antagonist, wherein the reference MPR rate is the MPR rate for a population of subjects who have received treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

165. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 136-164, wherein the treatment results in complete remission of pathology (pCR) and/or an increase in pCR rate as compared to a reference pCR rate.

166. The anti-TIGIT antagonist antibody for use according to embodiment 165 and the PD-1 axis binding antagonist, wherein the reference pCR rate is the pCR rate for a population of subjects who have received treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

167. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 136-166, wherein the treatment results in an increase in event-free survival (EFS) as compared to a reference EFS time.

168. The anti-TIGIT antagonist antibody for use according to embodiment 167 and the PD-1 axis binding antagonist, wherein the reference EFS time is the EFS time of a population of subjects who have received treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) 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 having resectable lung cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 600mg every three weeks, and the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

170. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having lung cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the-1 axis binding antagonist in one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, wherein at least one of the one or more dosing cycles comprises: an anti-TIGIT antagonist antibody formulated for administration at a dose of between about 30mg to about 600mg every three weeks, and a PD-1 axis binding antagonist formulated for administration at a dose of between about 80mg to about 1600mg every two weeks as neoadjuvant therapy.

171. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having resectable lung cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every two weeks, a platinum chemotherapeutic agent, and a non-platinum chemotherapeutic agent.

172. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having lung cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent in one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, wherein at least one of the one or more dosing cycles comprises: an anti-TIGIT antagonist antibody formulated for administration at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist formulated for administration at a dose between about 80mg to about 1600mg every two weeks, a platinum chemotherapeutic agent and a non-platinum 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 having resectable lung cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every two weeks, and: (a) (i) a platinum chemotherapeutic agent targeted to achieve a dose of AUC of 5mg/mL/min or AUC of 6mg/mL/min every three weeks; or (ii) a dose of about 75mg/m2 of a platinum-based chemotherapeutic agent every three weeks; and (b) (i) an antimetabolite at a dose of about 500mg/m2 every three weeks or at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each administration cycle; or (ii) a dose of taxane of about 100mg/m2, about 175mg/m2, or about 200mg/m2 every three weeks.

174. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having lung cancer, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in one or more dosing cycles comprising 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: (a) An anti-TIGIT antagonist antibody formulated for administration at a dose between about 30mg to about 600mg every three weeks; (b) A PD-1 axis binding antagonist formulated for administration at a dose of between about 80mg to about 1600mg every three weeks; (c) platinum chemotherapeutic agents: (i) A dose to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min for a target every three weeks; or (ii) a dose of about 75mg/m2 every three weeks; and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) An antimetabolite at a dose of about 500mg/m2 every three weeks or at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each administration cycle; or (ii) a taxane at a dose of about 100mg/m2, about 175mg/m2, or about 200mg/m2 every three weeks; wherein the treatment is neoadjuvant treatment.

175. Tenecteuzumab and atelizumab for use in a method of treating a subject having resectable lung cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising about a 600mg dose of tenecteuzumab every three weeks, about a 1200mg dose of atelizumab every three weeks, and:

(a)

(i) Carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or

(ii) Cisplatin at a dose of about 75mg/m2 every three weeks; or

(b)

(i) A dose of pemetrexed of about 500mg/m2 every three weeks, or gemcitabine at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each dosing cycle; or

(ii) Paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks.

176. Tirleiuzumab and attentizumab for use in a method of treating a subject having lung cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising tirleiuzumab, attentizumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent, wherein at least one of the dosing cycles comprises: (a) Ibritumomab tiuxetan formulated for administration at a dose of 600mg every three weeks; (b) Attrituzumab formulated for administration at a dose of 1200mg every three weeks; (c) a platinum chemotherapeutic agent, wherein the platinum chemotherapeutic agent is: (i) Carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) cisplatin at a dose of about 75mg/m2 every three weeks; and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) A dose of pemetrexed of about 500mg/m2 every three weeks or gemcitabine at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each dosing cycle; or (ii) paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; wherein the treatment is neoadjuvant treatment.

177. Tirayleigh immuzumab and atelizumab for use in a method of treating a subject having non-squamous NSCLC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising tirayleigh immuzumab and atelizumab, wherein: (a) At least one such dosing cycle includes as neoadjuvant therapy tirayleigh itumumab formulated for administration at a dose of about 600mg every three weeks and atelizumab formulated for administration at a dose of 1200mg every three weeks; and (b) at least one of the dosing cycles comprises as adjunctive therapy tipyluzumab formulated for administration at a dose of about 600mg every three weeks and atuzumab formulated for administration at a dose of about 1200mg every three weeks.

178. Antibodies to tirleiitumumab and astuzumab for use in a method of treating a subject having non-squamous NSCLC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising tirleiitumumab and attezumab, wherein: (I) at least one of the dosing cycles is neoadjuvant therapy: (a) Tirayleigh itumumab formulated for administration at a dose of about 600mg every three weeks; (b) Alemtuzumab formulated for administration at a dose of about 1200mg every three weeks as a neoadjuvant therapy; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and pemetrexed at a dose of about 500mg/m2 every three weeks; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and pemetrexed at a dose of about 500mg/m2 every three weeks; and (II) at least one of the dosing cycles comprises: as adjunctive therapy, securityluzumab formulated for administration at a dose between about 30mg to about 1200mg every three weeks and attentizumab formulated for administration at a dose between about 80mg to about 1600mg every three weeks.

179. Tirayleigh immuzumab and atelizumab for use in a method of treating a subject having lung cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising tirayleigh immuzumab and atelizumab, wherein: (I) At least one of the dosing cycles is neoadjuvant and comprises: (a) Ibritumomab tiuxetan formulated for administration at a dose of about 600mg every three weeks; (b) Alemtuzumab formulated for administration at a dose of about 1200mg every three weeks as a neoadjuvant therapy; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises: tenecteumab formulated for administration at a dose of between about 30mg to about 1200mg every three weeks and atelizumab formulated for administration at a dose of between about 80mg to about 1600mg every three weeks as adjuvant therapy.

180. Tirayleigh immuzumab and atelizumab for use in a method of treating a subject having lung cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising tirayleigh immuzumab and atelizumab, wherein:

(I) At least one of the dosing cycles is neoadjuvant and comprises:

(a) Ibritumomab tiuxetan formulated for administration at a dose of about 1200mg every three weeks;

(b) Alemtuzumab formulated for administration at a dose of about 1200mg every three weeks as a neoadjuvant therapy; and

(c)

(i) A dose of carboplatin targeted to achieve an AUC of 5mg/mL/min every three weeks, and a dose of gemcitabine of about 1000mg/m2 on days 1 and 8 of each dosing cycle;

(ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks, and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or

(iii) Cisplatin at a dose of about 75mg/m2 every three weeks, and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and

(II) at least one of the dosing cycles comprises: tenecteumab formulated for administration at a dose of between about 300mg to about 800mg every three weeks and atelizumab formulated for administration at a dose of between about 900mg to about 1500mg every three weeks as adjuvant therapy.

181. Tirayleigh immuzumab and atelizumab for use in a method of treating a subject having lung cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising tirayleigh immuzumab and atelizumab, wherein: (I) At least one of the dosing cycles is neoadjuvant and comprises: (a) Ibritumomab tiuxetan formulated for administration at a dose of about 600mg every three weeks; (b) Alemtuzumab formulated for administration at a dose of about 1200mg every three weeks as a neoadjuvant therapy; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises: as adjunctive therapy, securityluzumab formulated for administration at a dose of about 600mg every three weeks and attentizumab formulated for administration at a dose of about 1200mg every three weeks.

182. Tenelluloitumumab and atelizumab for use in a method of treating a subject having resectable squamous NSCLC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising tenellulomicrab and atelizumab, wherein: (I) At least one of the dosing cycles is neoadjuvant and comprises: (a) Ibritumomab tiuxetan formulated for administration at a dose of about 600mg every three weeks; (b) Alemtuzumab formulated for administration at a dose of about 1200mg every three weeks as a neoadjuvant therapy; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises: as adjunctive therapy, securityluzumab formulated for administration at a dose of about 600mg every three weeks and attentizumab formulated for administration at a dose of about 1200mg every three weeks.

183. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 136-182, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SP 263.

184. The anti-TIGIT antagonist antibody for use of embodiment 183 and the PD-1 axis binding antagonist, wherein the detectable protein expression level of PD-L1 is greater than or equal to 50% PD-L1 positive tumor cell fraction.

185. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 73, 114-121, and 136-184, wherein the lung cancer is NSCLC.

186. The anti-TIGIT antagonist antibody for use according to example 185 and a PD-1 axis binding antagonist, wherein the NSCLC is squamous NSCLC.

187. The anti-TIGIT antagonist antibody for use according to embodiment 185 and the PD-1 axis binding antagonist, wherein the NSCLC is non-squamous NSCLC.

188. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 72, wherein the cancer is cervical cancer.

189. 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 with a detectable PD-L1 expression level, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, and the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

190. 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 with a detectable level of PD-L1 expression, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 300mg to about 800mg every three weeks and the PD-1 axis binding antagonist at a dose of between about 900mg to about 1500mg every three 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 having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for said subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression on tumor cells that has been detected, an anti-TIGIT antagonist antibody formulated for administration at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist formulated for administration at a dose between about 80mg to about 1600mg every three weeks.

192. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 189-191, wherein cervical cancer is squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma.

193. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-191, wherein the cervical cancer is stage IVB, metastatic, recurrent, or persistent.

194. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 189-193, wherein the cervical cancer is metastatic and/or relapsed PD-L1-positive cervical cancer.

195. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-194, wherein the subject or subjects have received at least one prior line of therapy.

196. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-195, wherein the subject or subjects have received at least two prior lines of therapy.

197. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-196, wherein the subject or subjects did not receive at least two prior lines of therapy.

198. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-194, wherein the subject or subjects have not received prior therapy.

199. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 195-198, wherein the prior therapy is chemotherapy, surgery, and/or radiation therapy.

200. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 189 and 192-199, wherein the treatment results in a clinical response.

201. The anti-TIGIT antagonist antibody for use according to example 200 and the PD-1 axis binding antagonist, wherein the clinical response is an increase in Objective Remission Rate (ORR) of the population of subjects as compared to a reference ORR.

202. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 201, wherein the reference ORR is the median ORR of a population of subjects that have received treatment comprising the PD-1 axis binding antagonist but not with the anti-TIGIT antagonist antibody.

203. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 200, wherein the reference ORR is at least about 14.6% to about 26%.

204. The anti-TIGIT antagonist antibody for use according to embodiment 200 and the PD-1 axis binding antagonist, wherein the clinical response is CR or PR.

205. The anti-TIGIT antagonist antibody for use according to any one of embodiments 200-204, wherein the clinical response is an increase in Progression Free Survival (PFS) of the subject as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject as compared to a reference OS time.

206. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 205, wherein:

(a) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference DOR time is the median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

207. An anti-TIGIT antagonist antibody and atelizumab for use in a method of treating a subject having cervical cancer with a detectable level of PD-L1 expression, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in one or more dosing cycles comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 600mg every three weeks, and the atelizumab at a dose of about 1200mg every two weeks.

208. An anti-TIGIT antagonist antibody and atuzumab for use in a method of identifying a subject having cervical cancer who is likely to benefit from a therapy comprising one or more cycles of administration of the anti-TIGIT antagonist antibody and the atuzumab, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining; and

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on tumor cells, anti-TIGIT antagonist antibody formulated for administration at a dose of 600mg every three weeks and astuzumab formulated for administration at a dose of 1200mg every three weeks.

209. An anti-TIGIT antagonist antibody and atlizumab for use in a method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody formulated to be administered at a dose of 600mg every three weeks and atuzumab formulated to be administered at a dose of 1200mg every three weeks, based on PD-L1 expression on tumor cells that have been detected.

210. Tirleiitumumab and atelizumab for use in a method of treating a subject having cervical cancer with a detectable level of PD-L1 expression, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising a dose of about 600mg of tirleiuzumab per three weeks and a dose of about 1200mg of atelizumab per three weeks.

211. Teneligulizumab and atelizumab for use in a method of treating a subject having cervical cancer, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on the tumor cells, ibritumomab tiuxetan formulated for administration at a dose of 600mg every three weeks and altlizumab formulated for administration at a dose of 1200mg every three weeks; and

(d) Administering a therapy to the identified subject.

212. A terayleigh mab and atezumab for use in a method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on tumor cells, securityluzumab formulated for administration at a dose of 600mg every three weeks and attentizumab formulated for administration at a dose of 1200mg every three weeks.

213. Tirayleigh mab and atezumab for use in a method of treating a subject having metastatic and/or recurrent cervical cancer, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: (ii) based on PD-L1 expression on the tumor cells that have been detected, tenecteumab formulated for administration at a dose of 600mg every three weeks and atelizumab formulated for administration at a dose of 1200mg every three weeks; and

(d) Administering a therapy to the identified subject.

214. Teneliguriuzumab and atelizumab for use in a method of selecting a therapy for a subject having metastatic and/or recurrent cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on tumor cells, securityluzumab formulated for administration at a dose of 600mg every three weeks and attentizumab formulated for administration at a dose of 1200mg every three weeks.

215. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-214, wherein the subject is identified as a subject likely to benefit from treatment based on PD-L1 expression on tumor cells that has been detected.

216. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 189-215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP 263.

217. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-216, wherein the detectable PD-L1 expression level is greater than or equal to 5% tumor-associated immune cells (TICs) in the sample from the subject.

218. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 189-215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody 22C 3.

219. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 189-216, wherein the detectable PD-L1 expression level is a Composite Positive Score (CPS) of greater than or equal to 1 in a sample from the subject.

220. The anti-TIGIT antagonist antibody for use according to embodiment 72 and the PD-1 axis binding antagonist, wherein the cancer is breast cancer.

221. Tirayleigh mab and atezumab for use in a method of treating a subject or population of subjects having breast cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising one or more cycles of administration of: a dose of about 840mg of tenecteuzumab every four weeks, a dose of about 1680mg of alemtuzumab every four weeks, and nab-paclitaxel dosed at about 100mg/m2 for 3 weeks/withheld for 1 week.

222. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 220 or 221, wherein the breast cancer is Triple Negative Breast Cancer (TNBC).

223. The anti-TIGIT antagonist antibody for use of embodiment 222 and the PD-1 axis binding antagonist, wherein the TNBC is a non-resectable locally advanced or metastatic TNBC.

224. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 220-223, wherein the subject has not previously undergone systemic therapy for metastatic breast cancer.

225. The anti-TIGIT antagonist antibody for use according to any one of embodiments 220-224 and the PD-1 axis binding antagonist, wherein the treatment results in an ORR of at least about 53% to about 67.5% in a population of subjects.

226. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to any one of embodiments 222-225, wherein the treatment results in a median OS for the population of subjects of about 25.0 months.

227. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having early triple negative breast cancer (eTNBC), wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 10mg to about 1000mg every two weeks and the PD-1 axis binding antagonist is at a dose of about 20mg to about 1600mg every two weeks.

228. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to embodiment 227, wherein the treatment further comprises the use of one or more chemotherapeutic agents.

229. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to embodiment 228, wherein the one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 227, wherein the method further comprises (a) one or more cycles of administration 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) one or more cycles of administration of an anti-TIGIT antagonist antibody, a 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).

231. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 229 or 230, wherein the alkylating agent is cyclophosphamide.

232. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 231, wherein cyclophosphamide is formulated to be administered at a dose of about 600mg/m 2.

233. An anti-TIGIT antagonist antibody for use and a PD-1 axis binding antagonist according to any one of embodiments 227-229, 231, and 232, wherein the treatment further comprises use of G-CSF or GM-CSF.

234. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to embodiment 230 or 233, wherein G-CSF is pegylated filgrastim or filgrastim.

235. The anti-TIGIT antagonist antibody for use according to embodiment 234 and the PD-1 axis binding antagonist, wherein G-CSF is pegylated filgrastim.

236. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 235, wherein the pegylated filgrastim is formulated for administration at a dose of about 6 mg.

237. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 228, 229, and 231-236, wherein the treatment further comprises use of one or more subsequent doses of one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

238. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to any one of embodiments 228, 229, and 231-237, wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are each administered once weekly, once every two weeks, or once every three weeks.

239. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 229-238, wherein the platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered every week, the topoisomerase II inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF or the GM-CSF is administered every two weeks.

240. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 229-239, wherein the taxane or the taxane and the platinum-based chemotherapeutic agent are administered during the first 12 weeks of a dosing regimen.

241. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 229-240, wherein the topoisomerase II inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered on weeks 13 to 19 of a dosing regimen.

242. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 227-241, wherein the total length of the dosing regimen is 19 weeks.

243. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 227-242, wherein the method is neoadjuvant therapy.

244. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 227-243, wherein the dosing regimen is followed by surgery.

245. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 244, wherein surgery is performed between two to six weeks after the last dose of the dosing regimen.

246. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiments 244 or 245, wherein the surgery comprises mastectomy.

247. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 244-246, wherein surgery comprises axillary lymph node surgery.

248. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 229-247, wherein the topoisomerase II inhibitor is doxorubicin.

249. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 229-247, wherein the taxane is nab-paclitaxel, the platinum-based chemotherapeutic agent is carboplatin or cisplatin, and the topoisomerase II inhibitor is doxorubicin.

250. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to embodiment 248 or 249, wherein doxorubicin is formulated for administration at a dose of about 60mg/m 2.

251. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having eTNBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising: the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300mg to about 600mg every two weeks, the PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

252. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having eTNBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 300mg to about 600mg every two weeks, the PD-L1 binding antagonist is at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) Taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

253. An anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody for use in a method of treating a subject having eTNBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody in a dosing regimen comprising: the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300mg to about 600mg every two weeks, the PD-L1 axis binding antagonist is formulated for administration at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

254. Tenerriuzumab and an anti-PD-L1 antagonist antibody for use in a method of treating a subject having eTNBC, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody in a dosing regimen comprising: the tirayleigh itumumab is formulated for administration at a dose of about 300mg to about 600mg every two weeks, the PD-L1 axis binding antagonist is formulated for administration at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

255. An anti-TIGIT antagonist antibody and atuzumab for use in a method of treating a subject having eTNBC, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising: the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300mg to about 600mg every two weeks, the atelizumab at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

256. Tirayleigh itumumab and atezumab for use in a method of treating a subject with eTNBC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising: a dose of about 300mg to about 600mg every two weeks of tenerriuzumab, a dose of about 600mg to about 1200mg every two weeks of atelizumab, and:

(a)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly and carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

257. Tirayleigh itumumab and atezumab for use in a method of treating a subject with eTNBC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising: a dose of about 420mg of tirleivuzumab every two weeks, a dose of about 840mg of atuzumab every two weeks, and:

(a)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly and carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly during the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

258. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 220-257, wherein a detectable protein expression level of PD-L1 in a tumor sample from the subject determined by an IHC assay comprising staining with the anti-PD-L1 antibody SPl42 has been determined.

259. The anti-TIGIT antagonist antibody for use of embodiment 258 and the PD-1 axis binding antagonist, wherein the proportion of a tumor area in the tumor sample occupied by PD-L1-expressing tumor infiltrating Immune Cells (IC) is greater than or equal to 1%.

260. The anti-TIGIT antagonist antibody for use of any one of embodiments 227-259 and a PD-1 axis binding antagonist, wherein eTNBC appears as T2-4d TNBC.

261. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 227-260, wherein the eTNBC is represented by cT2-cT4, cN0-cN3, and cM0TNBC.

262. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 227-261, wherein the subject has not previously been treated for eTNBC.

263. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 227-262, wherein the treatment results in complete remission (pCR) of the pathology.

264. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 227-263, wherein the treatment results in an increase in Overall Survival (OS) or event-free survival (EFS).

265. The anti-TIGIT antagonist antibody for use of embodiment 72 and the PD-1 axis binding antagonist, wherein the cancer is a head and neck cancer.

266. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 265, wherein the head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN).

267. 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 level of PD-L1 expression, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist is administered at a dose of between about 80mg to about 1600mg every three weeks.

268. 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 level of PD-L1 expression, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 300mg to about 800mg every three weeks and the PD-1 axis binding antagonist is administered at a dose of between about 900mg to about 1500mg every three 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 having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject or population of subjects having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks, and the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks.

270. Tirayleigh mab and atelizumab for use in a method of treating a subject or population of subjects having SCCHN with detectable PD-L1 expression levels, wherein the treatment comprises use of tirayleigh immuzumab and an ate diagnostic in one or more dosing cycles, wherein tirayleigh immuzumab is formulated for administration at a dose of about 600mg every three weeks, and wherein atelizumab is at a dose of about 1200mg every three weeks.

271. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 267-270, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

272. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 266-271, wherein the SSCHN is Human Papilloma Virus (HPV) positive.

273. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 266-272, wherein the SSCHN is HPV negative.

274. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to embodiments 272 or 273, wherein HPV status is determined by p16IHC, in situ hybridization, or by PCR.

275. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 266-274, wherein SCCHN is recurrent and/or metastatic SCCHN.

276. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 265-275, wherein the subject or subjects have not received prior therapy.

277. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 276, wherein the prior therapy is prior systemic therapy for relapsed and/or metastatic disease.

278. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 265-268 and 270-277, wherein the treatment results in CR or PR.

279. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 265-268 and 270-277, wherein the treatment results in an increase in the Objective Remission Rate (ORR) of the population of subjects as compared to the reference ORR.

280. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 279, wherein the reference ORR is the median ORR of a population of subjects that have received treatment comprising the PD-1 axis binding antagonist but not with the anti-TIGIT antagonist antibody.

281. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiments 279 or 280, wherein the reference ORR is about 19% to about 36%.

282. The anti-TIGIT antagonist antibody for use according to any of embodiments 265-268 and 270-281, wherein the treatment results in an increase in Progression Free Survival (PFS) of the subject or population of subjects as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject or population of subjects as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject or population of subjects as compared to a reference OS time.

283. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 282, wherein:

(a) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference DOR time is the median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

284. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 282, wherein the reference DOR is at least about 6.7 months to about 23.4 months.

285. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 282, wherein the reference OS 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 having SCCHN having a detectable level of PD-L1 expression, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, the one or more dosing cycles comprising a dose of the PD-1 axis binding antagonist between about 80mg to about 1600mg every three weeks, and the anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks.

287. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having SCCHN having a detectable level of PD-L1 expression, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, the one or more dosing cycles comprising a dose of the PD-1 axis binding antagonist of about 1200mg every three weeks, and the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 600mg every three weeks.

288. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having SCCHN having a detectable level of PD-L1 expression, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, the one or more dosing cycles comprising a dose of the PD-L1 binding antagonist between about 80mg to about 1600mg every three weeks, and the anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks.

289. Tirayleigh mab and atelizumab for use in a method of treating a subject having SCCHN with a detectable PD-L1 expression level, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising a dose of atelizumab between about 80mg to about 1600mg every three weeks and a dose of tirayleigh mab between about 30mg to about 1200mg every three weeks.

290. Tirleiitumumab and atuzumab for use in a method of treating a subject having SCCHN with a detectable PD-L1 expression level, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising a dose of about 600mg of tirleiuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

291. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks; and

(d) Administering the therapy to the identified subject having a detectable PD-L1 expression level.

292. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay 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: a PD-1 axis binding antagonist at a dose of about 1200mg every three weeks, and an anti-TIGIT antagonist antibody is formulated for administration at a dose of about 600mg every three weeks; and

(d) Administering the therapy to a subject identified as having a detectable PD-L1 expression level.

293. Teneligulizumab and atelizumab for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay 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: a dose of between about 80mg to about 1600mg of atuzumab every three weeks, a dose of between about 30mg to about 1200mg of ibritumumab tiuxetan every three weeks; and

(d) Administering the therapy to a subject identified as having a detectable PD-L1 expression level.

294. Teneligulizumab and atelizumab for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: attrituzumab at a dose of about 1200mg every three weeks, ibritumomab tiuxetan at a dose of about 600mg every three weeks; and

(d) Administering the therapy to a subject identified as having a detectable PD-L1 expression level.

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 having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks, and the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks.

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 having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of about 1200mg of PD-1 axis binding antagonist every three weeks, and the anti-TIGIT antagonist antibody is formulated to be administered at a dose of about 600mg every three weeks.

297. A terayleigh mab and atezumab for use in a method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on the PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of atuzumab every three weeks and a dose of between about 30mg to about 1200mg of tiryleiguzumab every three weeks.

298. A terayleigh mab and atezumab for use in a method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on the PD-L1 expression that has been detected, a dose of about 1200mg of alemtuzumab every three weeks and a dose of about 600mg of tenecteuzumab every three weeks.

299. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 267-298, wherein the detectable PD-L1 expression level is a detectable protein expression level of PD-L1 as determined by an Immunohistochemistry (IHC) assay comprising staining with the anti-PD-L1 antibody SP 263.

300. The anti-TIGIT antagonist antibody for use according to embodiment 299 and the PD-1 axis binding antagonist, wherein the detectable protein expression level of PD-L1 is that a tumor associated immune cell (TIC) is:

(a) Greater than or equal to 5%;

(b) Greater than or equal to 5% and less than 20%; or

(c) Greater than or equal to 20%.

301. An anti-TIGIT antagonist antibody for use and a PD-1 axis binding antagonist that identify a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of the following: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 5% TIC identifies the subject as likely to benefit from the therapy.

302. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in identifying a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of the following: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein protein expression level of PD-L1 is greater than or equal to 5% and less than 20% of TIC identifies the subject as likely to benefit from the therapy.

303. An anti-TIGIT antagonist antibody for use and a PD-1 axis binding antagonist that identify a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of the following: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 20% of TIC identifies the subject as likely to benefit from the therapy.

304. The anti-TIGIT antagonist antibody for use according to any one of embodiments 301-303 and the PD-1 axis binding antagonist, 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 anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 301-304, wherein TIC is determined using the VentanaSP263IHC assay.

306. The anti-TIGIT antagonist antibody for use of any of embodiments 267-305 and PD-1 axis binding antagonist, wherein the subject or population of subjects is identified as a subject likely to benefit from treatment based on PD-L1 expression on tumor cells that have been detected.

307. The anti-TIGIT antagonist antibody for use according to embodiment 72 and the PD-1 axis binding antagonist, wherein the cancer is liver cancer.

308. The anti-TIGIT antagonist antibody for use according to embodiment 307 and the PD-1 axis binding antagonist, 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), wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated for administration, and the PD-1 axis binding antagonist, wherein the subject or population of subjects did not receive prior systemic therapy for HCC.

310. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 309, wherein the treatment further comprises 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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in one or more dosing cycles comprising an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist.

312. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiments 310 and 311, wherein the VEGF antagonist is formulated for administration at a dose of about 5mg/kg to about 25mg/kg every three weeks.

313. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 309-312, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30mg to about 1200mg every three weeks.

314. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 313, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 30mg to about 800mg every three weeks.

315. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 309-314, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 600mg every three weeks.

316. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 309-315, wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 80mg to about 1600mg every three weeks.

317. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 309-316, wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 900mg to about 1500mg every three weeks.

318. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 310 or 311, wherein the VEGF antagonist is formulated for administration at a dose of about 1mg/kg to about 20mg/kg biweekly.

319. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 318, wherein the VEGF antagonist is formulated for administration at a dose of about 5mg/kg to about 10mg/kg biweekly.

320. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 319, wherein the VEGF antagonist is formulated for administration at a dose of about 5mg/kg, about 7.5mg/kg, or about 10mg/kg biweekly.

321. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 309-311 and 318-320, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 10mg to about 1000mg biweekly.

322. The anti-TIGIT antagonist antibody for use of any of embodiments 309-311 and 318-321, wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 20mg to about 1600mg every two weeks.

323. The anti-TIGIT antagonist antibody for use of embodiments 309-311 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 200mg to about 2000mg every four weeks.

324. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 309-311 and 323, wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 80mg to about 2000mg every four weeks.

325. The anti-TIGIT antagonist antibody for use of any of embodiments 309-311, 323, and 324 and the PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is formulated for administration at a dose of about 1400mg to about 2000mg every four weeks.

326. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 309-325, wherein the HCC is locally advanced or metastatic HCC.

327. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 309-326, wherein the HCC is unresectable HCC.

328. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 309-327, wherein the subject or subjects have been determined to have adequate liver function.

329. An anti-TIGIT antagonist antibody for use according to embodiment 328 and a PD-1 axis binding antagonist, wherein sufficient liver function is characterized as Child-Pugh class a.

330. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 309-329, wherein HCC tumor samples obtained from the subject or subjects have been determined to have a detectable level of PD-L1 expression.

331. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 309-330, wherein the method comprises administering to the subject or population of subjects at least four dosing cycles.

332. The anti-TIGIT antagonist antibody for use of embodiment 331 and PD-1 axis binding antagonist, wherein the method comprises administering to a subject or population of subjects at least 16 dosing cycles.

333. Tirayleigh mab and atezumab for use in a method of treating a subject or population of subjects with HCC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in one or more dosing cycles comprising: a dose of about 600mg of tenecteukumab every three weeks, a dose of about 1200mg of atelizumab every three weeks, and a dose of about 15mg/kg of bevacizumab every three weeks.

334. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 311-333, wherein the subject or subjects did not have received prior systemic treatment for HCC.

335. The anti-TIGIT antagonist antibody for use according to any one of embodiments 309-334 and the PD-1 axis binding antagonist, wherein the treatment results in a median PFS for the population of subjects of at least about 5.6 months to at least about 6.83 months.

336. The anti-TIGIT antagonist antibody for use of embodiment 72 and the PD-1 axis binding antagonist, wherein the cancer is bladder cancer.

337. The anti-TIGIT antagonist antibody for use according to embodiment 336 and the PD-1 axis binding antagonist, wherein the 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 having MIBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose between about 80mg to about 1600mg every three weeks, wherein the subject is not eligible for treatment with a platinum-based chemotherapeutic agent.

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 having MIBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose between about 300mg to about 800mg every three weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose between about 900mg to about 1500mg every three weeks, wherein the subject is not eligible for treatment with a platinum-based chemotherapeutic agent.

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 having MIBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

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 having MIBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 300mg to about 800mg every three weeks and the PD-1 axis binding antagonist is administered at a dose of between about 900mg to about 1500mg every three weeks, wherein the treatment is a perioperative treatment.

342. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 338-341, wherein the subject or subjects have an inosine clearance < 60 mL/min.

343. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 338-342, wherein the subject or subjects have hearing loss greater than or equal to grade 2.

344. The anti-TIGIT antagonist antibody for use of any one of embodiments 338-343 and PD-1 axis binding antagonist, wherein the subject or subjects have a grade 2 or greater neuropathy.

345. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 338-344, wherein the subject or subjects have declined treatment with a platinum-based chemotherapeutic agent.

346. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 338 or 342-345, wherein the platinum-based chemotherapeutic agent is cisplatin.

347. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 338-346, wherein MIBC is operable.

348. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 347, wherein the method further comprises surgery.

349. The anti-TIGIT antagonist antibody for use of embodiment 348 and the PD-1 axis binding antagonist, wherein at least one dosing cycle is initiated prior to surgery.

350. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiments 348 or 349, wherein at least 1, 2, or 3 dosing cycles are completed prior to surgery.

351. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 348-350, wherein at least one dosing cycle is initiated between 4 and 6 weeks post-surgery.

352. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 351, wherein 1 to 17 dosing cycles are completed post-operatively.

353. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 348-352, wherein the surgery is cystectomy and/or lymph node clearing.

354. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 338-353, wherein the treatment results in complete remission (pCR) of the pathology.

355. The anti-TIGIT antagonist antibody for use according to any one of embodiments 338 to 354 and the PD-1 axis binding antagonist, wherein the treatment results in an increase in Relapse Free Survival (RFS) for the subject or subjects as compared to a reference RFS time, an increase in Event Free Survival (EFS) for the subject or subjects as compared to a reference EFS time, or an increase in OS for the subject or subjects as compared to a reference OS time.

356. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 355, wherein:

(a) The reference RFS time is the median RFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference EFS time is the median EFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

357. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 338-356, wherein the treatment results in pathological degradation.

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 having MIBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of between about 80mg to about 1600mg every three weeks, wherein the subject is not eligible for cisplatin use.

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 having MIBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist is formulated to be administered at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is a perioperative treatment.

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 having MIBC, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks and the PD-L1 binding antagonist is formulated to be administered at a dose of between about 80mg to about 1600mg every three weeks, wherein the subject is not eligible for cisplatin use.

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 having MIBC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in one or more dosing cycles, wherein the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks and the PD-L1 binding antagonist is formulated to be administered at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is a perioperative treatment.

362. Tirayleigh mab and atuzumab for use in a method of treating a subject or population of subjects having MIBC, wherein the treatment comprises the use of tirayleigh mab and atuzumab in one or more dosing cycles, wherein tirayleigh itumumab is formulated for administration at a dose between about 30mg to about 1200mg every three weeks and atuzumab is formulated for administration at a dose between about 80mg to about 1600mg every three weeks, wherein the subject is not eligible for cisplatin use.

363. Tirayleigh mab and atelizumab for use in a method of treating a subject or population of subjects having MIBC, wherein the treatment comprises use of tirayleigh mab and atelizumab in one or more dosing cycles, wherein tirayleigh itumumab is formulated for administration at a dose between about 30mg to about 1200mg every three weeks and atelizumab is formulated for administration at a dose between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

364. Tirayleigh mab and atuzumab for use in a method of treating a subject or population of subjects having MIBC, wherein the treatment comprises use of tirayleigh mab and atuzumab in one or more dosing cycles, wherein tirayleigh itumumab is formulated for administration at a dose of about 600mg every three weeks and atuzumab is formulated for administration at a dose of about 1200mg every three weeks, wherein the subject or subjects are not eligible for cisplatin use.

365. Tirayleigh immuzumab and atezumab for use in a method of treating a subject or population of subjects having MIBC, wherein the treatment comprises use of tirayleigh immuzumab and atelizumab in one or more dosing cycles, wherein tirayleigh immuzumab is formulated to be administered at a dose of about 600mg every three weeks and atelizumab is formulated to be administered at a dose of about 1200mg every three weeks, wherein the treatment is perioperative treatment.

366. The anti-TIGIT antagonist antibody for use according to any one of embodiments 338 to 365, wherein the treatment results in an ORR of at least about 13.4% to about 15% in the population of subjects.

367. The anti-TIGIT antagonist antibody for use according to any one of embodiments 338-366, and the PD-1 axis binding antagonist, wherein the treatment results in a median OS for the population of subjects of at least about 7.9 months to about 8.6 months.

368. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 338-367, wherein a detectable protein expression level of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SPl 42.

369. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 368, wherein the detectable protein expression level of PD-L1 is a fraction of PD-L1 positive tumor cells, wherein the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating Immune Cells (ICs) is greater than or equal to 5%.

370. The anti-TIGIT antagonist antibody for use according to embodiment 336 and the PD-1 axis binding antagonist, wherein the bladder cancer is Urothelial Cancer (UC).

371. The anti-TIGIT antagonist antibody for use of embodiment 370 and the PD-1 axis binding antagonist, wherein UC is metastatic urothelial cancer (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 having a uc, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more cycles of dosing of: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, and the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

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 having a uc, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more cycles of dosing of: the anti-TIGIT antagonist antibody is formulated to be administered at a dose between about 300mg to about 800mg every three weeks, and the PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

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 having mUC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles of: the anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, wherein the subject has not received prior cancer immunotherapy.

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 having mUC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more dosing cycles of: the anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist is at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is second line treatment.

376. The anti-TIGIT antagonist antibody for use according to any one of embodiments 372, 372 and 375 and a PD-1 axis binding antagonist, wherein the subject or subjects have not received prior cancer immunotherapy.

377. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 372-374, wherein the treatment is second line treatment.

378. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 372-377, wherein the mUC has progressed during or after platinum-containing therapy.

379. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 372-378, wherein 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 anti-TIGIT antagonist antibody for use of embodiment 379 and the PD-1 axis binding antagonist, 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 anti-TIGIT antagonist antibody for use according to embodiment 380 and the PD-1 axis binding antagonist, wherein the ADC is (a) vildagliptin-enritumumab or (b) govitegam-shaxituzumab.

382. The anti-TIGIT antagonist antibody for use according to example 381 and the PD-1 axis binding antagonist, wherein (a) vildagliptin-enfratuzumab is formulated to be administered at a dose of 1.25mg/kg weekly for 2 weeks/rest for 1 week, or (b) govittazin-sarituzumab is formulated to be administered at a dose of 10mg/kg weekly for 2 weeks/rest for 1 week.

383. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 381 or 382, wherein (a) vildagliptin-enfratuzumab is formulated to be administered at a dose of 1.25mg/kg on days 1 and 8 of each 21-day cycle, or (b) goverikang-shaxituzumab is formulated to be administered at a dose of 10mg/kg on days 1 and 8 of each 21-day cycle.

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 having a uc, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more cycles of dosing of: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, and the PD-L1 binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

385. Tirayleigh mab and atezumab for use in a method of treating a subject or population of subjects having a mUC, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising one or more cycles of administration of: a dose of between about 30mg to about 1200mg every three weeks and a dose of between about 80mg to about 1600mg every three weeks of atuzumab.

386. Tirayleigh immuzumab and atuzumab for use in a method of treating a subject or population of subjects having a mUC, wherein the treatment comprises use of tirayleigh immuzumab and an ate diagnostic in one or more dosing cycles, wherein tirayleigh immuzumab is formulated for administration at a dose of about 600mg every three weeks, and wherein atuzumab is at a dose of about 1200mg every three weeks.

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 having mUC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following cycles of dosing: the anti-TIGIT antagonist antibody is formulated to be administered at a dose between about 30mg to about 1200mg every three weeks, and the PD-1 axis binding antagonist is formulated to be administered at a dose between about 80mg to 1600mg every three weeks; and is provided with

(b) The second dosing regimen comprises one or more of the following for the dosing cycle: the PD-1 axis binding antagonist is formulated for administration at a dose of between about 80mg to about 1600mg every three weeks, and (i) the vildagliptin-enritumumab is formulated for administration at a dose of 1.25mg/kg per week for 2 weeks/withdrawal for 1 week, or (ii) the goveritazobactam-safiruzumab is formulated for administration at a dose of 10mg/kg per week for 2 weeks/withdrawal for 1 week, wherein the subject or population of subjects is administered a second dosing regimen after the subject or population of subjects has experienced disease progression or unacceptable toxicity during the first dosing regimen.

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 having mUC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg every three weeks, and the PD-L1 binding antagonist at a dose of between about 80mg to 1600mg every three weeks; and is

(b) The second dosing regimen comprises one or more of the following cycles of dosing: a PD-L1 binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and (i) vildagliptin-enfratuzumab is formulated for administration at a dose of 1.25mg/kg weekly for 2 weeks/withdrawal for 1 week, or (ii) govittazin-sarituzumab is formulated for administration at a dose of 10mg/kg weekly for 2 weeks/withdrawal for 1 week, wherein the subject is administered a second dosing regimen after the subject has experienced disease progression or unacceptable toxicity during the first dosing regimen.

389. Tirayleigh mab and atezumab for use in a method of treating a subject or population of subjects having a mUC, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: a dose of about 600mg of tireyueuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks; and

(b) The second dosing regimen comprises one or more of the following cycles of dosing: a dose of about 1200mg of alemtuzumab and (i) vildagliptin-enfratuzumab, every three weeks, is formulated to be administered at a dose of 1.25mg/kg weekly for 2 weeks/withdrawal for 1 week, or (ii) govitegam-sapitumomab is formulated to be administered at a dose of 10mg/kg weekly for 2 weeks/withdrawal for 1 week, wherein a second dosing regimen is administered to the subject after the subject has experienced disease progression or unacceptable toxicity during the first dosing regimen.

390. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 372-389, wherein the treatment results in an ORR of at least about 13.4% to at least about 31% for a population of subjects.

391. The anti-TIGIT antagonist antibody for use according to any one of embodiments 372-390 and PD-1 axis binding antagonist, wherein the treatment results in a median OS for the population of subjects of about 7.9 months to about 16.3 months.

392. The anti-TIGIT antagonist antibody for use of example 72 and the PD-1 axis binding antagonist, wherein the cancer is pancreatic cancer.

393. Tirayleigh mab and atezumab for use in a method of treating a subject or population of subjects with pancreatic cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 28 day dosing cycle: a dose of about 420mg of tiryleiguzumab at days 1 and 15 of each 28-day dosing cycle, a dose of about 840mg of atuzumab at days 1 and 15 of each 28-day dosing cycle, a dose of about 1000mg/m2 of gemcitabine at days 1, 8, and 15 of each 28-day dosing cycle, and a dose of about 125mg/m2 of nab-paclitaxel at days 1, 8, and 15 of each 28-day dosing cycle.

394. The anti-TIGIT antagonist antibody for use according to embodiments 392 or 393, wherein the pancreatic cancer is Pancreatic Ductal Adenocarcinoma (PDAC) and the PD-1 axis binding antagonist.

395. The anti-TIGIT antagonist antibody for use according to embodiment 394 and the PD-1 axis binding antagonist, wherein the PDAC is metastatic PDAC.

396. The anti-TIGIT antagonist antibody for use of any one of embodiments 392 to 395 and the PD-1 axis binding antagonist, wherein the subject or subjects did not have received prior systemic therapy for metastatic PDAC.

397. The anti-TIGIT antagonist antibody for use according to any one of embodiments 392-396, and PD-1 axis binding antagonist, wherein the treatment results in an ORR of the population of subjects of at least about 41.7% to about 46.7%.

398. The anti-TIGIT antagonist antibody for use of any of embodiments 392 to 397, wherein the treatment results in an at least about 20% increase in ORR as compared to a treatment comprising gemcitabine and nab-paclitaxel but without the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist.

399. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 392 to 398, wherein the treatment results in a median PFS of the population of subjects of at least about 5.5 months to about 7 months.

400. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 392 to 399, wherein the treatment results in a median OS for the population of subjects of at least about 8.5 months to about 10.6 months.

401. The anti-TIGIT antagonist antibody for use of example 72 and PD-1 axis binding antagonist, 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, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 21-day dosing cycle: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle, and the PD-1 axis binding antagonist is administered at a dose of between about 80mg to about 1600mg on day 1 of each dosing cycle.

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, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 21-day dosing cycle: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle, and the PD-1 axis binding antagonist is administered at a dose of between about 900mg to about 1500mg on day 1 of each dosing cycle.

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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 21-day dosing cycle: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle, and the PD-1 axis binding antagonist is administered at a dose of between about 80mg to about 1600mg on day 1 of each dosing cycle, wherein the subject has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 21-day dosing cycle: the anti-TIGIT antagonist antibody is formulated for administration at a dose of between about 300mg to about 800mg on day 1 of each dosing cycle, and the PD-1 axis binding antagonist is administered at a dose of between about 900mg to about 1500mg on day 1 of each dosing cycle, wherein the subject has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

406. The anti-TIGIT antagonist antibody for use of embodiment 402 or 403 and the PD-1 axis binding antagonist, wherein the subject or subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 404-406, wherein the subject or subjects have experienced disease progression or unacceptable toxicity during a previous treatment.

408. The anti-TIGIT antagonist antibody for use of embodiment 402 or 403 and the PD-1 axis binding antagonist, wherein the 21-day dosing cycle further comprises a platinum chemotherapeutic agent and a non-platinum chemotherapeutic agent.

409. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 408, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses.

410. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 404-409, wherein the platinum-based chemotherapeutic agent is cisplatin.

411. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 410, wherein the cisplatin is formulated for administration at a dose of about 80mg/m2 on day 1 of each dosing cycle.

412. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 404-411, wherein the non-platinum chemotherapeutic agent is an antimetabolite.

413. The anti-TIGIT antagonist antibody for use according to embodiment 412 and the PD-1 axis binding antagonist, wherein the antimetabolite is 5-fluorouracil.

414. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 413, wherein 5-fluorouracil platinum is formulated for administration at a dose of about 800mg/m2/24 hours on days 1-5 of each 21-day dosing cycle.

415. The anti-TIGIT antagonist antibody for use of any one of embodiments 404-414 and PD-1 axis binding antagonist, wherein the esophageal cancer is advanced or metastatic esophageal cancer.

416. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 402, 403, 408, and 409, wherein the subject or subjects were not previously treated 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, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 21-day dosing cycle: the anti-TIGIT antagonist antibody is formulated for administration at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle, the PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg on day 1 of each dosing cycle, the platinum-based chemotherapeutic agent at a dose of about 80mg/m2 on day 1 of each dosing cycle, and the non-platinum-based chemotherapeutic agent at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses.

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, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 21-day dosing cycle: the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 600mg on day 1 of each dosing cycle, a PD-1 axis binding antagonist at a dose of about 1200mg on day 1 of each dosing cycle, cisplatin at a dose of about 80mg/m2 on day 1 of each dosing cycle, and 5-fluorouracil at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses.

419. Tirayleigh immuzumab and atezumab for use in a method of treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein the treatment comprises use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose of about 600mg of tenecteuzumab on day 1 of each dosing cycle, a dose of about 1200mg of atelizumab on day 1 of each dosing cycle, a dose of about 80mg/m2 of cisplatin on day 1 of each dosing cycle, and a dose of 800mg/m2/24 hours of 5 days on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six 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 the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a first dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more 21-day dosing cycles of a platinum chemotherapeutic agent and a non-platinum chemotherapeutic agent, wherein the platinum chemotherapeutic agent is omitted from the dosing regimen after six doses of the platinum chemotherapeutic agent; and is

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle, and the PD-1 axis binding antagonist at a dose of between about 80mg to 1600mg on day 1 of each dosing cycle.

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, wherein the treatment comprises using the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist in a first dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 80mg/m2 of a platinum-based chemotherapeutic agent on day 1 of each dosing cycle and a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses; and is provided with

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: the anti-TIGIT antagonist antibody is formulated to be administered at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle, and the PD-1 axis binding antagonist at a dose of between about 80mg to 1600mg on day 1 of each dosing cycle.

422. Tirayleigh immuzumab and atezumab for use in a method of treating a subject or population of subjects with advanced or metastatic esophageal cancer, wherein the treatment comprises use of the anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in a first dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a 21 day dosing cycle: cisplatin at a dose of about 80mg/m2 on day 1 of each dosing cycle and 5-fluorouracil at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses; and is

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 600mg of securityluzumab on day 1 of each dosing cycle and a dose of about 1200mg of atezumab on day 1 of each dosing cycle.

423. The anti-TIGIT antagonist antibody for use according to any one of embodiments 402-422 and PD-1 axis binding antagonist, wherein the treatment results in an ORR of the population of subjects of at least about 14%.

424. The anti-TIGIT antagonist antibody for use according to any one of embodiments 47-423 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

An HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

an HVR-H2 sequence comprising the amino acid sequence of KTYYRRFKWYSDYASVSVKG (SEQ ID NO: 2);

an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

425. The anti-TIGIT antagonist antibody for use of embodiment 424 and PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable Framework Regions (FRs):

FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLLGERANC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (SEQ ID NO: 9); and

FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

426. The anti-TIGIT antagonist antibody for use according to embodiment 424 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs:

FR-H1 comprising the amino acid sequence of X1 VQLQQSGPVKPPSQTLSLTCASTGDSVS (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 anti-TIGIT antagonist antibody for use according to embodiment 426 and a PD-1 axis binding antagonist, wherein X1 is E.

428. The anti-TIGIT antagonist antibody for use according to embodiment 426 and a PD-1 axis binding antagonist, wherein X1 is Q.

429. The anti-TIGIT antagonist antibody for use according to any one of embodiments 424-428, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain as in (a) and a VL domain as in (b).

430. The anti-TIGIT antagonist antibody for use according to any one of embodiments 424-429 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO:17 or 18; and

(b) A VL domain comprising SEQ ID NO: 19.

431. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 424-427, 429, and 430, wherein the anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 17; and

(b) A VL domain comprising SEQ ID NO: 19.

432. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 424-427 and 429-431, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 33; and

(b) A light chain comprising SEQ ID NO: 34.

433. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 424-432, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

434. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 424-433, wherein the anti-TIGIT antagonist antibody is a human antibody.

435. The anti-TIGIT antagonist antibody for use of any of embodiments 424-434 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

436. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 424-427 and 429-436, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan.

437. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, 421, and 424-436, wherein the anti-TIGIT antagonist antibody is ibritumomab tirayleigh, wiborlizumab, etiilimab, EOS084448, SGN-TGT, or TJ-T6.

438. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist as described in example 437, wherein the anti-TIGIT antagonist antibody has intact Fc-mediated effector function.

439. An anti-TIGIT antagonist antibody for use and a PD-1 axis binding antagonist as described in example 437 or 438, wherein the anti-TIGIT antagonist antibody has enhanced Fc-mediated effector function.

440. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 437-439, wherein the anti-TIGIT antagonist antibody is SGN-TGT.

441. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use obtained according to any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, and 421, wherein the anti-TIGIT antagonist antibody is dommaramab, BMS-986207, ASP8374, or COM902.

442. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 424-431 or 441, wherein the anti-TIGIT antagonist antibody does not have Fc-mediated effector function.

443. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47-442, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

444. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 443, wherein the IgG class antibody is an IgG1 subclass antibody.

445. An anti-TIGIT antagonist antibody for use according to embodiment 444 and a PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan, wiborlizumab, etiglimicab, EOS084448, SGN-TGT, TJ-T6, BGB-a1217, AB308, domcanalimab, or BMS-986207.

446. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use obtained according to any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420 and 421, wherein the IgG class antibody is an IgG4 subclass antibody.

447. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 446, wherein the anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. The anti-TIGIT antagonist antibody for use according to any one of embodiments 424-434 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, bis-Fab, fab '-SH, fv, single chain variable fragment (scFv), and (Fab') 2 fragments.

449. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 424-448, wherein the anti-TIGIT antagonist antibody is a monospecific antibody.

450. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 424-448, wherein the anti-TIGIT antagonist antibody is a multispecific antibody.

451. The anti-TIGIT antagonist antibody for use according to embodiment 450 and the PD-1 axis binding antagonist, wherein the multispecific antibody is a bispecific antibody.

452. The anti-TIGIT antagonist antibody for use of any one of embodiments 424-451 and a PD-1 axis binding antagonist, 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 anti-TIGIT antagonist antibody for use according to embodiment 452 and the PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

454. The anti-TIGIT antagonist antibody for use of embodiment 453 and a PD-1 axis binding antagonist, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

455. The anti-TIGIT antagonist antibody for use according to example 454 and the PD-1 axis binding antagonist, 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 anti-TIGIT antagonist antibody for use of any one of embodiments 453-455 and the PD-1 axis binding antagonist, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist for use according to embodiment 456, wherein the anti-PD-L1 antagonist antibody is atelizumab, MDX-1105, devolumab, avermemab, SHR-1316, CS1001, envolumizumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cochlolizumab, lodalizumab, 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 anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 457, wherein the anti-PD-L1 antagonist antibody is atelizumab.

459. The anti-TIGIT antagonist antibody for use according to embodiment 456 and a PD-1 axis binding antagonist, wherein the anti-PD-L1 antagonist antibody comprises the following HVRs:

an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);

an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);

an HVR-H3 sequence comprising the amino acid sequence of RHWPGFDY (SEQ ID NO: 22);

an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);

An HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and

an HVR-L3 sequence comprising the amino acid sequence of QQYLLYHPAT (SEQ ID NO: 25).

460. The anti-TIGIT antagonist antibody for use according to embodiment 459 and the PD-1 axis binding antagonist, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:26 has at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:27 has an amino acid sequence of at least 95% sequence identity; or

(c) A VH domain as in (a) and a VL domain as in (b).

461. The anti-TIGIT antagonist antibody for use according to embodiment 460 and a PD-1 axis binding antagonist, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 26; and

(b) A VL domain comprising SEQ ID NO: 27.

462. The anti-TIGIT antagonist antibody for use according to embodiment 461 and a PD-1 axis binding antagonist, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 28; and

(b) A light chain comprising SEQ ID NO: 29.

463. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 459 to 462, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

464. The anti-TIGIT antagonist antibody for use of any one of embodiments 459-463, and a PD-1 axis binding antagonist, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

465. The anti-TIGIT antagonist antibody for use according to embodiment 463 or 464 and the PD-1 axis binding antagonist, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

466. The anti-TIGIT antagonist antibody for use of any one of embodiments 459-464 and PD-1 axis binding antagonist, wherein the anti-PD-L1 antagonist antibody is an antibody fragment selected from the group consisting of Fab, fab '-SH, fv, scFv, and (Fab') 2 fragments that binds to PD-L1.

467. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 459-465, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

468. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 467, wherein the IgG class antibody is an IgG1 subclass antibody.

469. The anti-TIGIT antagonist antibody for use of embodiment 452 and a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. The anti-TIGIT antagonist antibody for use according to embodiment 469 and the PD-1 axis binding antagonist, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.

471. The anti-TIGIT antagonist antibody for use of embodiment 470 and the PD-1 axis binding antagonist, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2.

472. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 469-471, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to example 472, wherein the anti-PD-1 antagonist antibody is nivolumab, palivizumab, MEDI-0680, sibaprimab, BGB-108, palonolizumab, carpriclizumab, sillimirumab, tirlizumab, tirralizumab, tereprimab, dolelizumab, refelizumab, sarlizumab, perinaprimab, CS1003, HLX10, SCT-I10A, serralimab, batilizumab, geminumab, BI 754091, cetilizumab, YBL-006, BAT1306, HX008, briralizumab, AMG 1110, CX-188, JTX-4014 a, sym021, lz 009, F520, SG001, AM0001, eng 388C 8, um end 4, um end 103-21 b, or STI-21 b.

474. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 469-471, wherein the PD-1 binding antagonist is an anti-Fc fusion protein.

475. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 474 wherein the Fc fusion protein is AMP-224.

476. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 80-112, 114-127, and 309-312, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody formulated for administration at a dose of between about 30mg to about 1200mg every three weeks.

477. An anti-TIGIT antagonist antibody for use and a PD-1 axis binding antagonist according to any one of embodiments 51, 54, 60, 62, 63, 65-67, 80-112, 114-127, 136-140, 169-174, 189, 191, 267, 269, 286, 288, 291, 295, 301, 302, 303, 313, 315, 338, 340, 358-361, 372, 384, 387, 388, 402-404, 417, 420, 421, and 476, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody formulated for administration at a dose of about 600mg every three weeks.

478. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 51, 54, 60, 62, 63, 65-67, 80-112, 114-127, 136-140, 169-174, 189, 191, 267, 269, 286, 288, 291, 295, 301, 302, 303, 309, 313, 315, 338, 340, 358-361, 372, 384, 387, 388, 402-404, 417, 420, 421, and 476, wherein the method comprises administering the anti-TIGIT antagonist antibody to a subject or population of subjects in a stepped dose based on the weight of the subject, wherein the weight of the subject is:

(a) Less than or equal to 15kg and the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 300mg every three weeks;

(b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 400mg every three weeks; or

(c) Greater than 40kg, and the anti-TIGIT antagonist antibody is formulated for administration at a dose of about 600mg every three weeks.

479. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47, 48, 77, 78, 82, and 83, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody formulated for administration at a dose of about 700mg to about 1000mg every four weeks.

480. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47, 48, 59, 67, 323, and 479, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody formulated for administration at a dose of about 840mg every four weeks.

481. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 49, 50, and 104, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody formulated for administration at a dose of about 300mg to about 600mg biweekly.

482. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 49, 50, 227, 251-253, 255, and 481, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody formulated for administration at a dose of about 420mg every two weeks.

483. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-482, wherein the anti-TIGIT antagonist antibody is at a fixed dose.

484. The anti-TIGIT antagonist antibody for use according to any one of embodiments 54, 62, 63, 65-67, 80-109, and 27-2698, wherein the method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist formulated for administration at a dose of between about 900mg to about 1500mg every three weeks.

485. An anti-TIGIT antagonist antibody for use according to any one of embodiments 54, 60, 62, 63, 65-67, 80-112, 114-127, 136-140, 169-172, 189, 191, 267, 269, 286, 288, 291, 295, 301-303, 309, 311, 313, 315, 338, 340, 358-361, 372-375, 384, 387, 388, 402-405, 417, 420, 421, and 484 and a PD-1 axis binding antagonist, wherein the method comprises administering to the subject a PD-1 axis binding antagonist formulated for administration at a dose of about 1200mg every three weeks.

486. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 47, 50, 80-109 and 324, wherein 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 1400 to 2000mg every four weeks.

487. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 47, 50, 59, 67, 324, and 479, wherein the method comprises administering to the subject a PD-1 axis binding antagonist formulated for administration at a dose of about 1680mg every four weeks.

488. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of examples 48, 49, 80-109, and 481, wherein the method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist formulated for administration at a dose of between about 600mg to about 1200mg every two weeks.

489. The anti-TIGIT antagonist antibody for use according to any one of embodiments 48, 49, 80-109, 227, 251-253, and 481, wherein the method comprises administering to the subject a PD-1 axis binding antagonist formulated for administration at a dose of about 840mg every two weeks.

490. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist for use according to any one of embodiments 47-489, wherein the PD-1 axis binding antagonist is a fixed dose.

491. The anti-TIGIT antagonist antibody for use of embodiment 60 or 61 and the PD-1 axis binding antagonist, wherein the method comprises administering to the subject a fixed dose of 200mg every three weeks or about 400mg every six weeks.

492. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 54, 60, 62, 63, 65, 80-109, and 191, wherein each of the one or more dosing cycles is 21 days in length.

493. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 47, 59, 67, 80-109, and 309-311, wherein each of the one or more dosing cycles is 28 days in length.

494. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to any one of embodiments 49, 80-109, and 309-311, wherein each of the one or more dosing cycles is 14 days in length.

495. An anti-TIGIT antagonist antibody for use and a PD-1 axis binding antagonist according to any one of embodiments 47-494, wherein the method comprises administering to a subject or population of subjects an anti-TIGIT antagonist antibody on day 1 of each of the one or more dosing cycles.

496. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47-495, wherein the method comprises administering the PD-1 axis binding antagonist to a subject or population of subjects on day 1 of each dosing cycle of the one or more dosing cycles.

497. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to embodiment 321 or 493, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody on day 15 of each of the one or more dosing cycles.

498. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to embodiment 321 or 493, wherein the method comprises administering the PD-1 axis binding antagonist to the subject on day 15 of each of the one or more dosing cycles.

499. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-498, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects prior to the anti-TIGIT antagonist antibody, or the anti-TIGIT antagonist antibody is prior to the PD-1 axis binding antagonist.

500. The anti-TIGIT antagonist antibody for use according to example 499 and a PD-1 axis binding antagonist, wherein the method comprises a first observation period after administration of the PD-1 axis binding antagonist or anti-TIGIT antagonist antibody.

501. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 500, wherein the length of the first observation period is between about 30 minutes and about 60 minutes.

502. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 500 or 501, wherein the method comprises a second observation period following administration of the anti-TIGIT antagonist antibody or the PD-1 axis binding antagonist.

503. The anti-TIGIT antagonist antibody for use of embodiment 502 and the PD-1 axis binding antagonist, wherein the length of the second observation period is between about 30 minutes and about 60 minutes.

504. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist for use according to any one of embodiments 47-503, wherein the method comprises administering the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody simultaneously to a subject or population of subjects.

505. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47-504, wherein the method comprises intravenously administering to a subject or population of subjects an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

506. The anti-TIGIT antagonist antibody for use according to embodiment 505 and the PD-1 axis binding antagonist, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

507. The anti-TIGIT antagonist antibody for use according to embodiments 505 or 506 and the PD-1 axis binding antagonist, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

508. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 47-114 and 116-507, wherein the level of PD-L1 expression has been determined for a tumor sample obtained from the subject or subjects.

509. The anti-TIGIT antagonist antibody for use of embodiment 508 and the PD-1 axis binding antagonist, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

510. The anti-TIGIT antagonist antibody for use according to embodiment 509 and the PD-1 axis binding antagonist, wherein the detectable protein expression level of PD-L1 is a detectable protein expression level of PD-L1.

511. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of example 510, wherein the detectable protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

512. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 511, wherein the anti-PD-L1 antibody suitable for staining is anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8.

513. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiments 511 or 512, wherein a detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, pharmDx 22C3 IHC assay, ventana SP142 IHC assay, or pharmDx 28-8 IHC assay.

514. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-109, 188, 220-265, and 307-423, wherein a detectable protein expression level of PD-L1 has been determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP 263.

515. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-220, 265-338, and 370-423, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP 142.

516. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-113, 136-187, and 220-423, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody 22C 3.

517. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-114 and 116-423, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8.

518. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% tumor-associated immune cells (TICs) in the tumor sample.

519. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% and less than 20% TIC in the tumor sample.

520. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% TIC in the tumor sample.

521. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 20% TIC in the tumor sample.

522. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% and less than 50% TIC in the tumor sample.

523. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to 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 anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of examples 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is a PD-L1 positive tumor cell fraction of greater than or equal to 1%.

525. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is at a PD-L1 positive tumor cell fraction of greater than or equal to 30%.

526. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is at a fraction of PD-L1 positive tumor cells in the tumor sample that is greater than or equal to 1% and less than 50%.

527. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is at a PD-L1 positive tumor cell fraction of greater than or equal to 50%.

528. The anti-TIGIT antagonist antibody for use according to example 515 and the PD-1 axis binding antagonist, wherein the PD-L1 positive tumor cell fraction is a proportion of a tumor area occupied by tumor infiltrating Immune Cells (ICs) that express PD-L1.

529. The anti-TIGIT antagonist antibody for use of embodiment 515 and the PD-1 axis binding antagonist, wherein the proportion of tumor area occupied by tumor infiltration IC expressing PD-L1 is greater than or equal to 1%.

530. The anti-TIGIT antagonist antibody for use of embodiment 515 and the PD-1 axis binding antagonist, wherein the proportion of tumor area occupied by tumor infiltration IC expressing PD-L1 is greater than or equal to 5%.

531. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 516, wherein the detectable protein expression level of PD-L1 is such that the Combined Positive Score (CPS) is greater than or equal to 1.

532. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 516, wherein the detectable protein expression level of PD-L1 is at a CPS greater than or equal to 10.

533. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 516, wherein the detectable protein expression level of PD-L1 is at a CPS greater than or equal to 20.

534. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 528-530, wherein the IHC assay is a Ventana SP142 IHC assay.

535. The anti-TIGIT antagonist antibody for use according to example 509 and the PD-1 axis binding antagonist, wherein the detectable nucleic acid expression level of PD-L1 is a detectable protein expression level of PD-L1.

536. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 535, wherein a detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, massARRAY technology, ISH, or a combination thereof.

537. The anti-TIGIT antagonist antibody for use according to any one of embodiments 47-423 and the PD-1 axis binding antagonist, wherein the treatment results in an increase in Overall Survival (OS) of the subject as compared to a reference OS time and/or an increase in Progression Free Survival (PFS) of the subject as compared to a reference PFS time.

538. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 537, wherein:

(a) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist; and/or

(b) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist.

539. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist according to 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 anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 539 wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to embodiments 69, 92, 127, 131, 249, and 540, wherein the carboplatin is administered at a dose sufficient to achieve AUC =5mg/ml/min or AUC =6 mg/ml/min.

542. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of examples 69, 127, 162, 164, 166, 168, and 540, wherein the cisplatin is formulated for administration at a dose of about 75mg/m2 or 80mg/m 2.

543. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 539-542, wherein the one or more non-platinum chemotherapeutic agents is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

544. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 62, 173, 174, and 543, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 69, 127, 162, and 544, wherein pemetrexed is formulated for administration at a dose of about 500mg/m 2.

546. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 63, 64, 162, 398 and 544, wherein gemcitabine is formulated for administration at a dose of about 1000mg/m2 or about 1250mg/m 2.

547. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 544, wherein the antimetabolite is capecitabine.

548. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 544 or 547, wherein capecitabine is formulated for administration at a dose of about 1250mg/m 2.

549. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 173, 174, 229, 230, 239, 240, and 543-548, wherein the taxane is paclitaxel or nab-paclitaxel.

550. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 69, 162, and 549, wherein paclitaxel is formulated for administration at a dose of about 175mg/m2 or about 200mg/m 2.

551. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 63, 64, 249, 398 and 549, wherein the nab-paclitaxel is formulated for administration at a dose of about 100mg/m 2.

552. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use according to any one of examples 80-91, 229, 230, 239, 241, 251-255, and 543-551, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331.

553. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 69, 92, and 552, wherein etoposide is formulated for administration at a dose of about 100mg/m 2.

554. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 543-553, wherein the one or more chemotherapeutic agents are each administered once a week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.

555. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 543-554, wherein the one or more chemotherapeutic agents are administered on day 1 of one or more dosing cycles.

556. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 544 to 555, wherein gemcitabine is administered three times every four weeks.

557. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 544 to 556, wherein gemcitabine is administered on days 1, 8, and/or 15 of one or more dosing cycles.

558. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 544-557, wherein gemcitabine is administered daily for two weeks.

559. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 544 to 558, wherein gemcitabine is administered on days 1 to 14 of one or more dosing cycles.

560. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 549-559, wherein nab-paclitaxel is administered three times every four weeks.

561. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 549-560, wherein nab-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles.

562. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 552-561, wherein etoposide is administered every three weeks on days 1-3.

563. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 552-562, wherein etoposide is administered on days 1 to 3 of one or more dosing cycles.

564. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 543-563, wherein the one or more chemotherapeutic agents are administered prior to the PD-1 axis binding antagonist and/or the anti-TIGIT antagonist antibody.

565. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of embodiments 543-564, wherein the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist and/or anti-TIGIT antagonist antibody.

566. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 543-565, wherein the one or more chemotherapeutic agents are administered intravenously or orally.

567. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 65, 310, and 311, wherein the VEGF antagonist is formulated for administration at a dose of about 5mg/kg to about 25mg/kg every three weeks.

568. The anti-TIGIT antagonist antibody for use of embodiment 312 or 567 and the PD-1 axis binding antagonist, wherein the VEGF antagonist is formulated for administration at a dose of about 10mg/kg to about 20mg/kg every three weeks.

569. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of embodiment 318 or 568, wherein the VEGF antagonist is formulated for administration at a dose of about 15mg/kg every three weeks.

570. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 65, 310-312, 318-320, and 567-569, wherein the VEGF antagonist is an anti-VEGF antibody.

571. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to embodiment 570, wherein the anti-VEGF antibody comprises the VH domain and the VL domain of bevacizumab.

572. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of embodiment 570 or 571, wherein the anti-VEGF antibody is bevacizumab.

573. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 65, 310-312, and 318-320, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan, the PD-1 axis binding antagonist is atlizumab, and the VEGF antagonist is bevacizumab.

574. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 65, 310-312, 318-320, and 567-573, wherein the method comprises administering to the subject a VEGF antagonist on day 1 of one or more dosing cycles.

575. The anti-TIGIT antagonist antibody for use and PD-1 axis binding antagonist of any one of embodiments 318-320, wherein the method comprises administering to the subject a VEGF antagonist on day 15 of one or more dosing cycles.

576. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 65, 310-312 and 318-320 and 567-575, wherein the VEGF antagonist is administered intravenously.

577. The anti-TIGIT antagonist antibody for use according to embodiment 576 and the PD-1 axis binding antagonist, wherein the VEGF antagonist is administered to the subject by intravenous infusion over 90 ± 15 minutes.

578. The anti-TIGIT antagonist antibody for use according to any one of embodiments 65, 310-312, 318-320, and 567-577, wherein the method comprises administering the PD-1 axis binding antagonist to the subject prior to the VEGF antagonist, and the VEGF antagonist precedes the anti-TIGIT antagonist antibody.

579. The anti-TIGIT antagonist antibody for use according to embodiment 578 and the PD-1 axis binding antagonist, 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 anti-TIGIT antagonist antibody for use of embodiment 579 and a PD-1 axis binding antagonist, wherein 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.

581. The tenerayleigh immuzumab and atezumab for use according to any one of claims 113, 128, 129 to 131, 175 to 182, 210 to 214, 221, 256, 257, 270, 289, 290, 293, 294, 297, 298, 333, 362 to 365, 385, 386, 389, 393, 419, and 422, wherein the tenerayleigh immuzumab and the atezumab are combined in an IV infusion bag prior to administration.

582. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist according to any one of embodiments 47-581, wherein the subject is human.

583. The anti-TIGIT antagonist antibody for use and the PD-1 axis binding antagonist of any one of embodiments 47-582, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

584. The anti-TIGIT antagonist antibody for use of any of embodiments 47-582 and the PD-1 axis binding antagonist, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

Example set C:

1. use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: a dose of about 500mg to about 700mg of an anti-TIGIT antagonist antibody every three weeks, a dose of about 900mg to about 1500mg of a PD-1 axis binding antagonist every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

2. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks.

3. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks.

4. The use according to embodiment 2 or 3, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

5. The use according to any one of embodiments 1 to 4, wherein the anti-TIGIT antagonist antibody is an IgG class antibody, in particular an IgG1 subclass antibody.

6. The use according to any one of embodiments 1 to 5, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

(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 KTYYRRFKWYSDYYAVSVKG (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) HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

7. The use of any one of embodiments 1 to 6, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region Framework Regions (FRs):

(a) FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLLGERANC (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 GVPDRFGSGSGSGTDTIS SLQAEDVYYC (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 X1 VQLQQSGPGLVKPPSQTLSLTCASGDSVS (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 use of any one of embodiments 1 to 7, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The use of any one of embodiments 1 to 8, wherein the anti-TIGIT antagonist antibody is securititumumab.

10. The use 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 use according to any one of embodiments 1 to 10, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The use according to any one of embodiments 1 to 11, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The use of embodiment 12, wherein the anti-PD-L1 antagonist antibody is Attributumab, MDX-1105, devolumab, avermemab, SHR-1316, CS1001, envollizumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cochlolizumab, lodalizumab, 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 use according to any one of embodiments 1 to 13, wherein the PD-1 axis binding antagonist is atelizumab.

15. The use according to any one of embodiments 1 to 11, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The use of example 15, wherein the anti-PD-1 antagonist antibody is nivolumab, parbolizumab, MEDI-0680, sibradizumab, cimaprimab, BGB-108, palonomab, carpelizumab, sendilizumab, tirezumab, terilizumab, tedeprizumab, dolaprimab, refelimab, saralalizumab, perindopril mab, CS1003, HLX10, SCT-I10A, sepiolimab, batilizumab, gemumab, jirimumab, BI 754091, cetimumab, YBL-006, BAT1306, HX008, breglizumab, AMG 404, CX-188, JTX-4014, 609A, sym021, LZM009, F520, SG001, AM0001, ENUM244C8, ENUM 388D4, AK-103, or hAb21.

17. The use according to any one of embodiments 2 to 16, wherein the method comprises administering to the subject an effective amount of a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

18. The use of embodiment 1 or 17 wherein the non-platinum chemotherapeutic agent is a topoisomerase II inhibitor.

19. The use according to embodiment 18, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid or HU-331, in particular etoposide.

20. The use according to embodiment 18 or 19, wherein the topoisomerase II inhibitor is administered at a dose of 100mg/m 2.

21. The use according to any one of embodiments 17 to 20, wherein the platinum chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin.

22. The use according to any one of embodiments 17 to 21, wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC =5mg/ml/min on the day of administration.

23. The use according to any one of embodiments 1 to 22, wherein the method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. The use of embodiment 23, wherein the induction period comprises four initial dosing cycles, and wherein 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.

25. The use of embodiment 23 or 24, wherein the maintenance period does not include administration of a platinum-based chemotherapeutic agent and/or a non-platinum-based chemotherapeutic agent.

26. The use according to any one of embodiments 1 to 25, wherein the treatment extends Progression Free Survival (PFS) in the subject compared to treatment without the anti-TIGIT antagonist antibody.

27. The use according to any one of embodiments 1 to 26, wherein the treatment extends overall survival of the subject compared to treatment without the anti-TIGIT antagonist antibody.

28. The use according to any one of embodiments 1 to 27, wherein the cancer is lung cancer.

29. The use according to embodiment 28, wherein the lung cancer is Small Cell Lung Cancer (SCLC), in particular extensive-stage SCLC (ES-SCLC).

30. The use according to embodiment 28, wherein the lung cancer is non-small cell lung cancer (NSCLC), in particular locally advanced unresectable NSCLC (stage IIIB NSCLC).

31. The use of embodiment 28, wherein the lung cancer is locally advanced unresectable NSCLC or metastatic non-squamous NSCLC.

32. The use of embodiment 28, wherein the lung cancer is resectable lung cancer.

33. The use according to any one of embodiments 1 to 27, wherein the cancer is cervical cancer.

34. The use according to any one of embodiments 1 to 27, wherein the cancer is early triple negative breast cancer (eTNBC).

35. The use according to any one of embodiments 1 to 27, wherein the cancer is head and neck cancer.

36. The use according to any one of embodiments 1 to 27, wherein the cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. The use according to any one of embodiments 1 to 27, wherein the cancer is bladder cancer.

38. The use of embodiment 37, wherein the cancer is Urothelial Cancer (UC), in particular metastatic urothelial cancer (mUC).

39. The use according to any one of embodiments 1 to 27, wherein the cancer is pancreatic cancer, in particular Pancreatic Ductal Adenocarcinoma (PDAC).

40. The use according to any one of embodiments 1 to 27, wherein the cancer is esophageal cancer, in particular advanced or metastatic esophageal cancer.

41. Use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for use in a method of treating a subject having cancer in combination with a PD-1 axis binding antagonist, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

42. Use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for use in a method of treating a subject having cancer in combination with a PD-1 axis binding antagonist, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks.

43. Use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for use in a method of treating a subject having cancer in combination with a PD-1 axis binding antagonist, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks.

Use of a pd-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer in combination with an anti-TIGIT antagonist antibody, wherein: (a) The method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; (b) The method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks; or (c) the method comprises administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks.

45. The use of embodiment 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

46. The use of embodiment 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

47. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 80mg to about 2000mg every four weeks.

48. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 20mg to about 1600mg every two weeks.

49. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 10mg to about 1000mg every two weeks and a PD-1 axis binding antagonist at a dose of about 20mg to about 1600mg every two weeks.

50. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 10mg to about 1000mg every two weeks and a PD-1 axis binding antagonist at a dose of about 80mg to about 2000mg every four weeks.

51. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of about 100mg to about 1000mg every six weeks.

52. The use according to any one of embodiments 47 to 51, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

53. The use of embodiment 52, wherein the method comprises administering to the subject a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

54. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

55. The use as described in embodiment 53 or 54, wherein the method comprises an induction phase and a maintenance phase.

56. The use of embodiment 55, wherein the induction phase and the maintenance phase each comprise one or more cycles of administration.

57. The use of embodiment 55 or 56, wherein the maintenance period does not include administration of a platinum-based chemotherapeutic agent.

58. The use of any one of embodiments 55-57, wherein the maintenance period does not include administration of the non-platinum chemotherapeutic agent.

59. The use of embodiment 58, wherein the maintenance period comprises one or more of the following cycles of administration: an anti-TIGIT antagonist antibody at a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 80mg to 2000mg every four weeks.

60. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks and an anti-PD-1 antagonist antibody at a dose of about 80mg to about 1600mg every three weeks, wherein the anti-PD-1 antagonist antibody is palbociclumab.

61. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of ibritumomab tiuxetan and palboclizumab, wherein palboclizumab is administered at a dose of between about 100mg to about 1000mg every six weeks.

62. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, and an antimetabolite administered twice daily at a dose between about 10mg/m2 to about 10000mg/m2, the antimetabolite administered 2 weeks per three weeks/withheld 1 week.

63. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, gemcitabine, and nab-paclitaxel.

64. The use according to embodiment 52, wherein the one or more chemotherapeutic agents are gemcitabine and nab-paclitaxel.

65. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, and a VEGF antagonist at a dose between about 1mg/kg to about 35mg/kg every three weeks.

66. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction phase includes one or more of the following cycles of administration: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is

(b) The maintenance phase includes one or more of the following additional dosing cycles: every three weeks of anti-TIGIT antagonist antibody, every three weeks of PD-1 axis binding antagonist, and every three weeks of a non-platinum chemotherapeutic agent, and wherein the maintenance phase does not include administration of a platinum chemotherapeutic agent.

67. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction phase includes one or more of the following cycles of administration: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is provided with

(b) The maintenance phase includes one or more additional cycles of administration of the following: an anti-TIGIT antagonist antibody at a dose of about 200mg to about 2000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 80mg to about 2000mg every four weeks, wherein the maintenance phase does not include administration of a platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent.

68. The use of any one of embodiments 56-59, 66, and 67, wherein the induction period comprises four to six dosing cycles.

69. The use according to any one of embodiments 53-59 and 66-68, wherein:

(a) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum chemotherapeutic agent is carboplatin, and the non-platinum chemotherapeutic agent is paclitaxel; or

(c) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is etoposide.

70. The use according to any one of embodiments 47 to 69, wherein the cancer is a solid tumor.

71. The use according to any one of embodiments 47 to 70, wherein the cancer is locally advanced or metastatic.

72. The use 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, gastric cancer, colorectal cancer, kidney cancer, renal cancer, melanoma, or ovarian cancer.

73. The use of embodiment 72, wherein the cancer is lung cancer.

74. The use of embodiment 73, wherein the lung cancer is NSCLC, particularly locally advanced unresectable NSCLC.

75. The use of embodiment 74, wherein the NSCLC is stage IIIB NSCLC.

76. The use of any one of embodiments 73-75, wherein the lung cancer is recurrent or metastatic NSCLC.

77. The use of embodiment 76, wherein the NSCLC is stage IV NSCLC.

78. The use of embodiment 77, wherein the subject has not been previously treated for stage IV NSCLC.

79. The use of embodiment 73, wherein the lung cancer is Small Cell Lung Cancer (SCLC).

80. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 an effective amount of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum chemotherapeutic agent, and a topoisomerase II inhibitor for one or more dosing cycles, wherein the treatment prolongs Progression Free Survival (PFS) of the subject as compared to treatment with the PD-1 axis binding antagonist, the platinum chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

81. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising an effective amount of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor for one or more dosing cycles, wherein the treatment results in a median PFS of the population of subjects from about 8.2 months to about 9.2 months.

82. The use of embodiment 80 or 81, wherein the treatment extends 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 without an anti-TIGIT antagonist antibody.

83. The use of any one of embodiments 80 to 82, wherein the treatment extends 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 without an anti-TIGIT antagonist antibody.

84. The use of embodiment 83, wherein the treatment extends PFS in the subject or population of subjects by at least about 3 months to about 4 months compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without an anti-TIGIT antagonist antibody.

85. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 an effective amount of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum chemotherapeutic agent, and a topoisomerase II inhibitor for one or more dosing cycles, wherein the treatment prolongs OS of the subject as compared to treatment with the PD-1 axis binding antagonist, the platinum chemotherapeutic agent, and the topoisomerase II inhibitor without the anti-TIGIT antagonist antibody.

86. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising an effective amount of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor for one or more dosing cycles, wherein the treatment results in a median OS for the population of subjects of about 15.3 months to about 17.6 months.

87. The use of any one of embodiments 82 to 86, wherein the treatment extends OS of the subject or population of subjects by at least about 3.3 months compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without an anti-TIGIT antagonist antibody.

88. The use of any one of embodiments 82 to 86, wherein the treatment extends OS of the subject or population of subjects by at least about 3 months to about 5.3 months as compared to treatment with a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor without an anti-TIGIT antagonist antibody.

89. The use of any one of embodiments 80-88, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered in each of four initial dosing cycles.

90. The use of any one of embodiments 80 to 89, wherein the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist are further administered in one or more additional cycles after the four initial dosing cycles.

91. The use of embodiment 90, wherein the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor are omitted in each of the one or more additional dosing cycles.

92. The use of any one of embodiments 80-91, wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide.

93. The use of any one of embodiments 80-92, wherein the lung cancer is Small Cell Lung Cancer (SCLC).

94. The use of example 93, wherein SCLC is extensive-term SCLC (ES-SCLC).

95. The use of embodiment 94, wherein the subject or subjects are treatment naive to ES-SCLC.

96. The use according to any one of embodiments 80 to 95, wherein the subject or subjects are absent or have no history of brain metastases.

97. The use according to any one of embodiments 80 to 96, wherein lung cancer is not selected for PD-L1 expression.

98. The use according to any one of embodiments 80 to 96, wherein lung cancer is selected for PD-L1 expression.

99. The use of embodiment 98, wherein the lung cancer is selected for PD-L1 expression by a detectable PD-L1 expression level.

100. The use of any one of embodiments 80-99, wherein the lung cancer is metastatic.

101. The use of embodiment 100, wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal glands.

102. The use of embodiment 100 or 101, wherein the lung cancer has not metastasized to the brain.

103. The use according to any one of embodiments 100 to 102, wherein the treatment results in Complete Remission (CR) or Partial Remission (PR).

104. The use of any one of embodiments 80 to 103, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30mg to about 1200mg every two, three or four weeks.

105. The use of any one of embodiments 80 to 104, wherein the PD-1 axis binding antagonist is administered at a dose of about 80mg to about 2000mg every two, three or four weeks.

106. The use 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 topoisomerase II inhibitor are administered sequentially.

107. The use of embodiment 106, wherein 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.

108. The use of any one of embodiments 80-107, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and topoisomerase II inhibitor are administered intravenously.

109. The use of any one of embodiments 80-108, wherein one or more of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a topoisomerase II inhibitor are administered subcutaneously.

110. Use of an anti-TIGIT antagonist antibody and atlizumab for the manufacture of a medicament for use in a method of treating a subject having SCLC, the method comprising administering to the subject one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg on day 1 of each dosing cycle, altlizumab at a dose of about 80mg to about 1600mg on day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each dosing cycle, wherein the treatment prolongs PFS and/or OS in the subject as compared to treatment with altlizumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

111. Use of an anti-TIGIT antagonist antibody and atuzumab for the manufacture of a medicament for use in a method of treating a subject having SCLC, the method comprising administering to the subject one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 800mg on day 1 of each dosing cycle, an altlizumab at a dose of about 900mg to about 1500mg on day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each dosing cycle, wherein the treatment prolongs PFS and/or OS in the subject as compared to treatment with altlizumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

112. The use of embodiment 110 or 111, further comprising administering to the subject one or more additional 21-day dosing cycles of: an anti-TIGIT antagonist antibody at a dose of about 30mg to about 1200mg on day 1 of each additional dosing cycle and atuzumab at a dose of about 80mg to about 1600mg on day 1 of each additional dosing cycle, wherein carboplatin and etoposide are omitted from each additional dosing cycle of the one or more additional dosing cycles.

113. Use of tirayleigh immuzumab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects with ES-SCLC, the method comprising administering four initial dosing cycles followed by one or more additional dosing cycles to the subject or population of subjects, wherein:

(a) The four initial dosing cycles include: administering tegraleigh itumumab at a dose of about 600mg on day 1 of each initial dosing cycle, atelizumab at a dose of about 1200mg on day 1 of each initial dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each initial dosing cycle, and etoposide at a dose of 100mg/m2 on days 1, 2, and 3 of each initial dosing cycle; and is

(b) The one or more additional dosing cycles comprise: administering tenectereuptab at a dose of about 600mg on day 1 of each additional dosing cycle, and administering atelizumab at a dose of about 1200mg on day 1 of each additional dosing cycle,

wherein the four initial dosing cycles and the one or more additional dosing cycles are each 21-day dosing cycles, and wherein the treatment prolongs PFS and/or OS in the subject or population of subjects as compared to treatment with attrituzumab, carboplatin, and etoposide without tiregumab.

114. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 one or more dosing cycles of the anti-TIGIT antagonist antibody, the 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.

115. The use of embodiment 114, wherein lung cancer has not been evaluated for PD-L1 expression.

116. The use of embodiment 114 or 115, wherein the subject or subjects have not been determined to have a PD-L1 positive tumor cell fraction of greater than or equal to 50%.

117. The use of embodiment 116, wherein the subject or subjects have been determined to have a PD-L1 positive tumor cell fraction of less than 50%.

118. The use of embodiment 116 or 117, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263 or 22C3.

119. The use of any one of embodiments 114 to 118, wherein the subject or subjects do not have Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations.

120. The use according to any one of embodiments 114-119, wherein the subject or subjects did not receive prior systemic therapy for lung cancer.

121. The use of any one of embodiments 114-120, wherein lung cancer is locally advanced lung cancer.

122. The use of any one of embodiments 114 to 121, wherein the lung cancer is NSCLC, particularly locally advanced unresectable NSCLC or metastatic non-squamous NSCLC.

123. The use of embodiment 122, wherein the non-squamous NSCLC is stage IV non-squamous NSCLC.

124. The use of any one of embodiments 114 to 123, wherein the dosing regimen comprises an induction period comprising four 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 are administered on day 1 of each dosing cycle of the induction period.

125. The use of embodiment 124, wherein the dosing regimen comprises a maintenance phase following the induction phase, wherein the maintenance phase comprises one or more dosing cycles, and wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, and non-platinum chemotherapeutic agent are administered on day 1 of each dosing cycle of the maintenance phase.

126. The use of embodiment 125, wherein the one or more dosing cycles of the maintenance phase does not include administration of a platinum-based chemotherapeutic agent.

127. The use of 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. Use of teneuizumab and atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects a dosing regimen comprising four 21-day dosing cycles of teneuizumab, atelizumab, carboplatin or cisplatin, and pemetrexed, wherein on day 1 of each of the four 21-day dosing cycles, teneuizumab is administered at a dose of about 600mg every three weeks, atelizumab is administered at a dose of about 1200mg every three weeks, carboplatin is administered at a dose sufficient to achieve AUC =5mg/ml/min or cisplatin is administered at a dose of 75mg/m2 every three weeks, and pemetrexed is administered at a dose of about 500mg/m2 every three weeks.

129. Use of tirayleigh umab and atuzumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects:

(i) The following of the four induction phase dosing cycles: a dose of about 600mg of tiregumab every three weeks, a dose of about 1200mg of altlizumab every three weeks, a dose of carboplatin sufficient to achieve an AUC =5mg/ml/min every three weeks, and a dose of pemetrexed of about 500mg/m2 every three weeks; and

(ii) One or more of the following maintenance phase dosing cycles: a dose of about 600mg of tirleiuzumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and a dose of about 500mg/m2 of pemetrexed every three weeks, wherein the one or more 21-day periods in the maintenance phase do not include administration of carboplatin, wherein the subject or population of subjects has not received prior systemic therapy for advanced non-squamous NSCLC.

130. Use of tirayleigh umab and atuzumab for the manufacture of a medicament for use in a method of treating a subject having advanced non-squamous NSCLC, the method comprising administering to the subject:

(i) The following of the four induction phase dosing cycles: a dose of about 600mg of tiregumab every three weeks, a dose of about 1200mg of altlizumab every three weeks, a dose of carboplatin sufficient to achieve an AUC =5mg/ml/min every three weeks, and a dose of pemetrexed of about 500mg/m2 every three weeks; and

(ii) One or more of the following maintenance phase dosing cycles: a dose of about 600mg of tenecteuzumab every three weeks, a dose of about 1200mg of alemtuzumab every three weeks, and a dose of about 500mg/m2 of pemetrexed every three weeks, wherein the one or more 21-day periods in the maintenance phase do not include administration of carboplatin wherein the subject has not received prior systemic therapy for advanced non-squamous NSCLC.

131. Use of tirayleigh mab and atuzumab for the manufacture of a medicament for use in a method of treating a subject having advanced non-squamous NSCLC, the method comprising administering to the subject a dosing regimen comprising four 21-day dosing cycles of tirayleigh mab, atuzumab, carboplatin or cisplatin and pemetrexed, wherein on day 1 of each of the four 21-day dosing cycles, tirayleigh mab is administered at a dose of about 600mg every three weeks, atuzumab is administered at a dose of about 1200mg, cisplatin is administered at a dose of 75mg/m2, and pemetrexed is administered at a dose of about 500mg/m 2.

132. The use according to any one of embodiments 114 to 131, wherein the treatment extends PFS in a subject or population of subjects by at least about 3.5 months or about 4.7 months.

133. The use according to any one of embodiments 114 to 132, wherein the treatment results in a median PFS in the population of subjects of about 12.5 months to about 14.7 months.

134. The use according to any one of embodiments 114 to 133, wherein the treatment extends OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months.

135. The use according to any one of embodiments 114 to 134, wherein the treatment results in a median OS for a population of subjects of about 27.5 months to about 32.0 months.

136. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having resectable lung cancer, the method comprising administering to the subject the following comprising one or more dosing cycles: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

137. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having resectable lung cancer, the method comprising administering to the subject comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

138. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist for one or more dosing cycles, wherein at least one of the dosing cycles comprises administering to the subject: as neoadjuvant therapy, the anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and the PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

139. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist for one or more dosing cycles, wherein at least one of the dosing cycles comprises administering to the subject: the anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and the PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks as neoadjuvant therapy.

140. The use of embodiment 138 or 139, wherein at least one of the dosing cycles comprises administering to the subject a dose of between about 30mg to about 1200mg of the anti-TIGIT antagonist antibody every three weeks and a dose of between about 80mg to about 1600mg of the PD-1 axis binding antagonist every three weeks as adjunctive therapy.

141. The use of embodiment 140, wherein at least one of the dosing cycles comprises administering to the subject a dose of between about 500mg to about 700mg of the anti-TIGIT antagonist antibody every three weeks and a dose of between about 900mg to about 1500mg of the PD-1 axis binding antagonist every three weeks as adjunctive therapy.

142. The use of any one of embodiments 138-141, wherein the lung cancer is resectable lung cancer.

143. The use of any one of embodiments 136-142, wherein the lung cancer is early stage lung cancer.

144. The use of any one of embodiments 136-143, wherein the lung cancer is stage II, stage IIIA, or stage IIIB lung cancer.

145. The use of 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 aberrations.

146. The use according to any one of embodiments 136-145, wherein the subject is eligible for an R0 resection for healing purposes.

147. The use of any one of embodiments 136-146, wherein the subject has not received prior therapy for lung cancer.

148. The use of embodiment 147, wherein the prior therapy is immunotherapy, chemotherapy, or radiation therapy.

149. The use of any one of embodiments 136-148, wherein the subject is eligible to receive a platinum-based chemotherapy regimen.

150. The use of any one of embodiments 136-149, wherein the first dosing cycle is initiated prior to surgery.

151. The use of embodiment 150, wherein at least 1, 2, 3, or 4 dosing cycles are completed prior to surgery.

152. The use of embodiment 150 or 151, wherein 4 dosing cycles are completed prior to surgery.

153. The use of any one of embodiments 136-152, wherein at least one dosing cycle is initiated after surgery.

154. The use of embodiment 153, wherein 16 dosing cycles are completed after surgery.

155. The use of any one of embodiments 150-154, wherein the surgery is a segmental resection, a lobectomy, a bilobalectomy, or a pulmonary resection.

156. The use according to any one of embodiments 136-155, wherein the method further comprises radiation therapy.

157. The use of embodiment 156, wherein the radiation therapy is post-operative radiation therapy.

158. The use according to any one of embodiments 136 to 157, wherein the method further comprises administering one or more chemotherapeutic agents.

159. The use according to embodiment 158, wherein the one or more chemotherapeutic agents are administered after surgery.

160. The use of embodiment 159, wherein the one or more chemotherapeutic agents are administered in 4 dosing cycles after surgery.

161. The use of any one of embodiments 158-160, wherein the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

162. The use of embodiment 161, wherein:

(a) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is gemcitabine;

(c) The platinum chemotherapeutic agent is carboplatin, and the non-platinum chemotherapeutic agent is paclitaxel;

(d) The platinum chemotherapeutic agent is cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed; or

(e) The platinum-based chemotherapeutic agent is cisplatin, and the non-platinum-based chemotherapeutic agent is gemcitabine.

163. The use of any one of embodiments 136 to 162, wherein the treatment results in an increase in a Major Pathological Remission (MPR) rate as compared to a reference MPR rate.

164. The use of embodiment 163, wherein the reference MPR rate is an MPR rate for a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

165. The use according to any one of embodiments 136 to 164, wherein the treatment results in complete remission of pathology (pCR) and/or an increase in pCR rate compared to a reference pCR rate.

166. The use of embodiment 165, wherein the reference pCR rate is the pCR rate of a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

167. The use of any one of embodiments 136 to 166, wherein the treatment results in an increase in event-free survival (EFS) as compared to a reference EFS time.

168. The use of embodiment 167, wherein the reference EFS time is the EFS time of a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

169. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having resectable lung cancer, the method comprising administering to the subject the following comprising one or more dosing cycles: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 600mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

170. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist for one or more dosing cycles, wherein at least one of the dosing cycles comprises administering to the subject: as neoadjuvant therapy, the anti-TIGIT antagonist antibody at a dose between about 30mg to about 600mg every three weeks and the PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

171. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having resectable lung cancer, the method comprising administering to the subject comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent at a dose between about 80mg to about 1600mg every three weeks.

172. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent for one or more dosing cycles, wherein at least one dosing cycle of the dosing cycles comprises administering to the subject the following: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, a platinum chemotherapeutic agent, and a non-platinum chemotherapeutic agent as neoadjuvant therapy.

173. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having resectable lung cancer, the method comprising administering to the subject comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, and: (a) (i) a platinum chemotherapeutic agent targeted to achieve a dose of AUC of 5mg/mL/min or AUC of 6mg/mL/min every three weeks; or (ii) a dose of about 75mg/m2 of a platinum chemotherapeutic agent every three weeks; and (b) (i) an antimetabolite at a dose of about 500mg/m2 every three weeks or at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each administration cycle; or (ii) a taxane at a dose of about 100mg/m2, about 175mg/m2, or about 200mg/m2 every three weeks.

174. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent for one or more dosing cycles, wherein at least one of the dosing cycles comprises administering to the subject: (a) An anti-TIGIT antagonist antibody at a dose between about 30mg to about 600mg every three weeks; (b) A PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks; (c) platinum chemotherapeutic agents: (i) A dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) a dose of about 75mg/m2 every three weeks; and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) An antimetabolite at a dose of about 500mg/m2 every three weeks or at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each administration cycle; or (ii) a taxane at a dose of about 100mg/m2, about 175mg/m2, or about 200mg/m2 every three weeks; wherein the treatment is neoadjuvant treatment.

175. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject having resectable lung cancer, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg of tirleivuzumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and:

(a)

(i) Carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or

(ii) Cisplatin at a dose of about 75mg/m2 every three weeks; or

(b)

(i) A dose of pemetrexed of about 500mg/m2 every three weeks, or gemcitabine at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each dosing cycle; or

(ii) Paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks.

176. Use of tirayleigh mab and atuzumab for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject tirayleigh mab, atuzumab, a platinum-based chemotherapeutic agent, and a non-platinum-based chemotherapeutic agent for one or more dosing cycles, wherein at least one of the dosing cycles comprises administering to the subject: (a) a dose of 600mg every three weeks of tirayleigh immuzumab; (b) a dose of 1200mg of atelizumab every three weeks; (c) a platinum chemotherapeutic agent, wherein the platinum chemotherapeutic agent is: (i) Carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or (ii) cisplatin at a dose of about 75mg/m2 every three weeks; and (d) a non-platinum chemotherapeutic agent, wherein the non-platinum chemotherapeutic agent is: (i) A dose of pemetrexed of about 500mg/m2 every three weeks or gemcitabine at a dose of about 1000mg/m2 or about 1250mg/m2 on days 1 and 8 of each dosing cycle; or (ii) paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; wherein the treatment is neoadjuvant treatment.

177. Use of tirayleigh immuzumab and atezumab for the manufacture of a medicament for use in a method of treating a subject having non-squamous NSCLC, the method comprising administering to the subject tirayleigh immuzumab and atezumab for one or more dosing cycles, wherein: (a) At least one of the dosing cycles comprises administering to the subject a dose of about 600mg of tiregumab every three weeks and a dose of 1200mg of atuzumab every three weeks as neoadjuvant therapy; and (b) at least one of the dosing cycles comprises administering to the subject a dose of about 600mg of tenecteuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks as adjunctive therapy.

178. Use of tirayleigh immuzumab and atezumab for the manufacture of a medicament for use in a method of treating a subject having non-squamous NSCLC, the method comprising administering to the subject tirayleigh immuzumab and atezumab for one or more dosing cycles, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of ibritumomab tiuxetan every three weeks; (b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and (c) (i) a dose of carboplatin targeted to achieve an AUC of 5mg/mL/min every three weeks and a dose of pemetrexed of about 500mg/m2 every three weeks; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and pemetrexed at a dose of about 500mg/m2 every three weeks; and (II) at least one such dosing cycle comprises administering to the subject: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks as adjunctive therapy.

179. Use of tirayleigh mab and atuzumab for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject tirayleigh uzumab and atuzumab for one or more dosing cycles, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of ibritumomab tiuxetan every three weeks; (b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises administering to the subject: a dose of between about 30mg to about 1200mg every three weeks and a dose of between about 80mg to about 1600mg every three weeks of atuzumab as adjunctive therapy.

180. Use of tirayleigh immuzumab and atelizumab for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject tirayleigh immuzumab and atelizumab for one or more dosing cycles, wherein:

(I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject:

(a) A dose of about 1200mg of ibritumomab tiuxetan every three weeks;

(b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and

(c)

(i) A dose of carboplatin targeted to achieve an AUC of 5mg/mL/min every three weeks, and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle;

(ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks, and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or

(iii) Cisplatin at a dose of about 75mg/m2 every three weeks, and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and

(II) at least one of the dosing cycles comprises administering to the subject a dose of between about 300mg to about 800mg of tiryleauuzumab and a dose of between about 900mg to about 1500mg of atuzumab every three weeks as adjunctive therapy.

181. Use of tirayleigh mab and atuzumab for the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject tirayleigh uzumab and atuzumab for one or more dosing cycles, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of ibritumomab tiuxetan every three weeks; (b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one of the dosing cycles comprises administering to the subject: as adjunctive therapy, a dose of about 600mg of tenecteuzumab and a dose of about 1200mg of atelizumab every three weeks were used.

182. Use of tiryleigh ewuzumab and atuzumab for the manufacture of a medicament for use in a method of treating a subject having resectable squamous NSCLC, the method comprising administering to the subject tiryleigh ewuzumab and atuzumab for one or more dosing cycles, wherein: (I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject: (a) a dose of about 600mg of ibritumomab tiuxetan every three weeks; (b) About 1200mg dose of alemtuzumab every three weeks as a neoadjuvant therapy; and (c) (i) carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks and gemcitabine at a dose of about 1000mg/m2 on days 1 and 8 of each dosing cycle; (ii) A dose of carboplatin targeted to achieve an AUC of 6mg/mL/min every three weeks and paclitaxel at a dose of about 175mg/m2 or about 200mg/m2 every three weeks; or (iii) cisplatin at a dose of about 75mg/m2 every three weeks and gemcitabine at a dose of about 1250mg/m2 on days 1 and 8 of each dosing cycle; and (II) at least one such dosing cycle comprises administering to the subject: tenecteuzumab at a dose of about 600mg every three weeks and attentizumab at a dose of about 1200mg every three weeks was used as adjuvant therapy.

183. The use of any one of embodiments 136 to 182, wherein a detectable protein expression level of PD-L1 as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 has been determined.

184. The use of embodiment 183, wherein the detectable protein expression level of PD-L1 is greater than or equal to 50% of PD-L1 positive tumor cells.

185. The use of any one of embodiments 73, 114 to 121, and 136 to 184, wherein the lung cancer is NSCLC.

186. The use of embodiment 185, wherein the NSCLC is squamous NSCLC.

187. The use of embodiment 185, wherein the NSCLC is non-squamous NSCLC.

188. The use of embodiment 72, wherein the cancer is cervical cancer.

189. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject or population of subjects for one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

190. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject or population of subjects for one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

191. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for said subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose of between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist administered at a dose of between about 80mg to about 1600mg every three weeks based on PD-L1 expression on tumor cells that has been detected.

192. The use of any one of embodiments 189 to 191, wherein cervical cancer is squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma.

193. The use of any one of embodiments 189 to 191, wherein the cervical cancer is stage IVB, metastatic, recurrent or persistent.

194. The use of any one of embodiments 189 to 193, wherein the cervical cancer is metastatic and/or relapsed PD-L1-positive cervical cancer.

195. The use according to any one of embodiments 189 to 194, wherein the subject or subjects have received at least one prior line of therapy.

196. The use according to any one of embodiments 189 to 195, wherein the subject or subjects have received two prior treatment lines.

197. The use of any one of embodiments 189 to 196, wherein the subject or subjects have received more than two prior lines of therapy.

198. The use of any one of embodiments 189 to 194, wherein the subject or subjects have not received prior therapy.

199. The use of any one of embodiments 195-198, wherein the prior therapy is chemotherapy, surgery, and/or radiation therapy.

200. The use according to any one of embodiments 189 and 192 to 199, wherein the treatment results in a clinical response.

201. The use of embodiment 200, wherein the clinical response is an increase in Objective Remission Rate (ORR) in a population of subjects as compared to a reference ORR.

202. The use of embodiment 201, wherein the reference ORR is the median ORR of a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

203. The use of embodiment 200, wherein the reference ORR is at least about 14.6% to about 26%.

204. The use of embodiment 200, wherein the clinical response is CR or PR.

205. The use of any one of embodiments 200 to 204, wherein the clinical response is an increase in progression-free survival (PFS) of the subject as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject as compared to a reference OS time.

206. The use of embodiment 205, wherein:

(a) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference DOR time is the median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but without an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

207. Use of an anti-TIGIT antagonist antibody and atuzumab for the manufacture of a medicament for use in a method of treating a subject having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a 600mg dose of anti-TIGIT antagonist antibody every three weeks and a 1200mg dose of atuzumab every three weeks.

208. Use of an anti-TIGIT antagonist antibody and atlizumab for the manufacture of a medicament for use in a method of identifying a subject having cervical cancer who may benefit from therapy comprising one or more cycles of administration of the anti-TIGIT antagonist antibody and the atlizumab, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining; and

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1200mg every three weeks based on PD-L1 expression on tumor cells that have been detected.

209. Use of an anti-TIGIT antagonist antibody and atlizumab for the manufacture of a medicament for use in a method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: anti-TIGIT antagonist antibody administered at a dose of 600mg every three weeks and astuzumab administered at a dose of 1200mg every three weeks based on PD-L1 expression on tumor cells that have been detected.

210. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg tireyueuzumab every three weeks, and a dose of about 1200mg atelizumab every three weeks.

211. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject having cervical cancer, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: (ii) based on the detected PD-L1 expression on the tumor cells, tirayleigh mab administered at a dose of 600mg every three weeks and atuzumab administered at a dose of 1200mg every three weeks; and

(d) Administering a therapy to the identified subject.

212. Use of tirayleigh immuzumab and atelizumab for the manufacture of a medicament for use in a method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on tumor cells, tenecteuzumab was administered at a dose of 600mg every three weeks and atelizumab at a dose of 1200mg every three weeks.

213. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject having metastatic and/or recurrent cervical cancer, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: (ii) based on the detected PD-L1 expression on the tumor cells, tirayleigh mab administered at a dose of 600mg every three weeks and atuzumab administered at a dose of 1200mg every three weeks; and

(d) Administering a therapy to the identified subject.

214. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of selecting a therapy for a subject having metastatic and/or recurrent cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable expression level of PD-L1, the therapy comprising one or more cycles of administration of: based on the detected PD-L1 expression on tumor cells, tenecteuzumab was administered at a dose of 600mg every three weeks and atelizumab was administered at a dose of 1200mg every three weeks.

215. The use of any one of embodiments 189 to 214, wherein the subject is identified as a subject likely to benefit from treatment based on PD-L1 expression on tumor cells that have been detected.

216. The use according to any one of embodiments 189 to 215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody SP 263.

217. The use of any one of embodiments 189 to 216, wherein the detectable PD-L1 expression level is greater than or equal to 5% tumor-associated immune cells (TICs) in the sample from the subject.

218. The use of any one of embodiments 189 to 215, wherein the PD-L1 expression level is detected using the anti-PD-L1 antibody 22C 3.

219. The use of any one of embodiments 189 to 216, wherein the detectable level of PD-L1 expression is a Composite Positive Score (CPS) of greater than or equal to 1 in a sample from the subject.

220. The use of embodiment 72, wherein the cancer is breast cancer.

221. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having breast cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more cycles of dosing of: a dose of about 840mg of tireyueuzumab every four weeks, a dose of about 1680mg of atuzumab every four weeks, and nab-paclitaxel dosed at about 100mg/m2 for 3 weeks/off for 1 week.

222. The use of embodiment 220 or 221, wherein the breast cancer is Triple Negative Breast Cancer (TNBC).

223. The use of embodiment 222, wherein the TNBC is unresectable locally advanced or metastatic TNBC.

224. The use of any one of embodiments 220-223, wherein the subject or subjects have not received prior systemic therapy for metastatic breast cancer.

225. The use according to any one of embodiments 220 to 224, wherein the treatment results in a population of subjects with an ORR of at least about 53% to about 67.5%.

226. The use according to any one of embodiments 222 to 225, wherein the treatment results in a median OS for a population of subjects of about 25.0 months.

227. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having early triple negative breast cancer (eTNBC), the method comprising administering to the subject a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of about 10mg to about 1000mg every two weeks and a PD-1 axis binding antagonist at a dose of about 20mg to about 1600mg every two weeks.

228. The use according to embodiment 227, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

229. The use of embodiment 228, wherein the one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

230. The use of embodiment 227, wherein the method further comprises administering (a) one or more dosing cycles of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent; and (b) one or more cycles of administration of an anti-TIGIT antagonist antibody, a 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).

231. The use according to embodiment 229 or 230, wherein the alkylating agent is cyclophosphamide.

232. The use of embodiment 231, wherein cyclophosphamide is administered at a dose of about 600mg/m 2.

233. The use according to any one of embodiments 227 to 229, 231 and 232, wherein the use comprises further administering G-CSF or GM-CSF to the subject.

234. The use according to embodiment 230 or 233, wherein G-CSF is pegylated filgrastim or filgrastim.

235. The use of embodiment 234, wherein G-CSF is pegylated filgrastim.

236. The use of embodiment 235, wherein the pegylated filgrastim is administered at a dose of about 6 mg.

237. The use according to any one of embodiments 228, 229 and 231 to 236, wherein the method further comprises administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

238. The use according to any one of embodiments 228, 229 and 231 to 237, wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are each administered once a week, once every two weeks or once every three weeks.

239. The use of any one of embodiments 229-238, wherein a platinum-based chemotherapeutic agent is administered every three weeks, a taxane is administered every week, a topoisomerase II inhibitor is administered every two weeks, an alkylating agent is administered every two weeks, and G-CSF or GM-CSF is administered every two weeks.

240. The use of any one of embodiments 229-239, wherein the taxane or the taxane and the platinum-based chemotherapeutic agent are administered in the first 12 weeks of a dosing regimen.

241. The use according to any one of embodiments 229 to 240, wherein the topoisomerase II inhibitor, the alkylating agent and G-CSF or GM-CSF are administered on weeks 13 to 19 of a dosing regimen.

242. The use of any one of embodiments 227 to 241, wherein the total length of the dosing regimen is 19 weeks.

243. The use according to any one of embodiments 227 to 242, wherein the method is neoadjuvant therapy.

244. The use of any one of embodiments 227 to 243, wherein the dosing regimen is followed by surgery.

245. The use of embodiment 244, wherein surgery is performed between two and six weeks after the last dose of the dosing regimen.

246. The use of embodiment 244 or 245, wherein the surgery comprises mastectomy.

247. The use of any one of embodiments 244-246, wherein surgery comprises axillary lymph node surgery.

248. The use according to any one of embodiments 229 to 247, wherein the topoisomerase II inhibitor is doxorubicin.

249. The use of any one of embodiments 229-247, wherein the taxane is nab-paclitaxel, the platinum-based chemotherapeutic agent is carboplatin, and the topoisomerase II inhibitor is doxorubicin.

250. The use according to embodiment 248 or 249, wherein doxorubicin is administered at a dose of about 60mg/m 2.

251. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

252. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, a PD-L1 binding antagonist at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane at a dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

253. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, an anti-PD-L1 antagonist antibody at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane at a dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

254. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: a dose of about 300mg to about 600mg every two weeks of tirayleigh immuzumab, a dose of about 600mg to about 1200mg every two weeks of an anti-PD-L1 antagonist antibody, and:

(a)

(i) A taxane dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

255. Use of an anti-TIGIT antagonist antibody and atlizumab for the manufacture of a medicament for use in a method of treating a subject having eTNBC, the method comprising administering to the subject a dosage regimen comprising: an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg every two weeks, atuzumab at a dose of about 600mg to about 1200mg every two weeks, and:

(a)

(i) A taxane at a dose of about 125mg/m2 weekly and a platinum agent at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) A taxane at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, a topoisomerase II inhibitor at a dose of about 60mg/m2 every two weeks, an alkylating agent at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

Wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

256. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject having eTNBC, the method comprising administering to the subject a dosage regimen comprising: a dose of about 300mg to about 600mg every two weeks of ibritumumab tiuxetan, a dose of about 600mg to about 1200mg every two weeks of atuzumab, and:

(a)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly and carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly during the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

257. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject having eTNBC, the method comprising administering to the subject a dosage regimen comprising: a dose of about 420mg of tirleivuzumab every two weeks, a dose of about 840mg of atuzumab every two weeks, and:

(a)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly and carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min every three weeks for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks; or

(b)

(i) Nab-paclitaxel at a dose of about 125mg/m2 weekly for the first 12 weeks of the dosing regimen; and

(ii) At weeks 13 to 19 of the dosing regimen, doxorubicin at a dose of about 60mg/m2 every two weeks, cyclophosphamide at a dose of about 600mg/m2 every two weeks, and G-CSF or GM-CSF every two weeks;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

258. The use according to any one of embodiments 220 to 257, wherein a detectable protein expression level of PD-L1 in a tumor sample from the subject has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SP 142.

259. The use of embodiment 258, wherein the proportion of tumor area in the tumor sample occupied by PD-L1-expressing tumor infiltrating Immune Cells (IC) is greater than or equal to 1%.

260. The use of any one of embodiments 227 to 259 wherein eTNBC appears as T2-4d TNBC.

261. The use of any one of embodiments 227 to 260, wherein the eTNBC is represented by cT2-cT4, cN0-cN3 and cM0TNBC.

262. The use of any one of embodiments 227 to 261, wherein the subject has not been previously treated for eTNBC.

263. The use according to any one of embodiments 227 to 262, wherein the treatment results in complete remission of the pathology (pCR).

264. The use 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 use of embodiment 72, wherein the cancer is a head and neck cancer.

266. The use of embodiment 265, wherein the head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN).

267. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject or population of subjects for one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks.

268. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having SCCHN with detectable PD-L1 expression levels, the method comprising administering to the subject or population of subjects for one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

269. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of selecting a therapy for a subject or population of subjects having uterine SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject or population of subjects having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks and a dose of between about 30mg to about 1200mg of anti-TIGIT antagonist antibody every three weeks.

270. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having SCCHN with detectable PD-L1 expression levels, the method comprising administering to the subject or population of subjects for one or more dosing cycles the following: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

271. The use of any one of embodiments 267-270, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

272. The use of any one of embodiments 266 to 271, wherein the SSCHN is positive for Human Papilloma Virus (HPV).

273. The use of any one of embodiments 266 to 272, wherein the SSCHN is HPV negative.

274. The use according to embodiment 272 or 273, wherein the HPV status is determined by p16IHC, in situ hybridization or by PCR.

275. The use of any one of embodiments 266 to 274, wherein SCCHN is recurrent and/or metastatic SCCHN.

276. The use of any one of embodiments 265 to 275, wherein the subject or subjects did not receive a previous therapy.

277. The use of embodiment 276, wherein the prior therapy is a prior systemic therapy for recurrent and/or metastatic disease.

278. The use according to any one of embodiments 265 to 268 and 270 to 277, wherein the treatment results in CR or PR.

279. The use of any one of embodiments 265 to 268 and 270 to 277, wherein the treatment results in an increase in the Objective Remission Rate (ORR) of the population of subjects as compared to the reference ORR.

280. The use of embodiment 279, wherein the reference ORR is the median ORR of a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

281. The use of embodiment 279 or 280, wherein the reference ORR is at least about 19% to about 36%.

282. The use according to any one of embodiments 265 to 268 and 270 to 281, wherein the treatment results in an increase in Progression Free Survival (PFS) of the subject or population of subjects as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject or population of subjects as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject or population of subjects as compared to a reference OS time.

283. The use of embodiment 282, wherein:

(a) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference DOR time is the median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but without an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

284. The use of embodiment 282, wherein the reference DOR time is at least about 6.7 months to about 23.4 months.

285. The use of embodiment 282, wherein the reference OS time is at least about 11.6 months to about 14.9 months.

286. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject for one or more dosing cycles the following: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks.

287. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having a SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more dosing cycles of: a PD-1 axis binding antagonist at a dose of about 1200mg every three weeks and an anti-TIGIT antagonist antibody at a dose of about 600mg every three weeks.

288. Use of an anti-TIGIT antagonist antibody and a PD-L1 binding antagonist for the manufacture of a medicament for use in a method of treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a PD-L1 binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks.

289. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject having SCCHN with a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of between about 80mg to about 1600mg of atuzumab every three weeks and a dose of between about 30mg to about 1200mg of tiryleiguzumab every three weeks.

290. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject having SCCHN with a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg tireyueuzumab every three weeks, and a dose of about 1200mg atelizumab every three weeks.

291. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks; and

(d) Administering the therapy to the identified subject having a detectable PD-L1 expression level.

292. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: a dose of about 1200mg PD-1 axis binding antagonist every three weeks, a dose of about 600mg anti-TIGIT antagonist antibody every three weeks; and

(d) Administering the therapy to a subject identified as having a detectable PD-L1 expression level.

293. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in the tumor sample by IHC assay 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: a dose of between about 80mg to about 1600mg of atuzumab every three weeks, a dose of between about 30mg to about 1200mg of ibritumumab tiuxetan every three weeks; and

(d) Administering the therapy to the identified subject having a detectable PD-L1 expression level.

294. Use of tirayleigh immuzumab and atelizumab for the manufacture of a medicament for use in a method of treating a subject having SCCHN, the method comprising:

(a) Obtaining a sample from a subject;

(b) Detecting the protein expression level of PD-L1 in a tumor sample by IHC assay using an anti-PD-L1 antibody suitable for staining;

(c) Identifying the subject as likely to benefit from a therapy comprising one or more cycles of administration of: attrituzumab at a dose of about 1200mg every three weeks, ibritumomab tiuxetan at a dose of about 600mg every three weeks; and

(d) Administering the therapy to a subject identified as having a detectable PD-L1 expression level.

295. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of PD-1 axis binding antagonist every three weeks and a dose of between about 30mg to about 1200mg of anti-TIGIT antagonist antibody every three weeks.

296. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a PD-1 axis binding antagonist at a dose of about 1200mg every three weeks and an anti-TIGIT antagonist antibody at a dose of about 600mg every three weeks.

297. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on the PD-L1 expression that has been detected, a dose of between about 80mg to about 1600mg of atuzumab every three weeks and a dose of between about 30mg to about 1200mg of tiryleiguzumab every three weeks.

298. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of selecting a therapy for a subject having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for a subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on the PD-L1 expression that has been detected, a dose of about 1200mg of alemtuzumab every three weeks and a dose of about 600mg of tenecteuzumab every three weeks.

299. The use of any one of embodiments 267-298, wherein the detectable PD-L1 expression level is a detectable protein expression level of PD-L1 as determined by an Immunohistochemistry (IHC) assay comprising staining with anti-PD-L1 antibody SP 263.

300. The use of embodiment 299, wherein the detectable protein expression level of PD-L1 is that tumor-associated immune cells (TICs) in the tumor sample are:

(a) Greater than or equal to 5%;

(b) Greater than or equal to 5% and less than 20%; or

(c) Greater than or equal to 20%.

301. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of identifying a subject having SCCHN as likely to benefit from therapy comprising the following of one or more dosing cycles: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 5% TIC identifies the subject as likely to benefit from the therapy.

302. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of identifying a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of the following: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 5% and less than 20% of TIC identifies the subject as likely to benefit from the therapy.

303. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of identifying a subject having SCCHN as likely to benefit from therapy comprising one or more cycles of administration of the following: a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks and an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, the method comprising determining by an IHC assay the protein expression level of PD-L1 in a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining, wherein a protein expression level of PD-L1 greater than or equal to 20% of TIC identifies the subject as likely to benefit from the therapy.

304. The use according to 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 use according to any one of embodiments 301 to 304, wherein TIC is determined using the Ventana SP263 IHC assay.

306. The use of any one of embodiments 267-305, wherein the subject or population of subjects is identified as a subject or population of subjects likely to benefit from treatment based on PD-L1 expression on tumor cells that has been detected.

307. The use of embodiment 72, wherein the cancer is liver cancer.

308. The use of embodiment 307, wherein the liver cancer is hepatocellular carcinoma (HCC).

309. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having hepatocellular carcinoma (HCC), the method comprising administering to the subject or population of subjects the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist for one or more dosing cycles, wherein the subject or population of subjects did not have received prior systemic treatment for HCC.

310. The use of embodiment 309, wherein the method further comprises administering a VEGF antagonist to the subject or population of subjects.

311. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from HCC, the method comprising administering to the subject or population of subjects one or more dosing cycles of the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and a VEGF antagonist.

312. The use of embodiments 310 and 311, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 25mg/kg every three weeks.

313. The use of any one of embodiments 309 to 312, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30mg to about 1200mg every three weeks.

314. The use of embodiment 313, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 30mg to about 800mg every three weeks.

315. The use of any one of embodiments 309 to 314, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 600mg every three weeks.

316. The use of any one of embodiments 309-315, wherein the PD-1 axis binding antagonist is administered at a dose of about 80mg to about 1600mg every three weeks.

317. The use of any one of embodiments 309-316, wherein the PD-1 axis binding antagonist is administered at a dose of about 900mg to about 1500mg every three weeks.

318. The use of embodiment 310 or 311, wherein the VEGF antagonist is administered at a dose of about 1mg/kg to about 20mg/kg biweekly.

319. The use of embodiment 318, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 10mg/kg every two weeks.

320. The use of embodiment 319, wherein the VEGF antagonist is administered at a dose of about 5mg/kg, about 7.5mg/kg, or about 10mg/kg biweekly.

321. The use of any one of embodiments 309-311 and 318-320, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 10mg to about 1000mg every two weeks.

322. The use of any one of embodiments 309-311 and 318-321, wherein the PD-1 axis binding antagonist is administered at a dose of about 20mg to about 1600mg every two weeks.

323. The use of embodiments 309-311, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 200mg to about 2000mg every four weeks.

324. The use of any one of embodiments 309-311 and 323, wherein the PD-1 axis binding antagonist is administered at a dose of about 80mg to about 2000mg every four weeks.

325. The use of any one of embodiments 309-311, 323, and 324, wherein the PD-1 axis binding antagonist is administered at a dose of about 1400mg to about 2000mg every four weeks.

326. The use according to any one of embodiments 309 to 325, wherein HCC is locally advanced or metastatic HCC.

327. The use of any one of embodiments 309 to 326, wherein the HCC is a non-resectable HCC.

328. The use of any one of embodiments 309 to 327, wherein the subject or subjects have been determined to have adequate liver function.

329. The use of embodiment 328, wherein the sufficient liver function is characterized as Child-Pugh class a.

330. The use of any one of embodiments 309-329, wherein the HCC tumor sample obtained from the subject or subjects has been determined to have a detectable level of PD-L1 expression.

331. The use according to any one of embodiments 309-330, wherein the method comprises administering to the subject or population of subjects at least four dosing cycles.

332. The use of embodiment 331, wherein the method comprises administering to the subject or population of subjects at least 16 dosing cycles.

333. Use of tirayleigh immuzumab and atelizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects with HCC, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg of tenecteukumab every three weeks, a dose of about 1200mg of atelizumab every three weeks, and a dose of about 15mg/kg of bevacizumab every three weeks.

334. The use of any one of embodiments 311 to 333, wherein the subject or subjects did not receive a previous systemic therapy for HCC.

335. The use according to any one of embodiments 309 to 334, wherein the treatment results in a median PFS in the population of subjects of at least about 5.6 months to at least about 6.83 months.

336. The use of embodiment 72, wherein the cancer is bladder cancer.

337. The use of embodiment 336, wherein the bladder cancer is Muscle Invasive Bladder Cancer (MIBC).

338. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of administration of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the subject is eligible for treatment with a platinum-based chemotherapeutic agent.

339. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, wherein the subject is eligible for treatment with a platinum-based chemotherapeutic agent.

340. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of administration of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

341. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of administration of: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, wherein the treatment is perioperative treatment.

342. The use of any one of embodiments 338-341, wherein the subject or subjects have a creatinine clearance < 60 mL/min.

343. The use of any one of embodiments 338-342, wherein the subject or subjects have a hearing loss greater than or equal to grade 2.

344. The use of any one of embodiments 338-343, wherein the subject or subjects have a grade 2 or greater neuropathy.

345. The use of any one of embodiments 338-344, wherein the subject or subjects have declined treatment with a platinum-based chemotherapeutic agent.

346. The use of any one of embodiments 338 or 342-345, wherein the platinum-based chemotherapeutic agent is cisplatin.

347. The use of any one of embodiments 338-346, wherein the MIBC is operable.

348. The use of embodiment 347, wherein the method further comprises surgery.

349. The use of embodiment 348, wherein at least one dosing cycle is initiated prior to surgery.

350. The use of embodiment 348 or 349, wherein at least 1, 2, or 3 dosing cycles are completed prior to surgery.

351. The use of any one of embodiments 348-350, wherein at least one dosing cycle is initiated between 4 and 6 weeks post-surgery.

352. The use of embodiment 351, wherein 1 to 17 dosing cycles are completed after surgery.

353. The use according to any one of embodiments 348 to 352, wherein the surgery is cystectomy and/or lymph node dissection.

354. The use according to any one of embodiments 338 to 353, wherein the treatment results in complete remission (pCR) of the pathology.

355. The use of any one of embodiments 338-354, wherein the treatment results in an increase in Relapse Free Survival (RFS) for the subject or subjects as compared to a reference RFS time, an increase in Event Free Survival (EFS) for the subject or subjects as compared to a reference EFS time, or an increase in OS for the subject or subjects as compared to a reference OS time.

356. The use of embodiment 355, wherein:

(a) The reference RFS time is the median RFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference EFS time is the median EFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

357. The use according to any one of embodiments 338 to 356, wherein the treatment results in pathological degradation.

358. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the subject is not eligible for cisplatin use.

359. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

360. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-L1 binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the subject is not eligible for cisplatin use.

361. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of administration of: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, a PD-L1 binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is perioperative treatment.

362. Use of tirayleigh immuzumab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of dosing of: a dose of between about 30mg to about 1200mg of tirleivuzumab every three weeks, a dose of between about 80mg to about 1600mg of atuzumab every three weeks, wherein the subject is eligible for cisplatin use.

363. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of between about 30mg to about 1200mg of tirleivuzumab every three weeks, a dose of between about 80mg to about 1600mg of atuzumab every three weeks, wherein the treatment is perioperative treatment.

364. Use of tirayleigh immuzumab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more cycles of dosing of: a dose of about 600mg tirayleigh-uzumab every three weeks, and a dose of about 1200mg atelizumab every three weeks, wherein the subject or subjects are not eligible for cisplatin.

365. Use of tirayleigh mab and atlizumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tirleiuzumab every three weeks, and a dose of about 1200mg of atezumab every three weeks, wherein the treatment is a perioperative treatment.

366. The use of any one of embodiments 338 to 365, wherein the treatment results in a population of subjects with an ORR of at least about 13.4% to about 15%.

367. The use according to any one of embodiments 338-366, wherein the treatment results in a median OS for the population of subjects of at least about 7.9 months to about 8.6 months.

368. The use of any one of embodiments 338 to 367, wherein a detectable protein expression level of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SP 142.

369. The use of embodiment 368, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction in which a proportion of a tumor area occupied by tumor infiltrating Immune Cells (ICs) that express PD-L1 is greater than or equal to 5%.

370. The use of embodiment 336, wherein the bladder cancer is Urothelial Cancer (UC).

371. The use of embodiment 370, wherein UC is metastatic urothelial cancer (mUC).

372. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a mUC, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

373. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a mUC, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of between about 300mg to about 800mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 900mg to about 1500mg every three weeks.

374. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having mUC, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks, wherein the subject has not received prior cancer immunotherapy.

375. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a mUC, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks, a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg every three weeks, wherein the treatment is second line treatment.

376. The use of any one of embodiments 372, 372 and 375, wherein the subject or subjects have not received prior cancer immunotherapy.

377. The use according to any one of embodiments 372-374, wherein the treatment is second line treatment.

378. The use of any one of embodiments 372-377, wherein the mUC has progression during or after platinization therapy.

379. The use according to any one of embodiments 372-378, wherein 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 use of embodiment 379, wherein the second dosing regimen comprises one or more cycles of dosing of the PD-1 axis binding antagonist and the antibody-drug conjugate (ADC).

381. The use of embodiment 380, wherein the ADC is (a) vildagliptin-enfratuzumab or (b) govitegam-shaxituzumab.

382. The use of embodiment 381 wherein (a) vildagliptin-enfratuzumab is administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (b) govitegam-shaxituzumab is administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week.

383. The use of embodiment 381 or 382, wherein (a) vildagliptin-enroflitumumab is administered at a dose of 1.25mg/kg on days 1 and 8 of each 21-day cycle, or (b) govericin-sarcistuzumab is administered at a dose of 10mg/kg on days 1 and 8 of each 21-day cycle.

384. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a mUC, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more cycles of dosing of: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks, a PD-L1 binding antagonist at a dose between about 80mg to about 1600mg every three weeks.

385. Use of tirayleigh mab and atezumab for the manufacture of a medicament for a method of treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: a dose of between about 30mg to about 1200mg every three weeks and a dose of between about 80mg to about 1600mg every three weeks of atuzumab.

386. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from a mUC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg tireyueuzumab every three weeks, and a dose of about 1200mg atelizumab every three weeks.

387. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a mUC, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-1 axis binding antagonist at a dose between about 80mg to 1600mg every three weeks; and is

(b) The second dosing regimen comprises one or more of the following for the dosing cycle: a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg every three weeks and (i) vildagliptin-enfratuzumab is administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (ii) govittazin-shacetuzumab is administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week, wherein a second dosing regimen is administered to a subject or population of subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity during a first dosing regimen.

388. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having a mUC, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg every three weeks and a PD-L1 binding antagonist at a dose between about 80mg to 1600mg every three weeks; and is

(b) The second dosing regimen comprises one or more of the following for the dosing cycle: a dose of between about 80mg to about 1600mg of a PD-L1 binding antagonist every three weeks and (i) vildagliptin-enfratuzumab is administered at a dose of 1.25mg/kg weekly for 2 weeks/withdrawal for 1 week, or (ii) govittazin-saxituzumab is administered at a dose of 10mg/kg weekly for 2 weeks/withdrawal for 1 week, wherein the subject is administered a second dosing regimen after the subject has experienced disease progression or unacceptable toxicity during the first dosing regimen.

389. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from a mUC, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: a dose of about 600mg of tireyueuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks; and

(b) The second dosing regimen comprises one or more of the following for the dosing cycle: about 1200mg dose of alemtuzumab and (i) vildagliptin-enfratuzumab administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week every three weeks, or (ii) govericin-shaxituzumab administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week, wherein the subject is administered a second dosing regimen after the subject has experienced disease progression or unacceptable toxicity during the first dosing regimen.

390. The use of any one of embodiments 372-389, wherein the treatment results in an ORR of a population of subjects of at least about 13.4% to at least about 31%.

391. The use according to any one of embodiments 372-390, wherein the treatment results in a median OS for the population of subjects of about 7.9 months to about 16.3 months.

392. The use of embodiment 72, wherein the cancer is pancreatic cancer.

393. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects suffering from pancreatic cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 28 day dosing cycle: a dose of about 420mg of tiryleiguzumab at days 1 and 15 of each 28-day dosing cycle, a dose of about 840mg of atuzumab at days 1 and 15 of each 28-day dosing cycle, a dose of about 1000mg/m2 of gemcitabine at days 1, 8, and 15 of each 28-day dosing cycle, and a dose of about 125mg/m2 of nab-paclitaxel at days 1, 8, and 15 of each 28-day dosing cycle.

394. The use of embodiment 392 or 393, wherein the pancreatic cancer is Pancreatic Ductal Adenocarcinoma (PDAC).

395. The use of embodiment 394, wherein the PDAC is a metastatic PDAC.

396. The use of any one of embodiments 392 to 395, wherein the subject or subjects have not received prior systemic therapy for metastatic PDAC.

397. The use of any one of embodiments 392 to 396, wherein the treatment results in an ORR of at least about 41.7% to about 46.7% in a population of subjects.

398. The use of any one of embodiments 392 to 397, wherein the treatment results in an increase in ORR of at least about 20% as compared to a treatment comprising gemcitabine and nab-paclitaxel without the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

399. The use of any one of embodiments 392 to 398, wherein the treatment results in a median PFS of at least about 5.5 months to about 7 months for the population of subjects.

400. The use of any one of embodiments 392 to 399, wherein the treatment results in a median OS for the population of subjects of at least about 8.5 months to about 10.6 months.

401. The use of embodiment 72, wherein the cancer is esophageal cancer.

402. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg on day 1 of each dosing cycle.

403. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg on day 1 of each dosing cycle.

404. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in a method of treating a subject or population of subjects having esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 80mg to about 1600mg on day 1 of each dosing cycle, wherein the subject has been previously 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 for the manufacture of a medicament for use in a method of treating a subject or population of subjects having esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 300mg to about 800mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg on day 1 of each dosing cycle, wherein the subject has been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

406. The use of embodiment 402 or 403, wherein the subject or subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

407. The use of any one of embodiments 404-406, wherein the subject or subjects have experienced disease progression or unacceptable toxicity during a previous treatment.

408. The use of embodiment 402 or 403, wherein the 21-day dosing cycle further comprises a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

409. The use of embodiment 408 wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six administrations.

410. The use of any one of embodiments 404-409 wherein the platinum-based chemotherapeutic agent is cisplatin.

411. The use of embodiment 410 wherein cisplatin is administered at a dose of about 80mg/m2 on day 1 of each dosing cycle.

412. The use of any one of embodiments 404 to 411, wherein the non-platinum chemotherapeutic agent is an antimetabolite.

413. The use of embodiment 412, wherein the antimetabolite is 5-fluorouracil.

414. The use of embodiment 413 wherein 5-fluorouracil is administered at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle.

415. The use according to any one of embodiments 404 to 414, wherein the esophageal cancer is advanced or metastatic esophageal cancer.

416. The use of any one of embodiments 402, 403, 408, or 409, wherein the subject or subjects have not previously been treated for metastatic esophageal cancer.

417. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg on day 1 of each dosing cycle, a PD-1 axis binding antagonist at a dose of between about 80mg to about 1600mg on day 1 of each dosing cycle, a platinum-based chemotherapeutic agent at a dose of about 80mg/m2 on day 1 of each dosing cycle, and a non-platinum-based chemotherapeutic agent at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six doses.

418. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 600mg on day 1 of each dosing cycle, a PD-1 axis binding antagonist at a dose of about 1200mg on day 1 of each dosing cycle, cisplatin at a dose of about 80mg/m2 on day 1 of each dosing cycle, and 5-fluorouracil at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses.

419. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose of about 600mg of tenecteuzumab on day 1 of each dosing cycle, a dose of about 1200mg of atuzumab on day 1 of each dosing cycle, a dose of about 80mg/m2 of cisplatin on day 1 of each dosing cycle, and a dose of 800mg/m2/24 hours of 5-fluorouracil on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses.

420. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more 21-day dosing cycles of a platinum chemotherapeutic agent and a non-platinum chemotherapeutic agent, wherein the platinum chemotherapeutic agent is omitted from the dosing regimen after six doses of the platinum chemotherapeutic agent; and is

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 80mg to 1600mg on day 1 of each dosing cycle.

421. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for the manufacture of a medicament for use in 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 dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 80mg/m2 of a platinum-based chemotherapeutic agent on day 1 of each dosing cycle and a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein the platinum-based chemotherapeutic agent is omitted from the dosing regimen after six administrations; and is

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 30mg to about 1200mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 80mg to 1600mg on day 1 of each dosing cycle.

422. Use of tirayleigh mab and atezumab for the manufacture of a medicament for use in a method of treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a 21 day dosing cycle: cisplatin at a dose of about 80mg/m2 on day 1 of each dosing cycle and 5-fluorouracil at a dose of 800mg/m2/24 hours on days 1 to 5 of each 21-day cycle, wherein cisplatin is omitted from the dosing regimen after six doses; and is provided with

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 600mg of securityluzumab on day 1 of each dosing cycle and a dose of about 1200mg of atezumab on day 1 of each dosing cycle.

423. The use according to any one of embodiments 402 to 422, wherein the treatment results in an ORR of the population of subjects of at least about 14%.

424. The use of any one of embodiments 47-423, wherein an anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

an HVR-H2 sequence comprising the amino acid sequence of KTYYRRFKWYSDYASVSVKG (SEQ ID NO: 2);

an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

425. The use of embodiment 424, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region Framework Regions (FRs):

FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLLGERANC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (SEQ ID NO: 9); and

FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

426. The use of embodiment 424, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs:

FR-H1 comprising the amino acid sequence of X1 VQLQQSGPGLVKPPSQTLSLTCASGDSVS (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 use of embodiment 426 wherein X1 is E.

428. The use of embodiment 426 wherein X1 is Q.

429. The use of any one of embodiments 424-428, wherein an anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain as in (a) and a VL domain as in (b).

430. The use of any one of embodiments 424-429, wherein an anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO:17 or 18; and

(b) A VL domain comprising SEQ ID NO: 19.

431. The use of any one of embodiments 424-427, 429, and 430, wherein the anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 17; and

(b) A VL domain comprising SEQ ID NO: 19.

432. The use of any one of embodiments 424-427 and 429-431, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 33; and

(b) A light chain comprising SEQ ID NO: 34.

433. The use of any one of embodiments 424-432, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

434. The use of any one of embodiments 424-433, wherein the anti-TIGIT antagonist antibody is a human antibody.

435. The use of any one of embodiments 424-434, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

436. The method of any one of embodiments 424-427 and 429-436, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan.

437. The use of any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, 421, and 424-436, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan, bevacizumab, etiglimab, EOS084448, SGN-TGT, or TJ-T6.

438. The use of embodiment 437, wherein the anti-TIGIT antagonist antibody has intact Fc-mediated effector function.

439. The use of embodiment 437 or 438, wherein the anti-TIGIT antagonist antibody has enhanced Fc-mediated effector function.

440. The use of any one of embodiments 437-439, wherein the anti-TIGIT antagonist antibody is SGN-TGT.

441. The use of any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420, and 421, wherein the anti-TIGIT antagonist antibody is dommaralizab, BMS-986207, ASP8374, or COM902.

442. The use of any one of embodiments 424-431 and 441, wherein the anti-TIGIT antagonist antibody does not have intact Fc-mediated effector function.

443. The use of any one of embodiments 47-442, wherein the TIGIT antagonist antibody is an IgG class antibody.

444. The use of embodiment 443, wherein the IgG class antibody is an IgG1 subclass antibody.

445. The use of embodiment 444, wherein the anti-TIGIT antagonist antibody is tirayleigh immitumab, wiborlizumab, etiglimicab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, domcanalimab, or BMS-986207.

446. The use according to any one of embodiments 47-112, 114-127, 136-174, 188-209, 227-253, 255, 265-269, 286-288, 291, 292, 295, 296, 301-332, 336-361, 370-384, 387, 388, 401-418, 420 and 421, wherein the IgG class antibody is an IgG4 subclass antibody.

447. The use of embodiment 446, wherein the anti-TIGIT antagonist antibody is ASP8374 or COM902.

448. The use of any one of embodiments 424-434, wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, dual Fab, fab '-SH, fv, single chain variable fragment (scFv), and (Fab') 2 fragments.

449. The use of any one of embodiments 424-448, wherein the anti-TIGIT antagonist antibody is a monospecific antibody.

450. The use of any one of embodiments 424-448, wherein the anti-TIGIT antagonist antibody is a multispecific antibody.

451. The use of embodiment 450, wherein the multispecific antibody is a bispecific antibody.

452. The use of any one of embodiments 424-451, 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 use of embodiment 452, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

454. The use 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 use 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 use of any one of embodiments 453 to 455, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

457. The use of embodiment 456, wherein the anti-PD-L1 antagonist antibody is Attributumab, MDX-1105, devolumab, avermemab, SHR-1316, CS1001, envolumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cochlizumab, lodalizumab, 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 use of embodiment 457, wherein the anti-PD-L1 antagonist antibody is atelizumab.

459. The use of embodiment 456, wherein the anti-PD-L1 antagonist antibody comprises the following HVRs:

An HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);

an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);

an HVR-H3 sequence comprising the amino acid sequence of RHWPGFDY (SEQ ID NO: 22);

an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);

an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and

an HVR-L3 sequence comprising the amino acid sequence of QQYLLYHPAT (SEQ ID NO: 25).

460. The use of embodiment 459, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:26 has at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:27 has an amino acid sequence of at least 95% sequence identity; or

(c) A VH domain as in (a) and a VL domain as in (b).

461. The use of embodiment 460, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 26; and

(b) A VL domain comprising SEQ ID NO: 27.

462. The use of embodiment 461, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 28; and

(b) A light chain comprising SEQ ID NO: 29.

463. The use of any one of embodiments 459 to 462, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

464. The use of any one of embodiments 459 to 463, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

465. The use of embodiment 463 or 464, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

466. The use of 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 '-SH, fv, scFv, and (Fab') 2 fragments.

467. The use of any one of embodiments 459 to 465, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

468. The use of embodiment 467, wherein the IgG class antibody is an IgG1 subclass antibody.

469. The use of embodiment 452, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

470. The use of embodiment 469, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.

471. The use of embodiment 470, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2.

472. The use according to any one of embodiments 469 to 471, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

473. The use of example 472, wherein the anti-PD-1 antagonist antibody is nivolumab, parbolizumab, MEDI-0680, sibatuzumab, cimaprimab, BGB-108, palonozumab, carpilizumab, neidilizumab, tirizumab, terieprizumab, dolaprimab, refelimab, fralizumab, saralalizumab, perindopril mab, CS1003, HLX10, SCT-I10A, sepiolizumab, batilizumab, gemumab, jirimumab, BI 754091, cetirizumab, YBL-006, BAT1306, HX008, breglizumab, AMG 404, CX-188, JTX-4014, 609A, sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, AK-103, or hAb21.

474. The use according to any one of embodiments 469 to 471, wherein the PD-1 binding antagonist is an Fc fusion protein.

475. The use of embodiment 474, wherein the Fc fusion protein is AMP-224.

476. The use of any one of embodiments 80-112, 114-127, and 309-312, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody at a dose of between about 30mg to about 1200mg every three weeks.

477. The use according to any one of embodiments 51, 54, 60, 62, 63, 65 to 67, 80 to 112, 114 to 127, 136 to 140, 169 to 174, 189, 191, 267, 269, 286, 288, 291, 295, 301, 302, 303, 313, 315, 338, 340, 358 to 361, 372, 384, 387, 388, 402 to 404, 417, 420, 421, and 476, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody at a dose of about 600mg every three weeks.

478. The use according to any one of embodiments 51, 54, 60, 62, 63, 65 to 67, 80 to 112, 114 to 127, 136 to 140, 169 to 174, 189, 191, 267, 269, 286, 288, 291, 295, 301, 302, 303, 309, 313, 315, 338, 340, 358 to 361, 372, 384, 387, 388, 402 to 404, 417, 420, 421 and 476, wherein the method comprises administering to a subject or population of subjects an anti-TIGIT antagonist antibody in a stepped dose based on the weight of the subject, wherein the weight of the subject is:

(a) Less than or equal to 15kg and the anti-TIGIT antagonist antibody is administered at a dose of about 300mg every three weeks;

(b) Greater than 15kg and less than or equal to 40kg, and the anti-TIGIT antagonist antibody is administered at a dose of about 400mg every three weeks; or

(c) Greater than 40kg, and the anti-TIGIT antagonist antibody is administered at about 600mg every three weeks.

479. The use of any one of embodiments 47, 48, 77, 78, 82, and 83, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks.

480. The use of any one of embodiments 47, 48, 59, 67, 323, and 479, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody at a dose of about 840mg every four weeks.

481. The use of any one of embodiments 49, 50, and 104, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody at a dose of about 300mg to about 600mg biweekly.

482. The use of any one of embodiments 49, 50, 227, 251 to 253, 255 and 481, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody at a dose of about 420mg every two weeks.

483. The use of any one of embodiments 47-482, wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose.

484. The use of any one of embodiments 54, 62, 63, 65 to 67, 80 to 109, and 27 to 2698, wherein the method comprises administering the PD-1 axis binding antagonist to a subject or population of subjects at a dose of between about 900mg to about 1500mg every three weeks.

485. The use according to any one of embodiments 54, 60, 62, 63, 65-67, 80-112, 114-127, 136-140, 169-172, 189, 191, 267, 269, 286, 288, 291, 295, 301-303, 309, 311, 313, 315, 338, 340, 358-361, 372-375, 384, 387, 388, 402-405, 417, 420, 421, and 484, wherein the method comprises administering to the subject an anti-PD-1 axis binding antagonist at a dose of about 1200mg every three weeks.

486. The use of any one of embodiments 47, 50, 80-109, and 324, wherein the method comprises administering a PD-1 axis binding antagonist to a subject or population of subjects at a dose of about 1400mg to 2000mg every four weeks.

487. The use according to any one of embodiments 47, 50, 59, 67, 324, and 479, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a dose of about 1680mg every four weeks.

488. The use of embodiments 48, 49, 80-109 and 481, wherein the method comprises administering to the subject or population of subjects a PD-1 axis binding antagonist at a dose of between about 600mg to about 1200mg every two weeks.

489. The use according to any one of embodiments 48, 49, 80 to 109, 227, 251 to 253 and 481, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a dose of about 840mg every two weeks.

490. The use of any one of embodiments 47-489 wherein the dose of the PD-1 axis binding antagonist is a fixed dose.

491. The use of embodiment 60 or 61, wherein the method comprises administering to the subject a fixed dose of about 200mg every three weeks or about 400mg every six weeks.

492. The use according to any one of embodiments 54, 60, 62, 63, 65, 80 to 109 and 191, wherein each of the one or more dosing cycles is 21 days in length.

493. The use of any one of embodiments 47, 59, 67, 80-109, and 309-311, wherein each of the one or more dosing cycles is 28 days in length.

494. The use of any one of embodiments 49, 80 to 109, and 309 to 311, wherein each of the one or more dosing cycles is 14 days in length.

495. The use according to any one of embodiments 47-494, wherein the method comprises administering to a subject or population of subjects an anti-TIGIT antagonist antibody on day 1 of each of the one or more dosing cycles.

496. The use according to any one of embodiments 47 to 495, wherein the method comprises administering a PD-1 axis binding antagonist to a subject or population of subjects on day 1 of each of the one or more dosing cycles.

497. The use of embodiment 321 or 493, wherein the method comprises administering to the subject an anti-TIGIT antagonist antibody on day 15 of each of the one or more dosing cycles.

498. The use of embodiment 321 or 493, wherein the method comprises administering the PD-1 axis binding antagonist to the subject on day 15 of each of the one or more dosing cycles.

499. The use of any one of embodiments 47-498, wherein the method comprises administering a PD-1 axis binding antagonist to the subject or population of subjects prior to the anti-TIGIT antagonist antibody, or the anti-TIGIT antagonist antibody precedes the PD-1 axis binding antagonist.

500. The use of embodiment 499 wherein the method comprises a first observation period following administration of the PD-1 axis binding antagonist or anti-TIGIT antagonist antibody.

501. The use of embodiment 500, wherein the length of the first observation period is between about 30 minutes and about 60 minutes.

502. The use of embodiment 500 or 501, wherein the method comprises a second observation period following administration of the anti-TIGIT antagonist antibody or the PD-1 axis binding antagonist.

503. The use of embodiment 502, wherein the length of the second observation period is between about 30 minutes and about 60 minutes.

504. The use of any one of embodiments 47-503, wherein the method comprises administering a PD-1 axis binding antagonist to a subject or population of subjects concurrently with the administration of the anti-TIGIT antagonist antibody.

505. The use of any one of embodiments 47-504, wherein the method comprises intravenously administering to a subject or population of subjects an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

506. The use of embodiment 505, wherein the method comprises administering the PD-1 axis binding antagonist to a subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

507. The use according to embodiment 505 or 506, wherein the method comprises administering to the subject or population of subjects an anti-TIGIT antagonist antibody by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

508. The use of any one of embodiments 47-114 and 116-507, wherein the PD-L1 expression level of a tumor sample obtained from the subject or subjects has been determined.

509. The use of embodiment 508, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

510. The use of embodiment 509, wherein the detectable PD-L1 expression level is a detectable protein expression level of PD-L1.

511. The use of embodiment 510, wherein the detectable protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

512. The use according to embodiment 511, wherein the anti-PD-L1 antibody suitable for staining is anti-PD-L1 antibody SP263, SP142, 22C3 or 28-8.

513. The use of embodiment 511 or 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 pharmDx 28-8 IHC assay.

514. The use according to any one of embodiments 47 to 109, 188, 220 to 265 and 307 to 423, wherein the detectable protein expression level of PD-L1 determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP263 has been determined.

515. The use of any one of embodiments 47 to 220, 265 to 338, and 370 to 423, wherein a detectable level of protein expression of PD-L1 determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP142 has been determined.

516. The use of any one of embodiments 47 to 113, 136 to 187, and 220 to 423, wherein a detectable level of protein expression of PD-L1 determined by an IHC assay comprising staining with anti-PD-L1 antibody 22C3 has been determined.

517. The use of any one of embodiments 47 to 114 and 116 to 423, wherein a detectable level of protein expression of PD-L1 as determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8 has been determined.

518. The use of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% tumor-associated immune cells (TICs) in the tumor sample.

519. The use of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% and less than 20% TIC in the tumor sample.

520. The use of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% TIC in the tumor sample.

521. The use of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 20% TIC in the tumor sample.

522. The use of embodiment 514, wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% and less than 50% TIC in the tumor sample.

523. The use 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 use 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 PD-L1-positive tumor cells.

525. The use of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is a fraction of PD-L1-positive tumor cells greater than or equal to 30%.

526. The use of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is a fraction of PD-L1 positive tumor cells in the tumor sample that is greater than or equal to 1% and less than 50%.

527. The use of any one of embodiments 514, 516, and 517, wherein the detectable protein expression level of PD-L1 is greater than or equal to 50% of PD-L1 positive tumor cell fraction.

528. The use of embodiment 515, wherein the PD-L1 positive tumor cell fraction is the proportion of the tumor area occupied by PD-L1-expressing tumor infiltrating Immune Cells (IC).

529. The use of embodiment 515, wherein the proportion of tumor area in the tumor sample occupied by PD-L1-expressing tumor infiltration IC is greater than or equal to 1%.

530. The use of embodiment 515, wherein the proportion of tumor area in the tumor sample occupied by PD-L1-expressing tumor infiltrating IC is greater than or equal to 5%.

531. The use as in embodiment 516, wherein the detectable protein expression level of PD-L1 is a Composite Positive Score (CPS) of greater than or equal to 1.

532. The use as in embodiment 516, wherein the detectable protein expression level of PD-L1 is CPS greater than or equal to 10.

533. The use as in embodiment 516, wherein the detectable protein expression level of PD-L1 is CPS greater than or equal to 20.

534. The use of any one of embodiments 528-530, wherein the IHC assay is a Ventana SP142 IHC assay.

535. The use of embodiment 509, wherein the detectable PD-L1 expression level is a detectable nucleic acid expression level of PD-L1.

536. The use of embodiment 535, wherein the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, massARRAY technology, ISH, or a combination thereof.

537. The use according to any one of embodiments 47-423, wherein the treatment results in an increase in Overall Survival (OS) of the subject as compared to a reference OS time and/or an increase in progression-free survival (PFS) of the subject as compared to a reference PFS time.

538. The use of embodiment 537, wherein:

(a) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist; and/or

(b) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist.

539. The use 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 use of embodiment 539 wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin.

541. The use of embodiments 69, 92, 127, 131, 249, and 540, wherein carboplatin is administered at a dose sufficient to achieve AUC =5mg/ml/min or AUC =6 mg/ml/min.

542. The use of embodiment 69, 127, 162, 164, 166, 168 and 540, wherein cisplatin is administered at a dose of about 75mg/m2 or 80mg/m 2.

543. The use of any one of embodiments 539-542, wherein the one or more non-platinum chemotherapeutic agents is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

544. The use of any one of embodiments 62, 173, 174, and 543, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

545. The use of any one of embodiments 69, 127, 162, and 544, wherein pemetrexed is administered at a dose of about 500mg/m 2.

546. The use of any one of embodiments 63, 64, 162, 398, and 544, wherein gemcitabine is to be administered at a dose of about 1000mg/m2 or about 1250mg/m 2.

547. The use of embodiment 544, wherein the antimetabolite is capecitabine.

548. The use of embodiment 544 or 547 wherein capecitabine is administered at a dose of about 1250mg/m 2.

549. The use of any one of claims 173, 174, 229, 230, 239, 240, and 543 to 548, wherein the taxane is paclitaxel or nab-paclitaxel.

550. The use of any one of embodiments 69, 162, and 549, wherein paclitaxel is administered at a dose of about 175mg/m2 or about 200mg/m 2.

551. The use of any one of embodiments 63, 64, 249, 398, and 549, wherein nab-paclitaxel is administered at a dose of about 100mg/m 2.

552. The use as described in any one of embodiments 80-91, 229, 230, 239, 241, 251-255, and 543-551, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331.

553. The use of any one of embodiments 69, 92 and 552, wherein etoposide is administered at a dose of about 100mg/m 2.

554. The use of any one of embodiments 543-553, wherein the one or more chemotherapeutic agents are each administered once a week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.

555. The use according to any one of embodiments 543 to 554, wherein the one or more chemotherapeutic agents are administered on day 1 of one or more dosing cycles.

556. The use of any one of embodiments 544 to 555, wherein gemcitabine is administered three times every four weeks.

557. The use of any one of embodiments 544 to 556, wherein gemcitabine is to be administered on days 1, 8, and/or 15 of one or more dosing cycles.

558. The use of any one of embodiments 544 to 557 wherein capecitabine is administered daily for two weeks.

559. The use of any one of embodiments 544 to 558, wherein capecitabine is administered on days 1 to 14 of one or more dosing cycles.

560. The use of any one of embodiments 549-559, wherein nab-paclitaxel is administered three times every four weeks.

561. The use of any one of embodiments 549 to 560, wherein nab-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles.

562. The use according to any one of embodiments 552 to 561 wherein etoposide is administered every three weeks on days 1 to 3.

563. The use according to any one of embodiments 552 to 562, wherein etoposide is administered on days 1 to 3 of one or more dosing cycles.

564. The use according to any one of embodiments 543 to 563, wherein the one or more chemotherapeutic agents are administered before the PD-1 axis binding antagonist and/or anti-TIGIT antagonist antibody.

565. The use according to any one of embodiments 543 to 564, wherein the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist and/or anti-TIGIT antagonist antibody.

566. The use according to any one of embodiments 543 to 565, wherein the one or more chemotherapeutic agents are administered intravenously or orally.

567. The use of any one of embodiments 65, 310, and 311, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 25mg/kg every three weeks.

568. The use of embodiment 312 or 567, wherein the VEGF antagonist is administered at a dose of about 10mg/kg to about 20mg/kg every three weeks.

569. The use of embodiment 318 or 568, wherein the VEGF antagonist is administered at a dose of about 15mg/kg every three weeks.

570. The use of any one of embodiments 65, 310 to 312, 318 to 320, and 567 to 569, wherein the VEGF antagonist is an anti-VEGF antibody.

571. The use of embodiment 570, wherein the anti-VEGF antibody comprises a VH domain and a VL domain of bevacizumab.

572. The use of embodiment 570 or 571, wherein the anti-VEGF antibody is bevacizumab.

573. The use of any one of embodiments 65, 310 to 312, and 318 to 320, wherein the anti-TIGIT antagonist antibody is tirayleigh itumumab, the PD-1 axis binding antagonist is atuzumab, and the VEGF antagonist is bevacizumab.

574. The use according to any one of embodiments 65, 310-312, 318-320, and 567-573, wherein the use comprises administering a VEGF antagonist to the subject on day 1 of one or more dosing cycles.

575. The use of any one of embodiments 318-320, wherein the method comprises administering a VEGF antagonist to the subject on day 15 of one or more dosing cycles.

576. The use of any one of embodiments 65, 310 to 312, 318 to 320, and 567 to 575, wherein the VEGF antagonist is administered intravenously.

577. The use of embodiment 576, wherein the VEGF antagonist is administered to the subject by intravenous infusion over 90 ± 15 minutes.

578. The use of any one of embodiments 65, 310-312, 318-320, and 567-577, wherein the use comprises administering a PD-1 axis binding antagonist to a subject prior to a VEGF antagonist, and the VEGF antagonist precedes an anti-TIGIT antagonist antibody.

579. The use 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 use of embodiment 579, wherein 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.

581. The use of any one of claims 113, 128, 129 to 131, 175 to 182, 210 to 214, 221, 256, 257, 270, 289, 290, 293, 294, 297, 298, 333, 362 to 365, 385, 386, 389, 393, 419, and 422, wherein before administration the tiryleigh ewolizumab and the atezumab are combined in an IV infusion bag.

582. The use according to any one of embodiments 47 to 581, wherein the subject is a human.

583. The use of any one of embodiments 47-582, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

584. The use of any one of embodiments 47-582, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the illustration and example should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Sequence listing

<110> Gene Tak Ltd

Hofmero GmbH

<120> method of treating cancer with 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 3.5 edition

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<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<400> 1

Ser Asn Ser Ala Ala Trp Asn

1 5

<210> 2

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<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> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis Structure

<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> Synthesis Structure

<400> 4

Lys Ser Ser Gln Thr Val Leu Tyr Ser Ser Asn Asn Lys Lys Tyr Leu

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Ala

<210> 5

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<400> 5

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 6

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis Structure

<400> 6

Gln Gln Tyr Tyr Ser Thr Pro Phe Thr

1 5

<210> 7

<211> 23

<212> PRT

<213> Artificial sequence

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<223> Synthesis of a Structure

<400> 7

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

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Glu Arg Ala Thr Ile Asn Cys

20

<210> 8

<211> 15

<212> PRT

<213> Artificial sequence

<220>

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<400> 8

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile Tyr

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<210> 9

<211> 32

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<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>

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<400> 10

Phe Gly Pro Gly Thr Lys Val Glu Ile Lys

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<223> Synthesis of a Structure

<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

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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>

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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> Synthesis of a Structure

<400> 13

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> Synthesis of a Structure

<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> Synthesis of a Structure

<400> 15

Glu Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

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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> Synthesis of a Structure

<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> Synthesis of a Structure

<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 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> Synthesis Structure

<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 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> 19

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<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

Lys

<210> 20

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis Structure

<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> Synthesis of a Structure

<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> Synthesis Structure

<400> 22

Arg His Trp Pro Gly Gly Phe Asp Tyr

1 5

<210> 23

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<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> Synthesis of a Structure

<400> 24

Ser Ala Ser Phe Leu Tyr Ser

1 5

<210> 25

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<400> 25

Gln Gln Tyr Leu Tyr His Pro Ala Thr

1 5

<210> 26

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<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> Synthesis Structure

<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 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

100 105

<210> 28

<211> 447

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis of a Structure

<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 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 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 Lys 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> Synthesis of a Structure

<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> Intelligent (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 Cys 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 Gln 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> Intelligent (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> Intelligent (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 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> Intelligent (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 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> Intelligent (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 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 Gln 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

195 200 205

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215 220

Claims (503)

1. A method of treating a subject having cancer, the method 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 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

2. A method of treating a subject having cancer, the method 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 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks.

3. A method of treating a subject having cancer, the method 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 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks.

4. The method of claim 2 or 3, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

5. The method of any one of claims 1 to 4, wherein the anti-TIGIT antagonist antibody is an IgG class antibody, particularly an IgG1 subclass antibody.

6. The method of any one of claims 1 to 5, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

(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 KTYYRRFKWYSDYYAVSVKG (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 of any one of claims 1-6, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region Framework Regions (FRs):

(a) FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLLGERANC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (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 FR:

(a) FR-H1 comprising X ₁ Amino acid sequence of VQLQQSGPGLVKPsQTLSLTCAISCGSVS (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 of any one of claims 1 to 7, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain comprising SEQ ID NO:17 or 18, and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

9. The method of any one of claims 1-8, wherein the anti-TIGIT antagonist antibody is teneuizumab.

10. The method of any one of claims 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 of any one of claims 1 to 10, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody or an anti-PD-1 antagonist antibody.

12. The method of any one of claims 1 to 11, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

13. The method of claim 12, wherein the anti-PD-L1 antagonist antibody is atuzumab, MDX-1105, devaluzumab, avizumab, SHR-1316, CS1001, enwaruzumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-a167, APL-502, chikulizumab, lodalizumab, 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 of any one of claims 1 to 13, wherein the PD-1 axis binding antagonist is atelizumab.

15. The method of any one of claims 1 to 11, wherein the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody.

16. The method of claim 15, wherein the anti-PD-1 antagonist antibody is nivolumab, palboclizumab, MEDI-0680, sibatuzumab, cimeprimab, BGB-108, palonolizumab, carpriclizumab, sillimlizumab, tirizumab, terilizumab, dolastalizumab, refelimab, saralalizumab, deaprizumab, CS1003, HLX10, SCT-I10A, serpalizumab, batilizumab, geminlizumab, BI 754091, cetirizumab, YBL-006, BAT1306, HX008, brilizumab, AMG 404, CX-188, JTX-4014, 609A, sym021, LZM009, F, SG001, AM0001, ENUM 244C8, ENUM 1110D 4, STI-103, or hAb21.

17. The method of any one of claims 2 to 16, wherein the method comprises 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, wherein the non-platinum chemotherapeutic agent is a topoisomerase II inhibitor.

19. The method according to claim 18, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid or HU-331, in particular etoposide.

20. The method of claim 18 or 19, wherein the topoisomerase II inhibitor is at 100mg/m ² The dosage of (a).

21. The method of any one of claims 17 to 20, wherein the platinum chemotherapeutic agent is carboplatin or cisplatin, in particular carboplatin.

22. The method of any one of claims 17 to 21, wherein the platinum-based chemotherapeutic agent is administered at a dose sufficient to achieve AUC =5mg/ml/min on the day of administration.

23. The method of any one of claims 1-22, wherein the method comprises a dosing regimen comprising an induction phase and a maintenance phase.

24. The method of claim 23, wherein the induction period comprises four initial dosing cycles, and wherein 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.

25. The method of claim 23 or 24, wherein the maintenance period does not include administration of the platinum-based chemotherapeutic agent and/or a non-platinum-based chemotherapeutic agent.

26. The method of any one of claims 1 to 25, wherein the treatment extends Progression Free Survival (PFS) of the subject as compared to treatment without the anti-TIGIT antagonist antibody.

27. The method of any one of claims 1 to 26, wherein the treatment extends overall survival of the subject as compared to treatment without the anti-TIGIT antagonist antibody.

28. The method of any one of claims 1 to 27, wherein the cancer is lung cancer.

29. The method of claim 28, wherein the lung cancer is Small Cell Lung Cancer (SCLC), in particular extensive-stage SCLC (ES-SCLC).

30. 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).

31. The method of claim 28, wherein the lung cancer is locally advanced unresectable NSCLC or metastatic non-squamous NSCLC.

32. The method of claim 28, wherein the lung cancer is resectable lung cancer.

33. The method of any one of claims 1 to 27, wherein the cancer is cervical cancer.

34. The method of any one of claims 1 to 27, wherein the cancer is early triple negative breast cancer (eTNBC).

35. The method of any one of claims 1 to 27, wherein the cancer is a head and neck cancer.

36. The method of any one of claims 1 to 27, wherein the cancer is liver cancer, in particular hepatocellular carcinoma (HCC).

37. The method of any one of claims 1 to 27, wherein the cancer is bladder cancer.

38. The method of claim 37, wherein the cancer is Urothelial Cancer (UC), in particular metastatic urothelial cancer (mUC).

39. The method of any one of claims 1 to 27, wherein the cancer is pancreatic cancer, in particular Pancreatic Ductal Adenocarcinoma (PDAC).

40. The method according to any one of claims 1 to 27, 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 to 40.

42. The kit of claim 41, wherein the kit further comprises 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, wherein the method is according to any one of claims 1 to 40.

44. Use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for treating a subject having cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is a method of any one of claims 1-40.

45. The use of claim 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

46. The use of claim 44, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

47. A method of treating a subject having cancer, the method 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 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks.

48. A method of treating a subject having cancer, the method 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 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks.

49. The method of claim 47 or 48, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

50. The method of claim 49, wherein the method comprises administering to the subject a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

51. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: a dose of about 500mg to about 700mg of an anti-TIGIT antagonist antibody every three weeks, a dose of about 900mg to about 1500mg of a PD-1 axis binding antagonist every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks.

52. The method of claim 50 or 51, wherein the method comprises 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 period does not include administration of the platinum-based chemotherapeutic agent.

55. The method of any one of claims 52-54, wherein the maintenance period does not include administration of the non-platinum chemotherapeutic agent.

56. The method of claim 55, wherein the maintenance period comprises one or more of the following for a dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks.

57. A method of treating a subject having cancer, the method 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 500mg to about 700mg every three weeks and an anti-PD-1 antagonist antibody at a dose of about 100mg to about 300mg every three weeks, wherein the anti-PD-1 antagonist antibody is palbociclumab.

58. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of ibritumumab tiuxetan and palboceprizumab, wherein the palbociclizumab is administered at a dose of between about 300mg to about 500mg every six weeks.

59. A method for treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, and at about 10mg/m ² To about 10000mg/m ² The dosage in between is twice daily for 2 weeks/1 week off for three weeks of the oral antimetabolite.

60. A method of treating a subject having cancer, the method 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 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900mg to about 1500mg every three weeks, gemcitabine, and nab-paclitaxel.

61. The method of claim 49, wherein the one or more chemotherapeutic agents are gemcitabine and nab-paclitaxel.

62. A method for treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, and a VEGF antagonist at a dose between about 1mg/kg to about 35mg/kg every three weeks.

63. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction period comprises one or more of the following cycles of administration: an anti-TIGIT antagonist antibody at a dose of about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is provided with

(b) The maintenance period includes one or more of the following additional dosing cycles: the anti-TIGIT antagonist antibody every three weeks, the PD-1 axis binding antagonist every three weeks, and the non-platinum chemotherapeutic agent every three weeks, and wherein the maintenance period does not include administration of the platinum chemotherapeutic agent.

64. A method of treating a subject having cancer, the method comprising administering to the subject a dosing regimen comprising an induction phase and a maintenance phase, wherein:

(a) The induction period comprises one or more of the following cycles of administration: an anti-TIGIT antagonist antibody at a dose of about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose of about 900mg to about 1500mg every three weeks, a platinum chemotherapeutic agent every three weeks, and a non-platinum chemotherapeutic agent every three weeks; and is

(b) The maintenance period comprises one or more additional cycles of administration of: an anti-TIGIT antagonist antibody at a dose of about 700mg to about 1000mg every four weeks and a PD-1 axis binding antagonist at a dose of about 1400mg to 2000mg every four weeks, wherein the maintenance period does not include administration of the platinum-based chemotherapeutic agent or a non-platinum-based chemotherapeutic agent.

65. The method of any one of claims 53-56, 63, and 64, wherein the induction period comprises four to six dosing cycles.

66. The method of any one of claims 50-56 and 63-65, wherein

(a) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is paclitaxel; or

(c) The platinum chemotherapeutic agent is carboplatin or cisplatin, and the non-platinum chemotherapeutic agent is etoposide.

67. The method of any one of claims 47-66, wherein the cancer is a solid tumor.

68. The method of any one of claims 47-67, wherein the cancer is locally advanced or metastatic.

69. The method of any one of claims 47-68, wherein the cancer is lung cancer, pancreatic cancer, cervical cancer, breast cancer, head and neck cancer, liver cancer, bladder cancer, esophageal cancer, gastric cancer, colorectal cancer, kidney cancer, renal cancer, melanoma, or ovarian cancer.

70. The method of claim 69, wherein the cancer is lung cancer.

71. The method of claim 70, wherein the lung cancer is NSCLC, particularly locally advanced unresectable NSCLC.

72. The method of claim 71, wherein the NSCLC is stage IIIB NSCLC.

73. The method of any one of claims 70-72, wherein the lung cancer is recurrent or metastatic NSCLC.

74. The method of claim 73, wherein the NSCLC is stage IV NSCLC.

75. The method of claim 74, wherein the subject has not been previously treated for stage IV NSCLC.

76. The method of claim 70, wherein the lung cancer is Small Cell Lung Cancer (SCLC).

77. 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 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 for one or more dosing cycles, wherein the treatment prolongs Progression Free Survival (PFS) of the subject 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.

78. A method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of effective amounts 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 population of subjects of about 8.2 months to about 9.2 months.

79. The method of claim 77 or 78, wherein the treatment extends Overall Survival (OS) of the subject or population of subjects 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.

80. The method of any one of claims 77-79, wherein the treatment extends PFS of the subject or population of subjects by at least about 2.4 months 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.

81. The method of claim 80, wherein the treatment extends PFS of the subject or population of subjects by at least about 3 months to about 4 months 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.

82. 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 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 for one or more dosing cycles, wherein the treatment prolongs OS of the subject 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.

83. A method of treating a population of subjects having lung cancer, the method comprising administering to the population of subjects a dosing regimen comprising one or more dosing cycles of effective amounts 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 population of subjects from about 15.3 months to about 17.6 months.

84. The method of any one of claims 79 to 83, wherein the treatment extends OS of the subject or population of subjects by at least about 3.3 months 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.

85. The method of any one of claims 79 to 83, wherein the treatment extends OS of the subject or population of subjects by at least about 3 months to about 5.3 months 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.

86. The method of any one of claims 77-85, wherein the anti-TIGIT antagonist antibody, PD-1 axis binding antagonist, platinum-based chemotherapeutic agent, and 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 four initial dosing cycles.

88. The method of claim 87, wherein the platinum-based chemotherapeutic agent and the topoisomerase II inhibitor are omitted in each of the one or more additional dosing cycles.

89. The method of any one of claims 77-88, wherein the platinum-based chemotherapeutic agent is carboplatin and the topoisomerase II inhibitor is etoposide.

90. The method of any one of claims 77-89, wherein the lung cancer is Small Cell Lung Cancer (SCLC).

91. The method of claim 90, wherein the SCLC is extensive-term SCLC (ES-SCLC).

92. The method of claim 91, wherein the subject or subjects are treatment naive to ES-SCLC.

93. The method of any one of claims 77-92, wherein the subject or subjects are absent or have no history of brain metastases.

94. The method of any one of claims 77-93, wherein the lung cancer is not selected for PD-L1 expression.

95. The method of any one of claims 77-93, 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 PD-L1 expression level.

97. The method of any one of claims 77-96, wherein the lung cancer is metastatic.

98. The method of claim 97, wherein the lung cancer has metastasized to the brain, liver, lymph nodes, and/or adrenal glands.

99. The method of claim 97 or 98, wherein the lung cancer has not metastasized to the brain.

100. The method of any one of claims 77-99, wherein the treatment results in Complete Remission (CR) or Partial Remission (PR).

101. For treating a subject or population of subjects suffering from SCLCA method comprising administering to the subject or population of subjects one or more of the following for a 21 day dosing cycle: an anti-TIGIT antagonist antibody at a dose of about 500mg to about 700mg on day 1 of each dosing cycle, an attrituximab at a dose of about 900mg to about 1500mg on day 1 of each dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each dosing cycle, and 100mg/m on days 1, 2, and 3 of each dosing cycle ² A dose of etoposide, wherein the treatment prolongs PFS and/or OS of the subject or population of subjects compared to treatment with attritumab, carboplatin, and etoposide without the anti-TIGIT antagonist antibody.

102. A method for treating a subject or population of subjects suffering from ES-SCLC, the method comprising administering to the subject or population of subjects four initial dosing cycles followed by one or more additional dosing cycles, wherein:

(a) The four initial dosing cycles comprise: administering ibritumumab tiuxetan at a dose of about 600mg on day 1 of each initial dosing cycle, alemtuzumab at a dose of about 1200mg on day 1 of each initial dosing cycle, carboplatin at a dose sufficient to achieve AUC =5mg/ml/min on day 1 of each initial dosing cycle, and 100mg/m on days 1, 2, and 3 of each initial dosing cycle ² Administering etoposide at a dosage of; and is

(b) The one or more additional dosing cycles comprise: administering tenecteuzumab at a dose of about 600mg on day 1 of each additional dosing cycle, and administering atelizumab at a dose of about 1200mg on day 1 of each additional dosing cycle, wherein the four initial dosing cycles and the one or more additional dosing cycles are each 21-day dosing cycles, and wherein the treatment prolongs the PFS and/or OS of the subject or population of subjects compared to a treatment with atelizumab, carboplatin, and etoposide without tenecteuzumab.

103. 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 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.

104. The method of claim 103, wherein the lung cancer has not been evaluated for PD-L1 expression.

105. The method of claim 103 or 104, wherein the subject or subjects have not been determined to have a PD-L1 positive tumor cell fraction of greater than or equal to 50%.

106. The method of claim 105, wherein the subject or subjects have been determined to have a PD-L1 positive tumor cell fraction of less than 50%.

107. The method of claim 105 or 106, wherein the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263 or 22C3.

108. The method of any one of claims 103-107, wherein the subject or subjects do not have Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations.

109. The method of any one of claims 103-108, wherein the subject or subjects have not received prior systemic therapy for the lung cancer.

110. The method of any one of claims 103-109, wherein the lung cancer is locally advanced lung cancer.

111. The method of any one of claims 103 to 110, wherein the lung cancer is NSCLC, in particular locally advanced unresectable NSCLC or metastatic non-squamous NSCLC.

112. The method of claim 111, wherein the non-squamous NSCLC is stage IV non-squamous NSCLC.

113. The method of any one of claims 103-112, wherein the dosing regimen comprises an induction period comprising four 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 are administered on day 1 of each dosing cycle of the induction period.

114. The method of claim 113, wherein the dosing regimen comprises a maintenance period following the induction period, wherein the maintenance period comprises 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 administered on day 1 of each dosing cycle of the maintenance period.

115. The method of claim 114, wherein the one or more dosing cycles of the maintenance period do not include administration of the platinum-based chemotherapeutic agent.

116. The method of any one of claims 103-115, wherein the platinum-based chemotherapeutic agent is carboplatin or cisplatin and the non-platinum-based chemotherapeutic agent is pemetrexed.

117. A method of treating a subject or population of subjects having advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects a dosing regimen comprising four 21-day dosing cycles of tiregumab, atelizumab, carboplatin, or cisplatin, and pemetrexed, wherein each dosing cycle in the four 21-day dosing cyclesDay 1 of the cycle, the tenecteukumab being administered at a dose of about 600mg every three weeks, the atelizumab being administered at a dose of about 1200mg every three weeks, the carboplatin being administered at a dose sufficient to achieve AUC =5mg/ml/min every three weeks or the cisplatin being administered at 75mg/m every three weeks ² And the pemetrexed is administered at a dose of about 500mg/m every three weeks ² The dosage of (a).

118. A method of treating a subject or population of subjects having advanced non-squamous NSCLC, the method comprising administering to the subject or population of subjects:

(i) The following of the four induction phase dosing cycles: a dose of about 600mg tirleiuzumab every three weeks, a dose of about 1200mg altuzumab every three weeks, a dose of carboplatin sufficient to achieve an AUC =5mg/ml/min every three weeks, and about 500mg/m every three weeks ² A dose of pemetrexed; and

(ii) One or more of the following maintenance phase dosing cycles: about 600mg dose of tiryleauuzumab every three weeks, about 1200mg dose of atelizumab every three weeks, and about 500mg/m every three weeks ² A dose of pemetrexed, wherein one or more 21-day periods in 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 non-squamous NSCLC.

119. The method of any one of claims 103-118, wherein said treatment extends PFS in said subject or population of subjects by at least about 3.5 months or about 4.7 months.

120. The method of any one of claims 103-118, wherein said treatment results in a median PFS of the population of subjects of about 12.5 months to about 14.7 months.

121. The method of any one of claims 103-118, wherein the treatment extends OS of the subject or population of subjects by at least about 5.5 months or about 8.0 months.

122. The method of any one of claims 103-118, wherein the treatment results in a median OS for the population of subjects of about 27.5 months to about 32.0 months.

123. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

124. A method for treating a subject having lung cancer, the method 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 the dosing cycles comprises administering to the subject: the anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks and the PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks as neoadjuvant therapy.

125. The method of claim 124, wherein at least one of the dosing cycles comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of between about 500mg to about 700mg every three weeks and the PD-1 axis binding antagonist at a dose of between about 900mg to about 1500mg every three weeks as adjunctive therapy.

126. The method of claim 124 or 125, wherein the lung cancer is resectable lung cancer.

127. The method of any one of claims 123-126, wherein the lung cancer is early stage lung cancer.

128. The method of any one of claims 123-127, wherein the lung cancer is stage II, stage IIIA, or stage IIIB lung cancer.

129. The method of any one of claims 123-128, wherein the subject is eligible for an R0 resection for healing purposes.

130. The method of any one of claims 123-129, wherein the subject has not received prior therapy for lung cancer.

131. The method of claim 130, wherein the prior therapy is immunotherapy, chemotherapy, or radiation therapy.

132. The method of any one of claims 123-131, wherein the subject is eligible to receive a platinum-based chemotherapy regimen.

133. The method of any one of claims 123-132, wherein the first dosing cycle is initiated prior to surgery.

134. The method of claim 133, wherein at least 1, 2, 3, or 4 dosing cycles are completed prior to the surgery.

135. The method of claim 133 or 134, wherein 4 dosing cycles are completed prior to the surgery.

136. The method of any one of claims 123-135, wherein at least one dosing cycle is initiated after surgery.

137. The method of claim 136, wherein 16 dosing cycles are completed after the surgery.

138. The method of any one of claims 133-137 wherein the procedure is a segmental resection, a lobectomy, a bilobalectomy, or a pneumonectomy.

139. The method of any one of claims 123-138, wherein the method further comprises radiation therapy.

140. The method of claim 139, wherein the radiation therapy is post-operative radiation therapy.

141. The method of any one of claims 123-140, wherein the method further comprises administering one or more chemotherapeutic agents.

142. The method of claim 141, wherein the one or more chemotherapeutic agents are administered after surgery.

143. The method of claim 142, wherein the one or more chemotherapeutic agents are administered in 4 dosing cycles after the surgery.

144. The method of any one of claims 141-143, wherein the one or more chemotherapeutic agents are a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

145. The method of claim 144, wherein:

(a) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is pemetrexed;

(b) The platinum-based chemotherapeutic agent is carboplatin and the non-platinum-based chemotherapeutic agent is gemcitabine;

(c) The platinum chemotherapeutic agent is carboplatin and the non-platinum chemotherapeutic agent is paclitaxel;

(d) The platinum chemotherapeutic agent is cisplatin, and the non-platinum chemotherapeutic agent is pemetrexed; or

(e) The platinum chemotherapeutic agent is cisplatin and the non-platinum chemotherapeutic agent is gemcitabine.

146. The method of any one of claims 123-145, wherein the treatment results in an increase in a Major Pathological Response (MPR) rate as compared to a reference MPR rate.

147. The method of claim 146, wherein the reference MPR rate is an MPR rate for a population of subjects having received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

148. The method of any one of claims 123-147, wherein the treatment results in complete remission of pathology (pCR) and/or an increase in pCR rate as compared to a reference pCR rate.

149. The method of claim 148, wherein the reference pCR rate is the pCR rate for a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

150. The method of any one of claims 123-149, wherein the treatment results in an increase in event-free survival (EFS) as compared to a reference EFS time.

151. The method of claim 150, wherein the reference EFS time is an EFS time for a population of subjects who have received a treatment comprising:

(a) PD-1 axis binding antagonist without the use of anti-TIGIT antagonist antibody; and/or

(b) Cisplatin and docetaxel, or cisplatin, docetaxel and bevacizumab.

152. A method for treating a subject having resectable lung cancer, the method comprising administering to the subject one or more dosing cycles of: a dose of about 600mg of tirleiuzumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and:

(a)

(i) Carboplatin at a dose targeted to achieve an AUC of 5mg/mL/min or an AUC of 6mg/mL/min every three weeks; or

(ii) About 75mg/m every three weeks ² A dose of cisplatin; or

(b)

(i) About 500mg/m every three weeks ² A dose of pemetrexed, or about 1000mg/m on days 1 and 8 of each dosing cycle ² Or about 1250mg/m ² A dose of gemcitabine; or

(ii) About 175mg/m every three weeks ² Or about 200mg/m ² The dose of paclitaxel.

153. A method for treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of tirayleigh immuzumab and atlizumab, wherein:

(I) At least one of the dosing cycles is neoadjuvant therapy and comprises administering to the subject:

(a) A dose of about 1200mg of ibritumomab tiuxetan every three weeks;

(b) About 1200mg dose of atuzumab as a neoadjuvant therapy every three weeks; and

(c)

(i) The target every three weeks is a dose of carboplatin to achieve an AUC of 5mg/mL/min, and about 1000mg/m on days 1 and 8 of each dosing cycle ² A dose of gemcitabine;

(ii) The target every three weeks was carboplatin at a dose to achieve an AUC of 6mg/mL/min, and about 175mg/m every three weeks ² Or about 200mg/m ² A dose of paclitaxel; or

(iii) About 75mg/m every three weeks ² A dose of cisplatin, and about 1250mg/m on days 1 and 8 of each dosing cycle ² A dose of gemcitabine; and

(II) at least one of the dosing cycles comprises administering to the subject a dose of between about 500mg to about 700mg every three weeks and a dose of between about 900mg to about 1500mg every three weeks of atuzumab as adjunctive therapy.

154. The method of any one of claims 123153, wherein a detectable level of protein expression of PD-L1 as determined by an IHC assay comprising staining with anti-PD-L1 antibody SP263 has been determined.

155. The method of claim 154, wherein the detectable protein expression level of PD-L1 is a PD-L1 positive tumor cell fraction greater than or equal to 50%.

156. The method of any one of claims 70, 103-110, and 123-155, wherein the lung cancer is NSCLC.

157. The method of claim 156, wherein the NSCLC is squamous NSCLC.

158. The method of claim 156, wherein the NSCLC is non-squamous NSCLC.

159. The method of claim 69, wherein the cancer is cervical cancer.

160. A method for treating a subject or population of subjects having cervical cancer with a detectable PD-L1 expression level, 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 between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

161. A method of selecting a therapy for a subject having cervical cancer, the method comprising:

(a) Detecting by an IHC assay the protein expression level of PD-L1 on tumor cells of a tumor sample from the subject using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for the subject having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: an anti-TIGIT antagonist antibody administered at a dose between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist administered at a dose between about 900mg to about 1500mg every three weeks based on PD-L1 expression on tumor cells that has been detected.

162. The method of claim 160 or 161, wherein the cervical cancer is squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma.

163. The method of any one of claims 160-162, wherein the cervical cancer is stage IVB, metastatic, recurrent or persistent.

164. The method of any one of claims 160-163, wherein the cervical cancer is metastatic and/or relapsed PD-L1-positive cervical cancer.

165. The method of any one of claims 160-164, wherein the subject or subjects have received at least one prior line of therapy.

166. The method of any one of claims 160-165, wherein the subject or subjects have received two prior normals of therapy.

167. The method of any one of claims 160-166, wherein the subject or subjects have received more than two prior normals of therapy.

168. The method of any one of claims 160-164, wherein the subject or subjects did not receive a previous therapy.

169. The method of any one of claims 165-168, wherein the prior therapy is chemotherapy, surgery, and/or radiation therapy.

170. The method of any one of claims 160 and 162-169, wherein the treatment results in a clinical response.

171. The method of claim 170, wherein the clinical response is an increase in Objective Remission Rate (ORR) from the population of subjects as compared to a reference ORR.

172. The method of claim 171, wherein the reference ORR is the median ORR of a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

173. The method of claim 170, wherein the reference ORR is at least about 14.6% to about 26%.

174. The method of claim 170, wherein the clinical response is CR or PR.

175. The method of any one of claims 170 to 174, wherein the clinical response is an increase in progression-free survival (PFS) of the subject as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject as compared to a reference OS time.

176. The method of claim 175, wherein:

(a) The reference PFS time is a median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference DOR time is a median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not using an anti-TIGIT antagonist antibody.

177. A method for treating a subject having cervical cancer with a detectable PD-L1 expression level, the method comprising administering to the subject one or more dosing cycles of: a dose of about 600mg of tenecteuzumab every three weeks, and a dose of about 1200mg of alemtuzumab every three weeks.

178. The method of any one of claims 160-177, wherein the subject is identified as a subject likely to benefit from treatment based on PD-L1 expression on tumor cells that have been detected.

179. The method of any one of claims 160-178, wherein the PD-L1 expression level is detected using anti-PD-L1 antibody SP 263.

180. The method of any one of claims 160 to 179, wherein the detectable PD-L1 expression level is greater than or equal to 5% tumor-associated immune cells (TICs) in the sample from the subject.

181. The method of any one of claims 160-178, wherein the PD-L1 expression level is detected using anti-PD-L1 antibody 22C 3.

182. The method of any one of claims 160-179, wherein the detectable PD-L1 expression level is a Composite Positive Score (CPS) of greater than or equal to 1 in a sample from the subject.

183. The method of claim 69, wherein the cancer is breast cancer.

184. A method of treating a subject or population of subjects having breast cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: a dose of about 840mg of tenecteuzumab every four weeks, a dose of about 1680mg of alemtuzumab every four weeks, and a dosage of about 100mg/m ² Nab-paclitaxel at doses of 3 weeks/1 week off.

185. The method of claim 183 or 184, wherein the breast cancer is Triple Negative Breast Cancer (TNBC).

186. The method of claim 185, wherein the TNBC is non-resectable locally advanced or metastatic TNBC.

187. The method of any one of claims 183-186, wherein the subject or subjects did not receive prior systemic therapy for metastatic breast cancer.

188. The method of any one of claims 183 to 187, wherein the treatment results in an ORR of at least about 53% to at least about 67.5% in the population of subjects.

189. The method of any one of claims 183-188, wherein the treatment results in a median OS for the population of subjects of about 25.0 months.

190. A method of treating a subject having early triple negative breast cancer (eTNBC), the method 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 300mg to about 600mg every two weeks and a PD-1 axis binding antagonist at a dose of about 600mg to about 1200mg every two weeks.

191. The method of claim 190, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

192. The method of claim 191, wherein the one or more chemotherapeutic agents is a platinum-based chemotherapeutic agent, a taxane, a topoisomerase II inhibitor, or an alkylating agent.

193. The method of claim 190, wherein the method further comprises administering (a) the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and a taxane or a taxane and a platinum-based chemotherapeutic agent for one or more dosing cycles; and (b) one or more cycles of administration of the anti-TIGIT antagonist antibody, the 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).

194. The method of claim 192 or 193, wherein said alkylating agent is cyclophosphamide.

195. The method of claim 194, wherein said cyclophosphamide is at about 600mg/m ² The dosage of (a).

196. A method according to any one of claims 190 to 192, 194 and 195, wherein the method comprises further administering G-CSF or GM-CSF to the subject.

197. The method of claim 193 or 196, wherein the G-CSF is pegylated filgrastim or filgrastim.

198. The method of claim 197, wherein the G-CSF is pegylated filgrastim.

199. The method of claim 198, wherein the pegylated filgrastim is administered at a dose of about 6 mg.

200. The method of any one of claims 191, 192, and 194-199, wherein the method further comprises administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents and/or G-CSF or GM-CSF.

201. The method of any one of claims 191, 192, and 194-200, wherein the one or more chemotherapeutic agents and/or G-CSF or GM-CSF are each administered once a week, once every two weeks, or once every three weeks.

202. The method of any one of claims 192-201, wherein the platinum-based chemotherapeutic agent is administered every three weeks, the taxane is administered every week, the topoisomerase II inhibitor is administered every two weeks, the alkylating agent is administered every two weeks, and the G-CSF or GM-CSF is administered every two weeks.

203. The method of any one of claims 192-202, wherein the taxane or the taxane and the platinum-based chemotherapeutic agent are administered in the first 12 weeks of the dosing regimen.

204. The method of any one of claims 192-203, wherein the topoisomerase II inhibitor, the alkylating agent, and the G-CSF or GM-CSF are administered between weeks 13 and 19 of the dosing regimen.

205. The method of any of claims 190-204, wherein the dosing regimen has a total length of 19 weeks.

206. The method of any one of claims 190-205, wherein the method is neoadjuvant therapy.

207. The method of any of claims 190-206, wherein the dosing regimen is followed by surgery.

208. The method of claim 207, wherein the surgery is performed between two and six weeks after the last dose of the dosing regimen.

209. The method of claim 207 or 208, wherein the procedure comprises a mastectomy.

210. The method of any one of claims 207-209, wherein the surgery comprises axillary lymph node surgery.

211. The method according to any one of claims 192-210, wherein the topoisomerase II inhibitor is doxorubicin.

212. The method of any one of claims 192-210, wherein the taxane is nab-paclitaxel, the platinum-based chemotherapeutic agent is carboplatin, and the topoisomerase II inhibitor is doxorubicin.

213. The method according to claim 211 or 212, wherein doxorubicin is at about 60mg/m ² The dosage of (a).

214. A method of treating a subject having eTNBC, the method comprising administering to the subject a dosing regimen comprising: a dose of about 420mg tirayleigh-uzumab every two weeks, a dose of about 840mg atelizumab every two weeks, and:

(a)

(i) About 125mg/m weekly during the first 12 weeks of the dosing regimen ² The dose of nab-paclitaxel and the dose of carboplatin targeted to achieve an AUC of 5mg/mL/min every three weeks; and

(ii) About 60mg/m biweekly between weeks 13 and 19 of the dosing regimen ² Dose of doxorubicin, about 600mg/m biweekly ² Of dosageCyclophosphamide and biweekly G-CSF or GM-CSF; or

(b)

(i) About 125mg/m weekly in the first 12 weeks of the dosing regimen ² A dosage of nab-paclitaxel; and

(ii) About 60mg/m biweekly between weeks 13 and 19 of the dosing regimen ² Dose of doxorubicin, about 600mg/m biweekly ² A dose of cyclophosphamide and biweekly G-CSF or GM-CSF;

wherein the method further comprises surgery between two and six weeks after the last dose of the dosing regimen.

215. The method of any one of claims 184-214, wherein a detectable protein expression level of PD-L1 in a tumor sample from the subject determined by an IHC assay comprising staining with anti-PD-L1 antibody SP142 has been determined.

216. The method of claim 215, wherein the proportion of a tumor area in the tumor sample occupied by PD-L1-expressing tumor infiltrating Immune Cells (IC) is greater than or equal to 1%.

217. The method of any one of claims 190-216, wherein the eTNBC is expressed as T2-4d TNBC.

218. The method of any one of claims 190-217, wherein the eTNBC is expressed as cT2-cT4, cN0-cN3, and cM0 TNBC.

219. The method of any one of claims 190-218, wherein the subject has not been previously treated for eTNBC.

220. The method of any one of claims 190-219, wherein the treatment results in complete remission of pathology (pCR).

221. The method of any of claims 190-220, wherein the treatment results in an increase in Overall Survival (OS) or event-free survival (EFS).

222. The method of claim 69, wherein the cancer is a head and neck cancer.

223. The method of claim 222, wherein the head and neck cancer is squamous cell carcinoma of the head and neck (SCCHN).

224. A method for treating a subject or population of subjects having a detectable SCCHN having a PD-L1 expression level, 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 between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

225. A method of selecting a therapy for a subject or population of subjects having SCCHN, the method comprising:

(a) Detecting the protein expression level of PD-L1 in a tumor sample from the subject or population of subjects by an IHC assay using an anti-PD-L1 antibody suitable for staining; and

(b) Selecting a therapy for the subject or population of subjects having a detectable PD-L1 expression level, the therapy comprising one or more cycles of administration of: based on PD-L1 expression that has been detected, a dose of PD-1 axis binding antagonist between about 900mg to about 1500mg every three weeks and an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks.

226. A method for treating a subject having SCCHN having a detectable PD-L1 expression level, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

227. The method of any one of claims 224 to 226, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

228. The method of any one of claims 223-227, wherein the SSCHN is Human Papilloma Virus (HPV) positive.

229. The method of any of claims 223-228, wherein the SSCHN is HPV negative.

230. The method of claim 228 or 229, wherein HPV status is determined by p16 IHC, in situ hybridization, or by PCR.

231. The method of any one of claims 223-230, wherein the SCCHN is a recurrent and/or metastatic SCCHN.

232. The method of any one of claims 222-231, wherein the subject or subjects did not receive a previous therapy.

233. The method of claim 232, wherein the prior therapy is a prior systemic therapy for recurrent and/or metastatic disease.

234. The method of any one of claims 222-224 and 226-233, wherein the treatment results in CR or PR.

235. The method of any one of claims 222-224 and 226-233, wherein the treatment results in an increase in the Objective Remission Rate (ORR) of the population of subjects as compared to a reference ORR.

236. The method of claim 235, wherein the reference ORR is the median ORR of a population of subjects who have received treatment comprising a PD-1 axis binding antagonist but not using an anti-TIGIT antagonist antibody.

237. The method of claim 235 or 236, wherein the reference ORR is at least about 19% to about 36%.

238. The method of any one of claims 222-224 and 226-237, wherein the treatment results in an increase in progression-free survival (PFS) of the subject or population of subjects as compared to a reference PFS time, an increase in duration of remission (DOR) of the subject or population of subjects as compared to a reference DOR time, or an increase in Overall Survival (OS) of the subject or population of subjects as compared to a reference OS time.

239. The method of claim 238, wherein:

(a) The reference PFS time is a median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference DOR time is a median DOR time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

240. The process of claim 238, wherein said reference DOR time is at least about 6.7 months to about 23.4 months.

241. The method of claim 238, wherein the reference OS time is at least about 11.6 months to about 14.9 months.

242. The method of any one of claims 224 to 241, wherein the detectable PD-L1 expression level is a detectable protein expression level of PD-L1 determined by an Immunohistochemistry (IHC) assay comprising staining with anti-PD-L1 antibody SP 263.

243. The method of claim 242, wherein the detectable protein expression level of PD-L1 is such that tumor-associated immune cells (TICs) in the tumor sample are:

(a) Greater than or equal to 5%;

(b) Greater than or equal to 5% and less than 20%; or

(c) Greater than or equal to 20%.

244. The method of any one of claims 224 to 243, wherein the subject or population of subjects is identified as a subject or population of subjects likely to benefit from treatment based on PD-L1 expression on tumor cells that have been detected.

245. The method of claim 69, wherein the cancer is liver cancer.

246. The method of claim 245, wherein the liver cancer is hepatocellular carcinoma (HCC).

247. A method of treating a subject or population of subjects having hepatocellular carcinoma (HCC), the 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 did not receive prior systemic treatment for HCC.

248. The method of claim 247, wherein the method further comprises administering a VEGF antagonist to the subject or population of subjects.

249. A method of treating a subject or population of subjects suffering from HCC, the method comprising administering to the subject or population of subjects one or more cycles of administration an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist, and a VEGF antagonist.

250. The method of claims 248 and 249, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 25mg/kg every three weeks.

251. The method of any one of claims 247 to 250, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 500mg to about 700mg every three weeks.

252. The method of any one of claims 247 to 251, wherein the PD-1 axis binding antagonist is administered at a dose of about 900mg to about 1500mg every three weeks.

253. The method of claim 248 or 249, wherein the VEGF antagonist is administered at a dose of about 1mg/kg to about 20mg/kg biweekly.

254. The method of claim 253, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 10mg/kg every two weeks.

255. The method of claim 254, wherein the VEGF antagonist is administered at a dose of about 5mg/kg, about 7.5mg/kg, or about 10mg/kg every two weeks.

256. The method of any one of claims 247 to 249 and 253 to 255, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 300mg to about 800mg every two weeks.

257. The method of any one of claims 247 to 249 and 253 to 256, wherein the PD-1 axis binding antagonist is administered at a dose of about 200mg to about 1200mg every two weeks.

258. The method of claims 247 to 249, wherein the anti-TIGIT antagonist antibody is administered at a dose of about 700mg to about 1000mg every four weeks.

259. The method of any one of claims 247 to 249 and 258, wherein the PD-1 axis binding antagonist is administered at a dose of about 1400mg to about 2000mg every four weeks.

260. The method of any one of claims 247 to 259, wherein the HCC is locally advanced or metastatic HCC.

261. The method of any of claims 247 to 260, wherein the HCC is a non-resectable HCC.

262. A method according to any one of claims 247 to 261, wherein the subject or subjects have been determined to have sufficient liver function.

263. The method of claim 262, wherein the sufficient liver function is characterized as Child-Pugh class a.

264. The method of any one of claims 247 to 263, wherein the HCC tumor sample obtained from the subject or subjects has been determined to have a detectable level of PD-L1 expression.

265. The method of any one of claims 247 to 264, wherein the method comprises administering to the subject or population of subjects at least four dosing cycles.

266. The method of claim 261, wherein the method comprises administering to the subject or population of subjects at least 16 dosing cycles.

267. A method of treating a subject or population of subjects suffering from HCC, the method comprising administering to the subject one or more cycles of administration of: a dose of about 600mg of tirleivuzumab every three weeks, a dose of about 1200mg of atuzumab every three weeks, and a dose of about 15mg/kg of bevacizumab every three weeks.

268. The method of any one of claims 249-267, wherein the subject or subjects have not received prior systemic therapy for HCC.

269. The method of any one of claims 247 to 268, wherein the treatment results in a median PFS of the population of subjects of at least about 5.6 months to at least about 6.83 months.

270. The method of claim 69, wherein the cancer is bladder cancer.

271. The method of claim 270, wherein the bladder cancer is Muscle Invasive Bladder Cancer (MIBC).

272. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject one or more dose cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks, a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, wherein the subject is not eligible for treatment with a platinum-based chemotherapeutic agent.

273. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject one or more dose cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks, wherein the treatment is perioperative treatment.

274. The method of claim 272 or 273, wherein the subject or subjects have a creatinine clearance <60 mL/min.

275. The method of any one of claims 272-274, wherein the subject or subjects have a hearing loss greater than or equal to grade 2.

276. The method of any one of claims 272-275, wherein the subject or subjects have a grade greater than or equal to 2 neuropathy.

277. The method of any one of claims 272-276, wherein the subject or subjects have declined treatment with a platinum-based chemotherapeutic agent.

278. The method of any one of claims 272 or 274-277, wherein the platinum-based chemotherapeutic agent is cisplatin.

279. The method of any one of claims 272-278, wherein the MIBC is surgically operable.

280. The method of claim 279, wherein the method further comprises surgery.

281. The method of claim 280, wherein at least one dosing cycle is initiated prior to the surgery.

282. The method of claim 280, wherein at least 1, 2, or 3 dosing cycles are completed prior to the surgery.

283. The method of any one of claims 280-282, wherein at least one dosing cycle is initiated between 4-6 weeks after the surgery.

284. The method of claim 283, wherein 1 to 17 dosing cycles are completed after the surgery.

285. The method of any one of claims 280-284, wherein the surgery is cystectomy and/or lymph node dissection.

286. The method of any one of claims 272-285, wherein the treatment results in complete remission of pathology (pCR).

287. The method of any one of claims 272 to 286, wherein the treatment results in an increase in Relapse Free Survival (RFS) of the subject or subjects as compared to a reference RFS time, an increase in Event Free Survival (EFS) of the subject or subjects as compared to a reference EFS time, or an increase in Overall Survival (OS) of the subject or subjects as compared to a reference OS time.

288. The method of claim 287, wherein:

(a) The reference RFS time is the median RFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody;

(b) The reference EFS time is the median EFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody; or

(c) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist but not with an anti-TIGIT antagonist antibody.

289. The method of any one of claims 272-288, wherein the treatment results in pathological degradation.

290. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tenecteuzumab every three weeks, and a dose of about 1200mg of atelizumab every three weeks, wherein the subject or subjects are not eligible to use cisplatin.

291. A method for treating a subject or population of subjects having MIBC, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tenecteuzumab every three weeks, and a dose of about 1200mg of atelizumab every three weeks, wherein the treatment is perioperative treatment.

292. The method of any one of claims 272 to 291, wherein the treatment results in an ORR of at least about 13.4% to at least about 15% in the population of subjects.

293. The method of any one of claims 272 to 292, wherein the treatment results in a median OS for the population of subjects of about 7.9 months to about 8.6 months.

294. The method of any one of claims 272 to 293, wherein a detectable protein expression level of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody SP 142.

295. The method of claim 294, wherein the detectable protein expression level of PD-L1 is a PD-L1-positive tumor cell fraction in which a proportion of a tumor area occupied by PD-L1-expressing tumor-infiltrating Immune Cells (ICs) is greater than or equal to 5%.

296. The method of claim 270, wherein the bladder cancer is Urothelial Cancer (UC).

297. The method of claim 296, wherein the UC is metastatic urothelial cancer (mUC).

298. A method for treating a subject or population of subjects having a uc, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg every three weeks and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg every three weeks.

299. The method of claim 298, wherein the subject or subjects have not received prior cancer immunotherapy.

300. The method of claim 298 or 299, wherein the treatment is second line treatment.

301. The method of any one of claims 298 to 300, wherein the mUC has progression during or after platinum-containing therapy.

302. The method of any one of claims 298 to 301, wherein the method further comprises 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.

303. 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).

304. The method of claim 303, wherein the ADC is (a) vildagliptin-enfratuzumab or (b) govittakang-shaxituzumab.

305. The method of claim 304 wherein (a) the vildagliptin-enfratuzumab is administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week, or (b) the govitegam-shaxituzumab is administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week.

306. A method for treating a subject or population of subjects having a uc, the method comprising administering to the subject or population of subjects one or more dosing cycles of: a dose of about 600mg of tirleivuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks.

307. A method for treating a subject or population of subjects suffering from a uc, the method comprising administering to the subject or population of subjects a first dosing regimen followed by a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a dosing cycle: a dose of about 600mg of tireyueuzumab every three weeks and a dose of about 1200mg of atuzumab every three weeks; and

(b) The second dosing regimen comprises one or more of the following for a dosing cycle: about 1200mg dose of alemtuzumab and (i) vildagliptin-enfratuzumab administered at a dose of 1.25mg/kg per week for 2 weeks/off for 1 week every three weeks, or (ii) govericin-shaxituzumab administered at a dose of 10mg/kg per week for 2 weeks/off for 1 week, wherein the second dosing regimen is administered to the subject or population of subjects after the subject or population of subjects has experienced disease progression or unacceptable toxicity during the first dosing regimen.

308. The method of any one of claims 298 to 307, wherein the treatment results in an ORR of at least about 13.4% to at least about 31% in the population of subjects.

309. The method of any one of claims 298 to 308, wherein the treatment results in a median OS for the population of subjects of about 7.9 months to about 16.3 months.

310. The method of claim 69, wherein the cancer is pancreatic cancer.

311. A method of treating a subject or subject having pancreatic cancerA method of a population of subjects, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 28 day dosing cycle: a dose of about 420mg of tenerriuzumab on days 1 and 15 of each 28-day dosing cycle, a dose of about 840mg of atelizumab on days 1 and 15 of each 28-day dosing cycle, about 1000mg/m on days 1, 8, and 15 of each 28-day dosing cycle ² Gemcitabine in a dose and about 125mg/m on days 1, 8 and 15 of each 28-day dosing cycle ² Dosage of nab-paclitaxel.

312. The method of claim 310 or 311, wherein the pancreatic cancer is Pancreatic Ductal Adenocarcinoma (PDAC).

313. The method of claim 312, wherein the PDAC is a metastatic PDAC.

314. The method of any one of claims 310-313, wherein subject or subjects have not received prior systemic therapy for metastatic PDAC.

315. The method of any one of claims 310 to 314, wherein the treatment results in an ORR of at least about 41.7% to about 46.7% in the population of subjects.

316. The method of any one of claims 310 to 315, wherein the treatment results in an increase in ORR of at least about 20% as compared to a treatment comprising gemcitabine and nab-paclitaxel without the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist.

317. The method of any one of claims 310-316, wherein the treatment results in a median PFS of the population of subjects of at least about 5.5 months to about 7 months.

318. The method of any one of claims 310 to 317, wherein the treatment results in a median OS for the population of subjects of at least about 8.5 months to about 10.6 months.

319. The method of claim 69, wherein the cancer is esophageal cancer.

320. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose of between about 500mg to about 700mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose of between about 900mg to about 1500mg on day 1 of each dosing cycle.

321. A method for treating a subject or population of subjects suffering from esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: an anti-TIGIT antagonist antibody at a dose between about 500mg to about 700mg on day 1 of each dosing cycle and a PD-1 axis binding antagonist at a dose between about 900mg to about 1500mg on day 1 of each dosing cycle, wherein the subject or subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

322. The method of claim 320, wherein the subject or subjects have been previously treated with a platinum-based chemotherapeutic agent and a non-platinum-based chemotherapeutic agent.

323. The method of claim 321 or 322, wherein the subject or subjects have experienced disease progression or unacceptable toxicity during the prior treatment.

324. The method of claim 320, wherein 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 the platinum chemotherapeutic agent is omitted from the dosing regimen after six doses.

326. The method of any one of claims 321-325, wherein the platinum-based chemotherapeutic agent is cisplatin.

327. The method of claim 326, wherein cisplatin is at about 80mg/m on day 1 of each dosing cycle ² The dosage of (a).

328. The method of any one of claims 321 to 327, wherein the non-platinum chemotherapeutic agent is an antimetabolite.

329. The method of claim 328, wherein the antimetabolite is 5-fluorouracil.

330. The method of claim 329, wherein 5-fluorouracil is at 800mg/m on days 1-5 of each 21-day cycle ² Dose administration per 24 hours.

331. The method of any one of claims 321-330, wherein the esophageal cancer is advanced or metastatic esophageal cancer.

332. The method of claim 320 or 331, wherein the subject or subjects have not previously been treated for metastatic esophageal cancer.

333. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a dosing regimen comprising one or more of the following for a 21-day dosing cycle: a dose of about 600mg of tiryleuizumab on day 1 of each dosing cycle, on each day About 1200mg dose of atelizumab on day 1 of the dosing cycle, about 80mg/m on day 1 of each dosing cycle ² Doses of cisplatin and 800mg/m on days 1 to 5 of each 21 day cycle ² 5-fluorouracil at a dose of 24 hours, wherein cisplatin is omitted from the dosing regimen after six doses.

334. A method for treating a subject or population of subjects with advanced or metastatic esophageal cancer, the method comprising administering to the subject or population of subjects a first dosing regimen and a second dosing regimen, wherein:

(a) The first dosing regimen comprises one or more of the following for a 21 day dosing cycle: about 80mg/m on day 1 of each dosing cycle ² Doses of cisplatin and 800mg/m on days 1 to 5 of each 21 day cycle ² 5-fluorouracil at a dose of/24 hours, in which cisplatin is omitted from the dosing regimen after six doses; and is

(b) The second dosing regimen comprises one or more of the following for a 21 day dosing cycle: a dose of about 600mg of tirayleigh immuzumab on day 1 of each dosing cycle and a dose of about 1200mg of atelizumab on day 1 of each dosing cycle.

335. The method of any one of claims 321-334, wherein the treatment results in an ORR of at least about 14% in the population of subjects.

336. The method of any one of claims 47-335, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

an HVR-H2 sequence comprising the amino acid sequence of KTYYRRFKWYSDYYAVSVKG (SEQ ID NO: 2);

an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

337. The method of claim 336, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region Framework Regions (FRs):

FR-L1 comprising the amino acid sequence of DIVMTQSPLDSLAVSLAVSLERRATINC (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 GVPDRFGSGSGTDFTTISSLQAEDVYYC (SEQ ID NO: 9); and

FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

338. The method of claim 336, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs:

FR-H1 comprising X ₁ Amino acid sequence of VQLQQSGPGLVKPQTLSLTCASGDSVS (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, wherein X ₁ Is E.

340. The method of claim 338, wherein X ₁ Is Q.

341. The method of any one of claims 336-340, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:17 or 18 having at least 95% sequence identity;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:19 having at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain as in (a) and a VL domain as in (b).

342. The method of any one of claims 336-341, wherein the anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO:17 or 18; and

(b) A VL domain comprising SEQ ID NO: 19.

343. The method of any one of claims 336-339, 341, and 342, wherein the anti-TIGIT antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 17; and

(b) A VL domain comprising SEQ ID NO: 19.

344. The method of any one of claims 336-339 and 341-343, wherein the anti-TIGIT antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 33; and

(b) A light chain comprising SEQ ID NO: 34.

345. The method of any one of claims 336-344, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

346. The method of any one of claims 336-345, wherein the anti-TIGIT antagonist antibody is a human antibody.

347. The method of any one of claims 336-346, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

348. The method of any one of claims 336-347, wherein the anti-TIGIT antagonist antibody has intact Fc-mediated effector function.

349. The method of any one of claims 336-339 and 341-348, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan.

350. The method of any one of claims 336-346, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of Fab, fab '-SH, fv, single chain variable fragment (scFv), and (Fab') ₂ Antibody fragments that bind to TIGIT of the group consisting of fragments.

351. The method of any one of claims 336-349, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

352. The method of claim 351, wherein the IgG class antibody is an IgG1 subclass antibody.

353. The method of any one of claims 336-352, 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.

354. The method of claim 353, 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.

356. The method of claim 355, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1.

357. The method of any one of claims 354 to 356, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

358. The method of claim 357, wherein the anti-PD-L1 antagonist antibody is atelizumab, MDX-1105, dewalimumab, avizumab, SHR-1316, CS1001, engolizumab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-a167, APL-502, chihlizumab, lodalizumab, FAZ053, TG-1501, BGB-a333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, or HS-636.

359. The method of claim 358, wherein the anti-PD-L1 antagonist antibody is atelizumab.

360. The method of claim 357, wherein the anti-PD-L1 antagonist antibody comprises the following HVRs:

an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20);

an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21);

an HVR-H3 sequence comprising the amino acid sequence of RHWPGFDY (SEQ ID NO: 22);

an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23);

An HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and

HVR-L3 sequence comprising the amino acid sequence of QQYLLYHPAT (SEQ ID NO: 25).

361. The method of claim 360, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain Variable (VH) domain comprising a VH sequence identical to SEQ ID NO:26 has at least 95% sequence identity to the amino acid sequence of seq id no;

(b) A light chain Variable (VL) domain comprising a sequence identical to SEQ ID NO:27 has at least 95% sequence identity to the amino acid sequence of seq id no; or

(c) A VH domain as in (a) and a VL domain as in (b).

362. The method of claim 361, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A VH domain comprising SEQ ID NO: 26; and

(b) A VL domain comprising SEQ ID NO: 27.

363. The method of claim 362, wherein the anti-PD-L1 antagonist antibody comprises:

(a) A heavy chain comprising SEQ ID NO: 28; and

(b) A light chain comprising SEQ ID NO: 29.

364. The method of any one of claims 360-363, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

365. The method of any one of claims 360-364, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

366. The method of claim 364 or 365, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

367. The method of any one of claims 360-365, wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds PD-L1 selected from the group consisting of: fab, fab '-SH, fv, scFv and (Fab') ₂ And (3) fragment.

368. The method of any one of claims 360-366, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

369. The method of claim 368, wherein the IgG class antibody is an IgG1 subclass antibody.

370. The method of claim 353, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

371. The method of claim 370, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.

372. The method of claim 371, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1, PD-L2, or both PD-L1 and PD-L2.

373. The method of any one of claims 370-372, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

374. The method of claim 373, wherein the anti-PD-1 antagonist antibody is nivolumab, palbociclizumab, MEDI-0680, sibatuzumab, cimeprimab, BGB-108, palonolizumab, carpriclizumab, sillimumab, tirizumab, terilizumab, dolastalizumab, refelimab, saralalizumab, deaprizumab, CS1003, HLX10, SCT-I10A, serpalizumab, batilizumab, geminlizumab, BI 754091, cetirizumab, YBL-006, BAT1306, HX008, brilizumab, AMG 404, CX-188, JTX-4014, 609A, sym021, LZM009, F, SG001, AM0001, ENUM 244C8, ENUM 1110D 4, STI-103, or hAb21.

375. The method of any one of claims 370-372, wherein the PD-1 binding antagonist is an Fc fusion protein.

376. The method of claim 375, wherein the Fc fusion protein is AMP-224.

377. The method of any one of claims 77-101, 103-116, 119-122, and 247-249, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of between about 500mg to about 700mg every three weeks.

378. The method of any one of claims 57, 59, 60, 62-64, 101, 123-151, 160, 161, 224, 225, 247-255, 272-289, 298-305, 320-332, and 377, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a dose of about 600mg every three weeks.

379. The method of any one of claims 77, 78, 82, and 83, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of about 700mg to about 1000mg every four weeks.

380. The method of any one of claims 47, 56, 64, 258, and 379, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a dose of about 840mg every four weeks.

381. The method of any one of claims 77, 78, 82, 83 and 256, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects at a dose of about 300mg to about 600mg biweekly.

382. The method of any one of claims 48, 190-213, 215-221, 256, and 381, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a dose of about 420mg every two weeks.

383. The method of any one of claims 47-382, wherein the dose of the anti-TIGIT antagonist antibody is a fixed dose.

384. The method of any one of claims 77-100, 103-116, 119-122, and 243-245, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of between about 900mg to about 1500mg every three weeks.

385. The method of any one of claims 59, 60, 62-64, 123-151, 160, 161, 224, 225, 247-258, 272-289, 298-305, 320-332, and 384, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a dose of about 1200mg every three weeks.

386. The method of any one of claims 77, 78, 82, and 83, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of about 1400 to 2000mg every four weeks.

387. The method of any one of claims 47, 56, 64, 259, and 386, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a dose of about 1680mg every four weeks.

388. The method of claims 77, 78, 82, 83, and 257, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects at a dose of between about 600mg to about 1200mg every two weeks.

389. The method of any one of claims 48, 190-213, 215-221, 257, and 388, wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 840mg every two weeks.

390. The method of any one of claims 47-389, wherein the dose of the PD-1 axis binding antagonist is a fixed dose.

391. The method of claim 58, wherein the method comprises administering to the subject palbociclumab at a fixed dose of about 400mg every six weeks.

392. The method of any one of claims 51, 57, 59, 60, 62, 77, 78, 82, 83, 103, and 161, wherein each of said one or more dosing cycles is 21 days in length.

393. The method of any one of claims 47, 56, 64, 77, 184-189, and 253-259, wherein each of the one or more dosing cycles is 28 days in length.

394. The method of any one of claims 47-393, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects on about day 1 of each dosing cycle of the one or more dosing cycles.

395. The method of any one of claims 47-394, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects on about day 1 of each dosing cycle of the one or more dosing cycles.

396. The method of claim 256, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject on about day 15 of each of the one or more dosing cycles.

397. The method of claim 257, 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.

398. The method of any one of claims 47-397, wherein the method comprises 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, wherein the method comprises a first observation period after administering the PD-1 axis binding antagonist.

400. The method of claim 399, wherein the length of said first observation period is between about 30 minutes to about 60 minutes.

401. The method of claim 399 or 400, wherein the method comprises a second observation period following administration of the anti-TIGIT antagonist antibody.

402. The method of claim 401, wherein the length of said second observation period is between about 30 minutes and about 60 minutes.

403. The method of any one of claims 47-397, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects concurrently with the administration of the anti-TIGIT antagonist antibody.

404. The method of any one of claims 47-403, wherein the method comprises intravenously administering the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist to the subject or population of subjects.

405. The method of claim 404, wherein the method comprises administering the PD-1 axis binding antagonist to the subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

406. The method of claim 404 or 405, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject or population of subjects by intravenous infusion over 30 ± 10 minutes and/or over 60 ± 10 minutes.

407. The method of any one of claims 47-103 and 105-406, wherein the PD-L1 expression level of a tumor sample obtained from the subject or subjects has been determined.

408. The method of claim 407, wherein the tumor sample obtained from the subject or subjects has been determined to have a detectable PD-L1 expression level.

409. The method of claim 408, wherein the detectable PD-L1 expression level is a detectable protein expression level of PD-L1.

410. The method of claim 409, wherein the detectable protein expression level of PD-L1 has been determined by an Immunohistochemistry (IHC) assay comprising staining with an anti-PD-L1 antibody suitable for staining.

411. The method of claim 410, wherein the anti-PD-L1 antibody suitable for staining is the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8.

412. The method of claim 410 or 411, wherein the detectable protein expression level of PD-L1 is determined using a Ventana SP263 IHC assay, pharmDx 22C3 IHC assay, ventana SP142 IHC assay, or pharmDx 28-8 IHC assay.

413. The method of any one of claims 47-102, 159, 181-223, and 245-335, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP 263.

414. The method of any one of claims 47-189, 222-269 and 296-335, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with the anti-PD-L1 antibody SP 142.

415. The method of any one of claims 47-189 and 222-335, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody 22C 3.

416. The method of any one of claims 47-103 and 105-335, wherein a detectable level of protein expression of PD-L1 has been determined by an IHC assay comprising staining with anti-PD-L1 antibody 28-8.

417. The method of claim 413, wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% tumor-associated immune cells (TICs) in the tumor sample.

418. The method of claim 413, wherein the detectable protein expression level of PD-L1 is greater than or equal to 5% and less than 20% TIC in the tumor sample.

419. The method of claim 413, wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% TIC in the tumor sample.

420. The method of claim 413, wherein the detectable protein expression level of PD-L1 is greater than or equal to 20% TIC in the tumor sample.

421. The method of claim 413, wherein the detectable protein expression level of PD-L1 is greater than or equal to 10% and less than 50% TIC in the tumor sample.

422. The method of claim 413, wherein the detectable protein expression level of PD-L1 is greater than or equal to 50% TIC in the tumor sample.

423. 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% PD-L1 positive tumor cell fraction.

424. The method of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is a fraction of PD-L1-positive tumor cells greater than or equal to 30%.

425. The method of any one of claims 413, 415, and 416, wherein the detectable protein expression level of PD-L1 is such that the fraction of PD-L1-positive tumor cells in the tumor sample is greater than or equal to 1% and less than 50%.

426. 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 50% PD-L1 positive tumor cell fraction.

427. The method of claim 414, wherein the PD-L1 positive tumor cell fraction is a proportion of a tumor area occupied by PD-L1-expressing tumor infiltrating Immune Cells (ICs).

428. The method of claim 414, wherein the proportion of tumor area occupied by PD-L1-expressing tumor-infiltrating IC is greater than or equal to 1%.

429. The method of claim 414, wherein the proportion of tumor area occupied by PD-L1-expressing tumor-infiltrating IC is greater than or equal to 5%.

430. The method of claim 415, wherein the detectable protein expression level of PD-L1 is a Composite Positive Score (CPS) of greater than or equal to 1.

431. The method of claim 415, wherein the detectable protein expression level of PD-L1 is CPS greater than or equal to 10.

432. The method of claim 415, wherein the detectable protein expression level of PD-L1 is CPS greater than or equal to 20.

433. The method of any one of claims 427-429, wherein the IHC assay is a Ventana SP142 IHC assay.

434. The method of claim 408, wherein the detectable PD-L1 expression level is a detectable nucleic acid expression level of PD-L1.

435. The method of claim 434, wherein the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, massARRAY technique, ISH, or a combination thereof.

436. The method of any one of claims 47-335, wherein the treatment results in an increase in Overall Survival (OS) of the subject as compared to a reference OS time and/or an increase in progression-free survival (PFS) of the subject as compared to a reference PFS time.

437. The method of claim 436, wherein:

(a) The reference OS time is the median OS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist; and/or

(b) The reference PFS time is the median PFS time for a population of subjects that have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody or treatment comprising an anti-TIGIT antagonist antibody without a PD-1 axis binding antagonist.

438. The method of any one of claims 49, 141, and 190, 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.

439. The method of claim 438 wherein the platinum chemotherapeutic agent is carboplatin or cisplatin.

440. The method of claims 66, 89, 116, 145, 212, and 439, wherein the carboplatin is administered at a dose sufficient to achieve AUC =5mg/ml/min or AUC =6 mg/ml/min.

441. The method of claims 66, 116, 145, 147, 149, 151, 278 and 326 wherein said cisplatin is at about 75mg/m ² Or 80mg/m ² The dosage of (a).

442. The method of any one of claims 438-441, wherein the one or more non-platinum chemotherapeutic agents is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

443. The method of claim 59 or 442, wherein said antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

444. According to the claimsThe method of any one of claims 66, 116, 145, and 443, wherein the pemetrexed is at about 500mg/m ² The dosage of (a).

445. The method of any one of claims 60, 61, 145, 316 or 443, wherein the gemcitabine is at about 1000mg/m ² Or about 1250mg/m ² The dosage of (a).

446. The method of claim 59 or 443, wherein the antimetabolite is capecitabine.

447. The method of claim 443 or 446, wherein the capecitabine is at about 1250mg/m ² The dosage of (a).

448. The method of any one of claims 193, 202, 203, and 442-447, wherein the taxane is paclitaxel or nab-paclitaxel.

449. The method of any one of claims 66, 145, and 448, wherein the paclitaxel is at about 175mg/m ² Or about 200mg/m ² Is administered.

450. The method of any one of claims 60, 61, 212, 316, and 448, wherein the nab-paclitaxel is at about 100mg/m ² Is administered.

451. The method of any one of claims 77, 78, 82, 83, 192, 193, and 442-450, wherein said topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331.

452. A method according to any one of claims 66, 89 and 451 wherein the etoposide is at about 100mg/m ² Is administered.

453. The method of any one of claims 438 to 452, wherein the one or more chemotherapeutic agents are each administered once a week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.

454. The method of any one of claims 438-453, wherein the one or more chemotherapeutic agents are administered on day 1 of one or more dosing cycles.

455. The method of any one of claims 443 to 454, wherein the gemcitabine is administered three times every four weeks.

456. 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.

457. The method of any one of claims 443 to 456, wherein the capecitabine is administered daily for two weeks.

458. 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 448-458, wherein the nab-paclitaxel is administered three times every four weeks.

460. The method of any one of claims 448 to 459, wherein the nab-paclitaxel is administered on days 1, 8, and 15 of one or more dosing cycles.

461. The method of any one of claims 451 to 460 wherein the etoposide is administered every three weeks on days 1 to 3.

462. The method of any one of claims 451 to 461, wherein the etoposide is administered on days 1 to 3 of one or more dosing cycles.

463. The method of any one of claims 438 to 462, wherein the one or more chemotherapeutic agents is administered prior to the PD-1 axis binding antagonist and/or the anti-TIGIT antagonist antibody.

464. The method of any one of claims 438-463, wherein the one or more chemotherapeutic agents are administered after the PD-1 axis binding antagonist and/or the anti-TIGIT antagonist antibody.

465. The method of any one of claims 438 to 464, wherein the one or more chemotherapeutic agents are administered intravenously or orally.

466. The method of any one of claims 62, 248 and 249, wherein the VEGF antagonist is administered at a dose of about 5mg/kg to about 25mg/kg every three weeks.

467. The method of claim 250 or 466, wherein the VEGF antagonist is administered at a dose of about 10mg/kg to about 20mg/kg every three weeks.

468. The method of claim 467, wherein the VEGF antagonist is administered at a dose of about 15mg/kg every three weeks.

469. The method of any one of claims 62, 248-250, 253-255, and 466-468, wherein the VEGF antagonist is an anti-VEGF antibody.

470. The method of claim 469 wherein said anti-VEGF antibody is bevacizumab.

471. The method of any one of claims 62, 248-250, and 253-255, wherein the anti-TIGIT antagonist antibody is tirayleigh itumumab, the PD-1 axis binding antagonist is atezumab, and the VEGF antagonist is bevacizumab.

472. The method of any one of claims 62, 248-250, 253-255, and 466-471, wherein the method comprises administering the VEGF antagonist to the subject on day 1 of one or more dosing cycles.

473. The method of any one of claims 253-255, wherein the method comprises administering the VEGF antagonist to the subject on day 15 of one or more dosing cycles.

474. The method of any one of claims 62, 248-250, 253-255, and 466-471, wherein the VEGF antagonist is administered intravenously.

475. The method of claim 474, wherein said VEGF antagonist is administered to the subject by intravenous infusion over 90 ± 15 minutes.

476. The method of any one of claims 62, 248-250, 253-255, and 466-475, wherein the method comprises administering the PD-1 axis binding antagonist to the subject prior to the VEGF antagonist, and the VEGF antagonist precedes the anti-TIGIT antagonist antibody.

477. The method of claim 476, 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.

478. The method of claim 477, wherein 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.

479. The method of any one of claims 102, 117, 118, 152, 153, 177, 184, 214, 226, 267, 290, 291, 306, 307, 311, 333, and 334, wherein before administration, ibritumomab tiuxetan and altlizumab are combined in an IV infusion bag.

480. A method according to one of claims 47-479, wherein the subject is human.

481. A kit comprising a PD-1 axis binding antagonist and/or an anti-TIGIT antagonist antibody for treating a subject having cancer according to the method of any one of claims 47-160, 162-224, and 226-480.

482. 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 claims 47-160, 162-224, and 226-480.

483. The kit of claim 482, wherein the kit further comprises an anti-TIGIT antagonist antibody.

484. The kit of any one of claims 481-483, wherein the anti-TIGIT antagonist antibody is teneuiuzumab.

485. The kit of any one of claims 481 to 484, wherein the PD-1 axis binding antagonist is atelizumab.

486. 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 47-160, 162-224, and 226-480.

487. The kit of claim 486, wherein the kit further comprises a PD-1 axis binding antagonist.

488. The kit of claim 486 or 487, wherein the PD-1 axis binding antagonist is atelizumab.

489. The kit of any one of claims 486-488, wherein the anti-TIGIT antagonist antibody is ibritumomab tiuxetan.

490. The kit of any one of claims 486-489, wherein the kit further comprises one or more chemotherapeutic agents.

491. The kit 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.

492. The kit of claim 491 wherein the one or more platinum chemotherapeutic agents is carboplatin or cisplatin.

493. The kit of claim 491 or 492, wherein the one or more non-platinum chemotherapeutic agents is an antimetabolite, a taxane, or a topoisomerase II inhibitor.

494. The kit of claim 493, wherein the antimetabolite is pemetrexed, gemcitabine, capecitabine, or 5-fluorouracil.

495. The kit of claim 493 or 494, wherein the taxane is paclitaxel or nab-paclitaxel.

496. The kit of any one of claims 493 to 495, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunomycin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331.

497. The kit of claims 481-496, wherein said kit further comprises a VEGF antagonist.

498. A kit according to claim 497, wherein said VEGF antagonist is an anti-VEGF antibody.

499. The kit of claim 498, wherein the anti-VEGF antibody is bevacizumab.

500. 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 carried out according to any one of claims 47-160, 162-224, and 226-480.

501. Use of an anti-TIGIT antagonist antibody for the manufacture of a medicament for treating a subject or population of subjects having cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is a method according to any one of claims 47-160, 162-224, and 226-480.

502. The use of claim 501, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in separate formulations.

503. The use of claim 501, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are provided in a single formulation.

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